Received any biological and/or targeted therapy (including but not limited to vaccines, antibodies, tyrosine kinase inhibitors) or hormonal therapy for management and/or treatment of epithelial ovarian or peritoneal primary cancer
Immunotherapy or therapy with monoclonal antibodies or small tyrosine kinase inhibitors within the past 4 weeks prior to treatment with the trial drug
Patients who have received >= 7 days of prior ibrutinib or any prior treatment with another Bruton tyrosine kinase (BTK) inhibitor are not eligible
The addition of cytotoxic agents for “cytoreduction” with the exception of tyrosine kinase inhibitors (such as imatinib), cytokine therapy, hydroxyurea, low dose cytarabine, chlorambucil, or Rituxan will not be allowed within three weeks of the initiation of conditioning
ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C): Patient will not be enrolled if they received prior chemotherapy within 2 weeks before enrollment with the following exceptions: to reduce the circulating lymphoblast count or palliation (i.e., steroids or hydroxyurea) or for ALL maintenance (mercaptopurine, methotrexate, vincristine, thioguanine, and/or tyrosine kinase inhibitors)
ELIGIBILITY CRITERIA - PHASE II (ARM D): Patient will not be enrolled if they received prior chemotherapy within 2 weeks before enrollment with the following exceptions: to reduce the circulating lymphoblast count or palliation (i.e., steroids or hydroxyurea), for ALL maintenance (mercaptopurine, methotrexate, vincristine, thioguanine, and/or tyrosine kinase inhibitors)
Received prior tyrosine kinase inhibitor therapy or palliative radiation within 7 days of first dose of study treatment.
Renal cell patients must have had at least one prior VEGF tyrosine kinase inhibitor (TKI)
Prior treatment with a Bruton's tyrosine kinase inhibitor (eg, ibrutinib).
For Phase 2 - Prior exposure to a receptor tyrosine kinase or mammalian target of Rapamycin inhibitor
Must have received at least one course of therapy with a VEGFR-targeting tyrosine kinase inhibitor (eg, sorafenib, sunitinib, axitinib, pazopanib or tivozanib) and progressed within 6 months of planned first dose of study treatment
Untreated disease EXCEPT for corticosteroids, hydroxyurea, leukapheresis, and/or tyrosine kinase inhibitors for up to 2 weeks prior to initiation of study therapy
Eligible participants must have received at least one line of prior therapy; note: patients will be eligible for participation despite prior treatment with known RET tyrosine kinase inhibitors (TKIs) (e.g. vandetanib, sorafenib, XL-184)
Prior EGFR tyrosine kinase inhibitor therapy (including gefitinib, erlotinib, or any experimental EGFR tyrosine kinase inhibitor [TKI] agent)
Resistance or intolerance to prior kinase inhibitor therapy (e.g., lenvatinib, sorafenib). A patient who is considered inappropriate for, or who has refused, kinase inhibitor therapy may be enrolled with approval of the Medical Monitor.
Participants who have had oral targeted therapy or oral tyrosine kinase inhibitors (TKIs) within 5 half-lives prior to entering the study
Allowable prior therapies:\r\n* Subjects must have had clinical or radiographic progression on imatinib; those who were taken off of imatinib for intolerance must have progressed on at least one other tyrosine kinase inhibitor (TKI)\r\n* Subjects must have received >= 1 prior systemic therapy (including imatinib); a maximum of 4 prior therapies for metastatic disease are allowed
Treatment with chemotherapy (not including tyrosine kinase inhibitors) or radiotherapy within 4 weeks (6 weeks from nitrosoureas or mitomycin C), or treatment with monoclonal antibody therapy within 4 weeks prior to start of study treatment\r\n* Note: no minimum washout period is required for tyrosine kinase inhibitor therapy (eg, imatinib or sunitinib)
Participants who have received prior oral tyrosine kinase inhibitors (TKIs) will be allowed on study if at least 5 half-lives have elapsed since the date of their last dose of TKI
If using hydroxyurea, tyrosine kinase inhibitors (TKIs)/src inhibitors (including fms related tyrosine kinase 3 [FLT-3] inhibitors), other non-cytotoxics, or leukapheresis for blast count control, the patient must be off these therapies for >= 24 hours (hrs) before starting sertraline
Previous therapy with Bruton's tyrosine kinase (BTK) inhibition
Previous anti-cancer and investigational agents within 2 weeks before first dose of INC280; if previous treatment is a small molecule tyrosine kinase inhibitor (TKI), last dose must be at least 7 days before first dose of INC280; a shorter washout period may be allowed after discussion with the principal investigator
Molecular targeted agents including monoclonal antibodies and tyrosine kinase inhibitors: at least two weeks since last therapy
Patients who have received prior therapy targeting EGFR with small molecule tyrosine kinase inhibitors or monoclonal antibodies are NOT eligible
Treated with at least one line of chemotherapy in the palliative setting or with neoadjuvant or adjuvant chemotherapy within the prior six months; the allowable window between treatments is 21 days for chemotherapy or a tyrosine kinase inhibitor (TKI) or 5 half-lives for a TKI (whichever is shorter), 21 days and progression by CT for immunotherapy, 21 days for RT, 21 days for surgery, or 28 days for an investigational agent
Prior therapy with EGFR tyrosine kinase inhibitor (TKI) therapy
Subjects with Ph+ disease are eligible if they are intolerant to tyrosine kinase inhibitor (TKI) therapy, or if they have relapsed/refractory disease despite treatment with at least 2 different TKIs
Chemo-, or immunotherapy or therapy with monoclonal antibodies or small tyrosine kinase inhibitors within the past 2 weeks prior to treatment with the trial drug
May have received prior hormonal therapy in the context of definitive treatment of a primary tumor\r\n* Patients may have had one prior systemic non-chemotherapeutic treatment (i.e. immunotherapy, receptor tyrosine kinase inhibitor, antiangiogenic agent, differentiating agent) for recurrent or metastatic disease
Any line of prior treatment for patients under 65 years (y), over 65y must have at least one prior line of tyrosine kinase inhibitor (TKI) treatment (excluding anaplastic patients).
The addition of cytotoxic agents for “cytoreduction” with the exception of tyrosine kinase inhibitors (such as imatinib), cytokine therapy, hydroxyurea, low dose cytarabine, chlorambucil, or Rituxan will not be allowed within three weeks of the initiation of conditioning
Patients with activating EGFR mutation or ALK rearrangement which is expected to be responsive to available tyrosine kinase inhibitor therapy, must have been previously treated with an applicable tyrosine kinase inhibitor
For participants in the dose-finding phase, a minimum washout period of at least 5 half-lives between the last dose of tyrosine kinase inhibitors (TKI) therapy and the first dose of study treatment is required; for patients on crizotinib, a 7 day washout is sufficient; a shorter washout period may be considered in the event of disease flare, after discussion with the sponsor; no washout is required if the most recent anti-neoplastic therapy is alectinib
Concurrent use of other tyrosine kinase inhibitors
Chemotherapy, tyrosine kinase inhibitor, or radiation therapy within 4 weeks
Prior to initiating chemotherapy in this study, twenty-one or more days must have elapsed since the patient's last radiation or chemotherapy administration (Hydrea, Gleevec and other tyrosine kinase inhibitors [TKI] as well as intrathecal therapy are accepted exceptions).
Receipt of the tyrosine kinase inhibitor sunitinib within 90 days before the first dose of study therapy
Chemotherapy administration in the 14 days preceding enrollment with the exception of hydroxyurea, which can be continued until through cycle 2; a washout period for oral tyrosine kinase inhibitors (e.g. Jakafi, etc) is not required, although tyrosine kinase inhibitors therapy must be discontinued prior to enrollment
Known severe allergic or other prohibitive reactions to other tyrosine kinase inhibitors (TKI)
Receipt of the last dose of chemotherapy or tyrosine kinase inhibitors should be at least 3 weeks prior to durvalumab and tremelimumab dosing; monoclonal antibodies such as bevacizumab, ziv-aflibercept, ramucirumab, cetuximab, and panitumumab should be at least 6 weeks prior to durvalumab and tremelimumab therapy
Patients must be receiving treatment or planning to start treatment with a tyrosine kinase inhibitor targeting the activated gene
Previous chemotherapy except for antiangiogenic agent or tyrosine kinase inhibitor (TKI) will be allowed as long as it is more than 5 years
Prior therapy with any HER2 directed tyrosine kinase inhibitor (TKI) (e.g., lapatinib, afatinib, dacominib, neratinib, capecitabine) or anti-EGFR antibody therapy (e.g., cetuximab)
Chemotherapy, hormonal therapy, radiotherapy (except for brain and extremities), immunotherapy or therapy with monoclonal antibodies or small tyrosine kinase inhibitors within the past 4 weeks prior to treatment with the trial drug
Has received prior therapy with an EGFR tyrosine kinase inhibitor (such as erlotinib, gefitinib, afatinib, rociletinib, or AZD9291) for NSCLC
The patient has received chemotherapy, surgery, radiotherapy (for therapeutic purposes), tyrosine kinase inhibitor (TKI) (e.g. erlotinib, gefitinib), investigational drugs, chronic use of systemic corticosteroids or statin therapy within 2 weeks prior to leukapheresis.
Patients must have discontinued systemic antineoplastic therapy (including systemic corticosteroids and excluding tyrosine kinase inhibitors for CML) at least four (4) weeks prior to enrollment.
Patients receiving cytotoxic therapy, radiation therapy, immunotherapy or non-topical steroids for HM within four (4) weeks of enrollment, excluding tyrosine kinase inhibitors in patients with CML.
CLL who are beyond first remission and who have failed combination chemoimmunotherapy with regimens containing a purine analogue and anti-CD20 antibody, or who have failed tyrosine kinase or phosphatidylinositol 3 (PI3) kinase inhibitors, or who were not eligible for or declined such therapy; patients with fludarabine refractory disease are eligible
Patients must demonstrate progressive disease at the time of treatment\r\n*Note: patients who have received tyrosine kinase inhibitors (e.g. vemurafenib) may be treated if they present with stable disease at the time of treatment
Treatment with crizotinib within 7 days prior to enrollment; for all other ALK tyrosine-kinase inhibitors (TKIs), the washout period should be >= 5 half-lives prior to enrollment
Phase 1: Subjects must have previously received and progressed on or after treatment with an EGFR tyrosine kinase inhibitor (TKI). Additional lines of systemic therapy including investigational agents for locally advanced or metastatic NSCLC are allowed.
Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of trametinib and during the study; patients previously treated with v-raf murine sarcoma (RAF) and/or mitogen-activated protein kinase (MEK) inhibitors are excluded from the study; multikinase antiangiogenic tyrosine kinase inhibitors such as regorafenib, sorafenib, sunitinib, etc. whose primary mechanism of action is not RAF inhibition, are allowed; if there are any questions, please contact study's principal investigator
Chemotherapy, immunotherapy, biologically targeted therapy, other investigational agent, or radiation therapy within 3 weeks of initiation of enzalutamide therapy; for patients with objectively progressive disease on a Bruton tyrosine kinase (BTK)-targeting agent whom in the opinion of the investigator would not tolerate a 21 day washout period, a > 5 half-lives washout period will be allowed
Prior chemotherapy/radiotherapy/investigational therapy within 2 weeks before the start of study drugs with the following exceptions: \r\n* To reduce the circulating lymphoblast count or palliation: steroids, hydroxyurea; no washout necessary for these agents \r\n* For ALL maintenance/CML treatment: mercaptopurine, methotrexate, vincristine, single-agent, single-dose of cytarabine and/or tyrosine kinase inhibitors; these agents should be discontinued at least 48 hours prior to start of study drugs; (Note: the interval of time from last dose of any approved tyrosine kinase inhibitor [TKI] to start of protocol treatment is 48 hours regardless of the indication for treatment with the TKI)
Prior treatment with VEGFR tyrosine kinase inhibitors
Previous therapy with T-DM1 or any HER2 tyrosine kinase inhibitor (TKI) including neratinib for any malignancy.
Prior treatment with any VEGFR tyrosine kinase inhibitor
Prior use of MEK162 or concurrent use of other approved anticancer or investigational agents is not allowed; patients treated with prior EGFR tyrosine kinase inhibitor (TKI) therapy (including erlotinib) are allowed to enroll
Prior bevacizumab or tyrosine-kinase inhibitor
Have not received a tyrosine kinase inhibitor (TKI) with activity against the specific documented EGFR exon 20 insertion.
Treatment with chemotherapy or targeted therapy (e.g. tyrosine kinase inhibitor) =< 28 days prior to registration
Patient with known hypersensitivity to receptor tyrosine kinase inhibitors or any of the components of poziotinib tablets or T-DM1 IV solution.
Ongoing or previous treatment with anti-FGFR directed therapies (e.g. receptor tyrosine kinase inhibitors including rogaratinib or FGFRspecific antibodies) or with taxanes or vinflunine
Received any kinase inhibitors within 2 weeks prior to study treatment.
Prior treatment with phosphatidylinositol 3-kinase (PI3K) delta inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, janus kinase inhibitor (JAK) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, or spleen tyrosine kinase (Syk) inhibitors
Patients receiving systemic chemotherapy (includes tyrosine kinase inhibitors)
Patients who have received therapy with an oral tyrosine kinase inhibitor (eg, erlotinib) within 14 days prior to entry into the protocol.
Prior treatment with a tyrosine kinase c-kit inhibitor
Previous treatment with any Tyrosine Kinase Inhibitor
Patient previously treated by tyrosine kinase inhibitors except imatinib in case of inclusion criteria 2
Patient has received any chemotherapy, surgery, radiotherapy (for therapeutic purposes), tyrosine kinase inhibitors, investigational drugs, chronic use of systemic corticosteroids or statin therapy within 2 weeks prior to the leukapheresis
Patients who have had immunotherapy or tyrosine kinase inhibitor (TKI) therapy within two weeks prior to entering the study
Prior systemic anti-cancer treatment (e.g. chemotherapy, tyrosine kinase inhibitors, immunotherapy, or investigational agents)(except for hydroxyurea and/or leukapheresis)
Patients at least 3 weeks from last cytotoxic chemotherapy. Patients may continue tyrosine kinase inhibitors or other targeted therapies until at least two weeks prior to administration of lymphodepleting chemotherapy.
Group 1 - patients must have pathologically documented, definitively diagnosed locally advanced or metastatic NSCLC with a RET rearrangement that was previously treated with a tyrosine kinase inhibitor (TKI) that inhibits RET, such as cabozantinib, vandetanib, ponatinib, sorafenib and alectinib.
Phase 2 Only: Prior progression while receiving approved or investigational tyrosine kinase inhibitors targeting TRK, including entrectinib, crizotinib and lestaurtanib. Patients who received a TRK inhibitor for less than 28 days of treatment and discontinued because of intolerance remain eligible.
Patients enrolled to the prior treatment arm of the expansion cohort must have been exposed to a tyrosine kinase inhibitor (TKI) for metastatic disease; exposure to TKI as part of (neo)adjuvant treatment that completed within 1 year of study qualifies as prior exposure as well
Patients who have received prior treatment with tyrosine kinase inhibitors (e.g. erlotinib), or anti-EGFR agents (e.g. cetuximab, panitumumab)
Patients who have received hydroxyurea alone or have previously received “non-cytotoxic” therapies for myelodysplastic syndromes (MDS) or myeloproliferative neoplasms (MPN) (e.g., thalidomide or lenalidomide, 5-azacytidine or decitabine, histone deacetylase inhibitors, low-dose Cytoxan, tyrosine kinase or dual tyrosine kinase [TK]/SRC inhibitors) will be allowed
Prior exposure to a Bruton agammaglobulinemia tyrosine-protein kinase (BTK) inhibitor
Prior therapy with a tyrosine kinase inhibitors (TKI) other than nilotinib is allowable, however, nilotinib must be the current therapy; all patients must be under the care of a Moffitt Cancer Center physician, and enrollment is expected to be complete within six months
Patients must not have received any prior systemic anticancer therapy for advanced or metastatic disease including chemotherapy or EGFR tyrosine kinase inhibitor therapy (including gefitinib, erlotinib, afatinib, or any experimental EGFR tyrosine kinase inhibitors [TKI] agents); prior chemotherapy for non-metastatic disease (i.e. adjuvant therapy or concurrent chemo-radiotherapy) is allowed as long as > 12 months has passed since completion of therapy; adjuvant EGFR-directed therapy is not allowed; local therapy (i.e. palliative radiotherapy) is allowed as long as a period of 7 days has passed since the last dose was received and the patient has recovered from any associated toxicity at the time of registration
Received previous therapy with capecitabine, neratinib, lapatinib, or any other HER2 directed tyrosine kinase inhibitor.
Progressive disease with radiographic evidence of disease progression per investigator assessment during therapy with an EGFR tyrosine kinase inhibitor in the metastatic setting; patients may continue EGFR inhibitor therapy throughout the screening period until the day prior to nab-paclitaxel treatment initiation
Prior exposure to EGFR tyrosine kinase inhibitors
Part 1: Progression of disease following up to three lines of prior therapy, including at least one approved VEGF receptor tyrosine kinase inhibitor for RCC. Adjuvant therapy is permitted as one line of prior therapy.
Tyrosine kinase inhibitors and hydroxyurea must be stopped > 72 hours prior to CTL019 infusion
Prior treatment with any VEGFR tyrosine kinase inhibitor
Treatment with kinase inhibitors </= 2 weeks before study treatment
Prior systemic regimens must include previously approved therapies, including a platinum-containing chemotherapy regimen; a tyrosine kinase inhibitor for tumors with driver mutations; and checkpoint inhibitors where approved.
Prior treatment with lenvatinib or any tyrosine kinase inhibitor (TKI) - (except for combination therapy of radiation and reduced dose of TKI given for the purpose of radiosensitization).
Previous treatment with another Bruton's Tyrosine Kinase (BTK) -inhibitor.
No Bruton’s tyrosine kinase inhibitor at any point prior to enrollment
Prior exposure to a Bruton's tyrosine kinase (BTK) inhibitor
Prior tyrosine kinase inhibitor therapy or palliative radiation within 7 days of first dose of study medication
Patients must be willing to be off EGFR-tyrosine-kinase inhibitor (TKI) therapy for a minimum of one week; (in expansion cohort A patients on erlotinib do not have to discontinue treatment)
The addition of cytotoxic agents for “cytoreduction” with the exception of tyrosine kinase inhibitors (such as imatinib mesylate), cytokine therapy, hydroxyurea, low dose cytarabine, chlorambucil, or Rituxan will not be allowed within three weeks of the initiation of conditioning
Arm B only: ibrutinib or other Bruton's tyrosine kinase (BTK) inhibitor;
Patients who have previously received ibrutinib or another inhibitor of Bruton's tyrosine kinase (BTK)
Patients at least 3 weeks from last cytotoxic chemotherapy; patients may continue tyrosine kinase inhibitors and/or lenalidomide until the day of study consent
Prior therapy with ibrutinib or other kinase inhibitors that target Bruton’s tyrosine kinase (BTK); patients who previously received therapy with the phosphoinositide-3 kinase (PI3K) delta inhibitor idelalisib (Zydelig) are allowed to be enrolled
Chemotherapy, radiotherapy or immunotherapy must have stopped more than 14 days prior to receiving study drug; however, small field palliative radiotherapy, tyrosine-kinase inhibitor (TKI) therapies, and hormonal therapies are allowed
Newly diagnosed previously untreated ALL or lymphoblastic lymphoma; allow urgent administration of cytarabine/hydroxyurea (hydrea)/all-trans retinoic acid (atra) prior to starting treatment on protocol; allow previous administration of up to one course of hyper-CVAD and/or Food and Drug Administration (FDA) approved tyrosine kinase inhibitor (TKI)
Prior or concurrent therapy with a Janus kinase inhibitor or Bruton's tyrosine kinase inhibitor
Subjects with Ph+ disease are eligible if they are intolerant to tyrosine kinase inhibitor (TKI) therapy, or if they have relapsed/refractory disease despite treatment with at least 2 different TKIs
Participants who have had < 28 days since the last chemotherapy, immunotherapy, biological therapy, or < 14 days from approved tyrosine kinase inhibitor (TKI) therapy (sunitinib, sorafenib, vemurafenib, dabrafenib, cobretinib), or systemic or inhaled steroid therapy at doses greater than 10mg of prednisone or equivalent before administration of the first dose of study medication.
Chemo-, hormone-, radio-(except for brain and extremities) or immunotherapy or therapy with monoclonal antibodies or small tyrosine kinase inhibitors within the past 4 weeks prior to treatment with the trial drug.
Prior chemotherapy or tyrosine kinase inhibitor (TKI) treatment, aside from dasatinib, must be >= 7 days before first investigational agent dose
Have T790M-positive status using a test validated and performed locally after disease progression on EGFR tyrosine kinase inhibitor (TKI) treatment.
Known cysteine-481 Bruton's tyrosine kinase (BTK) mutation or CLL refractory to or progressed during ibrutinib or other cysteine (Cys)-481 binding BTK inhibitor treatment
Twenty-one or more days must have elapsed since the patient's last radiation or chemotherapy administration before beginning treatment for stem cell transplant; Hydrea, Gleevec and other tyrosine kinase inhibitors (TKI) as well as intrathecal therapy are accepted exceptions
Patients who have received EGFR tyrosine kinase inhibitors within 72 hours of initiation of study treatment, or treatment with other anti-cancer agents within 21 days of study treatment
Previous therapy with ibrutinib, or any drug that specifically inhibits Bruton's tyrosine kinase (BTK)
Any prior treatment with an aurora kinase inhibitor (either an aurora A kinase or pan-aurora kinase inhibitor)
History of treatment with a tyrosine kinase inhibitor (eg, imatinib), purine analogs or other cancer chemotherapy in the 4 weeks prior to starting study drug.
Any prior medical treatment for CML, including tyrosine kinase inhibitors (TKIs), with the exception of hydroxyurea and/or anagrelide treatment, which are permitted for up to 6 months prior to study entry (signature of ICF) if suitably approved for use in the subject's region.
No prior chemotherapy, Bruton's tyrosine kinase (BTK) inhibitor therapy, or monoclonal anti-body therapy for treatment of CLL or SLL
?2 prior Tyrosine Kinase Inhibitors (TKI) therapies for CML
Tyrosine kinase inhibitor within 7 days of randomization
Patients must not have received prior therapy with a tyrosine kinase inhibitor (TKI)
No prior treatment with erlotinib, gefitinib, or other EGFR tyrosine kinase inhibitors
Subjects (other than those in the ibrutinib + JCAR017 combination therapy arm) must have received and failed Bruton tyrosine kinase inhibitor (BTKi) treatment or have been deemed ineligible for BTKi therapy.
Prior therapy with Bruton's tyrosine kinase (BTK) inhibitor
Subjects may have received up to three prior systemic anticancer treatment regimens for adenocarcinoma of the lung (including adjuvant therapies and tyrosine-kinase inhibitors [TKI]), unless discussed with the sponsor.
Last chemotherapy or treatment with another systemic anti-cancer agent must have stopped >= 4 weeks prior to enrollment (or >= 5 half-lives for oral tyrosine-kinase inhibitors); participants with EGFR mutations and ALK gene rearrangement who have not received a tyrosine kinase inhibitor targeting their molecular abnormality (e.g., erlotinib or crizotinib respectively); participants must have recovered (CTCAE =< 1) from acute toxicities of any previous therapy (with the exception of alopecia)
After failure of 2nd line treatment with up to two prior lines of therapy, one of which may be an oral tyrosine kinase inhibitor (TKI)
Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol with the exception of intrathecal chemotherapy; this includes the tyrosine kinase inhibitor sorafenib which must not be initiated until patient demonstrates count recovery
Patient has received a minimum of 3 years of tyrosine kinase inhibitor treatment (first with imatinib (> 4 weeks) and then switched to nilotinib) since initial diagnosis
Prior therapy with other tyrosine kinase inhibitors (TKI) inhibitors or any other type of investigational agent is allowed if it was an adjunct to definitive local therapy, was given for =< 6 months, and was completed at least 12 months before initiating therapy for metastatic disease
Previous treatment with any other tyrosine kinase inhibitor
Chronic myelogenous leukemia who have failed second generation (2G)-tyrosine kinase inhibitors (TKI)
The addition of cytotoxic agents for “cytoreduction” with the exception of tyrosine kinase inhibitors (such as imatinib), cytokine therapy, hydroxyurea, low dose cytarabine, chlorambucil, or Rituxan will not be allowed within three weeks of the initiation of conditioning
Previously treated with and developed resistance or intolerance to dasatinib or nilotinib OR developed the T3151 mutation after any tyrosine kinase inhibitor (TKI) therapy
Patients with CML must have demonstrated resistance and/or intolerance to therapy with at least 2 tyrosine kinase inhibitors (TKI)
Previous treatment with lapatinib, neratinib, afatinib, tucatinib, or other investigational EGFR family receptor tyrosine kinase inhibitor or HER2 tyrosine kinase inhibitor
No evidence of exon 20 T790M mutation after progression on prior EGFR tyrosine kinase inhibitor(TKI) therapy.
No prior treatment with an EGFR tyrosine kinase inhibitor (TKI)
Prior investigational therapy with an agent that is known or proposed to be active by action on any component of the EGFR tyrosine kinase, IGF1R, mTOR, or c-MET pathways
Patients who have received any targeted therapy (including but not limited to vaccines, antibodies, tyrosine kinase inhibitors) or hormonal therapy for management of their epithelial ovarian or peritoneal primary cancer.
Liver function tests (LFTs) (bilirubin, AST, and/or ALT) may be acceptable if the elevation is secondary to leukemia infiltration or leukemia therapy with tyrosine kinase inhibitors
The addition of cytotoxic agents for 'cytoreduction' with the exception of tyrosine kinase inhibitors (such as imatinib mesylate), cytokine therapy, hydroxyurea, low dose cytarabine, chlorambucil, or rituxan will not be allowed within three weeks of the initiation of conditioning
Has received prior therapy with imatinib or another tyrosine kinase inhibitor
Ph+ B-ALL if subjects are intolerant to or ineligible for tyrosine kinase inhibitor (TKI) therapy, or have progressed after at least one line of TKI therapy
Subject has received treatment with any other agent with antitumor activity including chemotherapy, radiotherapy, or immunotherapy within 14 days as well as EGFR tyrosine kinase inhibitor within 6 days prior to first dose of study drug.
Prior exposure to dasatinib (> 7 days), Bruton’s tyrosine kinase inhibitor exposure, or prior chemotherapy for ALL (up to 7 days of steroids are allowed)
Subject has received prior treatment with any EGFR tyrosine kinase inhibitor
Prior therapy with hydroxyurea, chemotherapy, biological or targeted therapy (e.g. fms-related tyrosine kinase 3 [FLT3] inhibitors, other kinase inhibitors), or hematopoietic growth factors is allowed
Chemotherapy, hormonal therapy, radiotherapy (except for brain and extremities) or immunotherapy or therapy with monoclonal antibodies or small tyrosine kinase inhibitors within the past 4 weeks prior to treatment with the trial drug
Patients with advanced phase CML or acute leukemia must have failed at least one prior TKI; patients with chronic phase CML must have failed, have resistance or suboptimal response to at least two tyrosine kinase inhibitors, or have intolerance to two prior tyrosine kinase inhibitors; for patients with prior intolerance, they should have received at least 2 TKI and experienced intolerance to one TKI and resistance/suboptimal, a. failure to tyrosine kinase inhibitors will be defined per European-Leukemia-Net (ELN) recommendations, b. resistance or suboptimal response to at least two prior Abl-kinase inhibitor, specifically: i. chronic-phase with resistance to imatinib, dasatinib, nilotinib, bosutinib or ponatinib defined as 1. loss of complete cytogenetic response (CCyR) at any time or failure to achieve CCyR after >= 18 months, 2. loss of major cytogenetic response (MCyR) at any time or failure to achieve partial cytogenetic response (PCyR) after >= 12 months, 3. failure to achieve any cytogenetic response (CyR) (ie, >= 65% Philadelphia chromosome [Ph]+) after >= 6 months, 4. hematologic relapse or failure to achieve complete hematologic response (CHR) after >= 3 months, ii. chronic-phase with suboptimal response to imatinib, defined as 1. failure to achieve PCyR after >= 6 months, 2. failure to achieve CCyR after >= 12 months, iii. chronic-phase with suboptimal response to nilotinib, bosutinib, dasatinib or ponatinib, defined as 1. failure to achieve PCyR after >= 3 months, 2. failure to achieve CCyR after >= 6 months of therapy
Must have relapsed/refractory disease after receiving 1 or more lines of therapy, including a Bruton tyrosine kinase (BTK) inhibitor (eg ibrutinib) if approved by the local health authority and commercially accessible. All Arms:
Prior exposure to VEGFR tyrosine kinase inhibitor (small molecule or antibody) or VEGFR antibody.
Tyrosine Kinase Inhibitor (TKI) within 2 weeks.
Has, at the initiation of study drug, received cytotoxic chemotherapy or a Bruton's tyrosine kinase (BTK)-inhibitor (e.g. ibrutinib) within the past 3 weeks or rituximab within the past 2 months
Prior treatment with a spleen tyrosine kinase (SYK) inhibitor
Prior exposure to bruton tyrosine kinase (BTK) inhibitor
Received erlotinib or other EGFR tyrosine kinase inhibitor (TKI) treatment for at least 2 weeks prior to enrollment
Relapsed or refractory to at least one second generation tyrosine kinase inhibitor (TKI) (dasatinib, nilotinib, bosutinib, ponatinib)
No more than one prior line of antitumor therapy for metastatic disease, excluding prior treatment with tyrosine kinase inhibitors. An interval of at least 1 week is required for washout of the tyrosine kinase inhibitor.
Receipt of any prior cytotoxic chemotherapy for ALK-positive NSCLC within 4 weeks prior to Day 1. Patients who received crizotinib or any other tyrosine kinase inhibitors need to have a minimum 2-week washout period before the first dose
The last dose of anti-VEGF tyrosine kinase inhibitor must be at least 7-days but not more than 56-days from enrollment
Must be 14 days from administration of non-cytotoxic agents (e.g., bevacizumab (except COHORT 2b), interferon, tamoxifen, thalidomide, cis-retinoic acid, tyrosine kinase inhibitor, etc.).
Patients are allowed prior VEGFR-tyrosine kinase inhibitor (TKI); patients will be stratified based on prior VEGFR-TKI therapy
Currently or previously treated with AMG 386, or other molecules that primarily inhibit the angiopoietins or TEK tyrosine kinase, endothelial (Tie2) receptor
Any number of prior treatment regimens, including treatment naive subjects. Prior treatment with tyrosine kinase inhibitors is permitted.
Progressive disease after 1-2 prior VEGF-directed tyrosine kinase inhibitors (TKIs).
Chemotherapy, hormone therapy, immunotherapy with monoclonal antibodies, treatment with tyrosine kinase inhibitors, or radiotherapy (except for treatment of extremities) within the past four weeks prior to treatment with the trial drug, i.e., the minimum time elapsed since the last anticancer therapy and the first administration of BIBF 1120 must be four weeks
Either treatment naive to, relapsed/refractory to, or experienced treatment failure due to other reasons with ibrutinib, idelalisib, or any other investigational B-cell receptor (BCR) pathway inhibitors not directly targeting spleen tyrosine kinase (SYK).
Patients who have received or will receive medication that could affect their hematologic state (tyrosine kinase inhibitors, cytotoxic chemotherapy)
GIST patients with iron deficiency anemia (IDA) planned to start or are receiving systemic therapy with tyrosine kinase inhibitors (TKIs)
Be on same oral tyrosine kinase inhibitor (TKI) for >= 3 months
Prior treatment with a Bruton's tyrosine kinase (BTK) inhibitor
Currently in remission and not on any active anti-cancer therapies (survivors receiving maintenance tyrosine kinase inhibitors are NOT eligible).
Participants who were taking EGFR tyrosine kinase inhibitors within 3 months of study entry
Targeted agents including small-molecule tyrosine kinase inhibitors: 2 weeks
Prior exposure to approved receptor tyrosine kinase inhibitors is permitted; at least 5 half-lives must have elapsed since the completion of the kinase inhibitor and the initiation of study treatment
Targeted agents, including small-molecular tyrosine kinase inhibitors: 2 weeks
Planned post-transplant therapy, including use of tyrosine-kinase inhibitors (TKI).
Concurrent administration of lapatinib or other tyrosine kinase inhibitors other than sorafenib
Subjects who have received dasatinib beyond first or second line treatment and meet other enrollment criteria are eligible for the study provided prior Tyrosine-kinase inhibitors (TKI) were discontinued due to intolerance or lack efficacy, although only one instance of lack of efficacy to TKI is allowed.
The patient has either failed, demonstrated intolerance, or a combination of prior failure and intolerance, to prior treatments with at least 2 tyrosine kinase inhibitors (TKI's). Failure of TKI treatment may either be primary (never achieved a response) or secondary resistance (loss of response).
CML in blast phase, resistant or intolerant to tyrosine kinase inhibitor therapy
Patients with EGFR and ALK alterations should have been treated with at least 1 line of targeted tyrosine kinase inhibitor
Has had prior chemotherapy, within 2 weeks prior to study treatment; patients on targeted therapy (tyrosine kinase inhibitor) may go on the study after 5 days off therapy
Group 1a and 1b: NSCLC: Patients with NSCLC must have had disease recurrence or progression during or after no more than one prior systemic chemotherapy regimen (platinum doublet-based) for advanced or metastatic disease. Prior maintenance therapy is allowed (e.g. pemetrexed, erlotinib, bevacizumab). Only patients with EGFR mutation-negative tumor are eligible (defined as negative for exon 19 deletions and for the L858R mutation in EGFR at a minimum; however, if more extensive EGFR mutation testing has been performed, the tumor must not harbor any known activating EGFR mutations in Exons 18-21 in order to be considered EGFR mutation-negative). All patients must be tested for EGFR mutational status and, for ALK translocation status if no mutation is detected in EGFR. Patients with ALK translocation-positive NSCLC must have had disease progression following treatment with a corresponding inhibitor and no more than one systemic chemotherapy regimen (platinum doublet-based), in any sequence.
For Arm A: must have received 1 prior line of therapy with an EGFR TKI and confirmed T790M negative
Receipt of an EGFR TKI within 14 days of the first dose of study treatment.
Prior treatment with appropriate tyrosine kinase inhibitors (TKIs) as follows:\r\n* ALK-positive NSCLC (Cohorts B and D): Participants must have progressed on or after 1 or more next-generation ALK-TKI(s)\r\n* EGFR-mutant NSCLC (Cohorts A and C): Participants must have progressed on or after 1 or more third-generation, T790M mutant-selective EGFR-TKI(s)
NSCLC patients with EGFR mutant tumors.
For Part 2: Cohort A and B: Participants disease must have most recently progressed following treatment with a marketed EGFR inhibitor. Exception: In participants diagnosed with mutations associated with de novo EGFR inhibitor resistance (for example, exon 20 insertions), only previous treatment with combination platinum-based chemotherapy is required. Cohort C: Participants must have been previously treated with a third generation EGFR TKI (eg, osimertinib). Cohort D: Participants must have been previously diagnosed with an EGFR Exon 20 insertion
Participant has had prior chemotherapy, targeted cancer therapy, immunotherapy, or treatment with an investigational anticancer agent within 2 weeks or 4 half-lives whichever is longer, before the first administration of JNJ-61186372. For agents with long half-lives, the maximum required time since last dose is 4 weeks. Toxicities from previous anticancer therapies should have resolved to baseline levels or to Grade 1 or less, (except for alopecia [any grade] and Grade less than or equal to [=<] 2 peripheral neuropathy). For Part 2 only: Cohorts A and B: Prior treatment with chemotherapy for metastatic disease is not allowed unless the tumor mutation carries de-novo resistance to EGFR tyrosine kinase inhibitor (TKI) (eg, exon 20 insertions). Cohort C: Prior treatment with more than 2 lines of cytotoxic chemotherapy for metastatic disease (maintenance therapy is not included). Cohort D: Previous treatment with an investigational third generation EGFR TKI with activity against EGFR Exon 20 insertions (such as poziotinib)
Acquired resistance to EGFR TKI (1st or 2nd génération)
Prior treatment with 3rd generation TKI
Has documented disease progression while receiving at least 30 days of treatment with a currently approved EGFR tyrosine kinase inhibitor (TKI) (e.g., erlotinib, gefitinib or afatinib) with intervening treatment after most recent EGFR TKI therapy (not required for \de novo\ T790M EGFR mutation).
Known T790M EGFR mutation (not applicable for Part C Period 2).
Partial Inclusion criteria:\n\n        Evidence of histologically or cytologically confirmed diagnosis of locally advanced or\n        metastatic EGFRm (del 19 or L858R) NSCLC:\n\n          1. As detected by local EGFR mutation test that includes QIAGEN therascreen EGFR RGQ PCR\n             kit, Roche cobas® EGFR Mutation Test or a sponsor-approved laboratory developed test\n             that is validated in a CLIA laboratory (with tissue submitted for central laboratory\n             confirmation via FDA approved QIAGEN therascreen RCQ PCR kit).\n\n          2. T790M disease as follows:\n\n             Phase 1 If a repeat biopsy was performed on the tumor following prior EGFR TKI\n             therapy, then T790M positive disease must be present. Patients of unknown T790M status\n             following EGFR TKI progression (ie, no post EGFR TKI progression biopsy was performed)\n             are eligible.\n\n             In the PK sub-studies involving food/antacid and CYP3A4 effects, patients with EGFRm\n             (del 19 or L858R) with any T790M status are eligible to enroll.\n\n             Studies at RP2D Cohort 1: Patients may have de novo T790M mutation, but it is not\n             required. Cohort 2 and Cohort 3: Patients must have EGRFm (del 19 AND T790M or L858R\n             AND T790M) NSCLC tumors as detected by local EGFR mutation test that includes QIAGEN\n             Therascreen EGFR RGQ PCR kit, Roche cobas® EGFR Mutation Test or a sponsor-approved\n             laboratory developed test that is validated in a CLIA laboratory, which will then be\n             retrospectively confirmed by the central validated Thermo Fisher Scientific Oncomine\n             Next Generation Sequencing (NGS) cancer panel test. Patients will also be enrolled if\n             they solely test positive for EGFR (del 19 AND T790M or L858R AND T790M) NSCLC in\n             plasma detected by local EGFR mutation test that includes QIAGEN Therascreen EGFR\n             Plasma RGQ kit, Roche cobas® EGFR mutation test v2 (US-IVD) or Sysmex Inostic's\n             OncoBEAMTM EGFR test or a sponsor-approved laboratory developed test that is validated\n             in a CLIA laboratory, which will then be retrospectively confirmed by a validated\n             cfDNA test as determined by the Sponsor.\n\n          3. Prior treatment for EGFRm NSCLC as follows:\n\n        Phase 1 Has progressed after at least 1 prior line of therapy including and EGFR TKI.\n        Patients may have also received other lines of therapy before or after the EGFR TKI.\n\n        Studies at RP2D Cohort 1: no prior treatment for locally advanced or metastatic EGFRm\n        NSCLC. Cohorts 2 and 3: must have had disease progression on treatment with an approved 1st\n        or 2nd generation EGFR TKI. Patients who have been treated with a 3rd generation EGFR TKI\n        are ineligible for this study. Patients may have had multiple lines of therapy; however,\n        the last therapy prior to study treatment must have been an approved EGFR TKI and received\n        within 6 weeks prior to study registration.\n\n        Patients must have at least one measurable lesion as defined by RECIST version 1.1 that has\n        not been previously irradiated.\n\n        Tumor tissue available. Requesting formalin fixed paraffin embedded (FFPE) block or 15\n        unstained sections (5 micron). If a lesser amount of tissue is available, contact the\n        sponsor. An archival specimen is acceptable for Phase 1; a de novo specimen is required for\n        Cohorts 2, and 3 if the T790M status was confirmed by tissue biopsy.\n\n        Partial Exclusion Criteria:\n\n        For All Phases/Cohorts Previously diagnosed brain metastases, unless the patient has\n        completed the treatment that is clinically indicated, if any, and has recovered from the\n        acute effects of any treatment that was delivered prior to study registration, have\n        discontinued corticosteroid treatment for these metastases prior to registration, and are\n        neurologically stable.\n\n        Major surgery within 2 weeks prior to registration.\n\n        Radiation therapy, excluding stereotactic radiosurgery (SRS), within 1 week prior to\n        registration.\n\n        Systemic anti cancer therapy within 2 weeks or 5 half-lives (whichever is longer) of\n        registration excluding EGFR TKIs. Patients on EGFR TKIs must discontinue the agent for a\n        minimum of:\n\n          -  2 days prior to registration for erlotinib or afatinib, or 3 days for gefitinib if\n             they will be part of the lead-in single dose PF-06747775 PK study (Phase 1 Dose\n             Escalation Single and Multiple dose PK and ECG Assessments; Phase 1 Sildenafil at MTD;\n             and Phase 1b/2 First-Line Single Agent). Please contact the Sponsor for direction for\n             any other EGFR TKI.\n\n          -  5 half-lives or 5 days (whichever is longer) prior to registration if they will be\n             starting on continuous PF-06747775 dosing directly (Phase 1 PK sub-studies at RP2D;\n             Phase 1b/2 Combination with Palbociclib; Phase 1b Combination with Avelumab).\n\n        Partial Exclusions for Cohort 2A and 2B (Palbociclib combo):\n\n        Prior treatment with a CDK 4/6 inhibitor.\n\n        Partial Exclusions for Cohort 3 (Avelumab combo):\n\n        Prior therapy with an anti PD 1, anti PD L1, anti PD L2, anti CD137, or anti cytotoxic T\n        lymphocyte associated antigen 4 (CTLA 4) antibody (including ipilimumab, tremelimumab or\n        any other antibody or drug specifically targeting T cell co stimulation or immune\n        checkpoint pathways).\n\n        Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent.\n        Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid disease not\n        requiring immunosuppressive treatment are eligible\n\n        Use of immunosuppressive medication at time of randomization
Progression on a first generation EGFR TKI (T790M negative), or progression on a third generation TKI (if T790M positive at time of progression on a first or second generation TKI)
Prior afatinib therapy, unless patient received an intervening third generation EGFR TKI after concluding prior afatinib and before enrollment on this clinical study
EGFR amplifications in the absence of EGFR-activating mutations
Previous treatment with erlotinib or any other EGFR inhibitor
Confirmation that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) OR must have experienced clinical benefit from EGFR TKI, according to the Jackman criteria (followed by systemic objective progression (RECIST or World Health Organization [WHO]) while on continuous treatment with an EGFR TKI.
An EGFR TKI (e.g., erlotinib, gefitinib, or osimertinib) within 8 days or approximately 5 times the half-life of the specific drug, whichever is longer, of the first dose of study treatment. (If sufficient wash-out time has not occurred due to scheduling or PK properties, an alternative appropriate wash-out time based on known duration and time to reversibility of drug-related adverse events must be agreed upon by Hansoh and the Investigator).
Previously untreated NSCLC patients. To be eligible for this study, patients must have received and progressed on EGFR TKI therapy.
No prior treatment with an EGFR TKI for the advanced NSCLC
Prior EGFR inhibitors
EGFR mutated non-small cell lung cancer (NSCLC) that has previously received a first line platinum doublet and all applicable EGFR TKIs
EGFR-mutation positive patients must have progressed on or had intolerance to an EGFR small molecule tyrosine kinase inhibitor
Confirmation that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity OR
Must have experienced clinical benefit from EGFR TKI, according to the Jackman criteria followed by systemic objective progression while on continuous treatment with EGFR TKI
Dose Expansion cohort(s): subjects in the dose expansion cohorts must also have confirmation of tumor T790M mutation status (confirmed positive) by cobas® EGFR Mutation Test v2 from formalin-fixed paraffin-embedded tumor tissue (FFPET) or circulating-free tumor DNA (cfDNA) plasma sample taken after disease progression on the most recent treatment regimen (EGFR TKI or chemotherapy or other therapy).
Cytotoxic chemotherapy, investigational agents, or any anticancer therapy for the treatment of advanced NSCLC (other than EGFR TKI) within 21 days of the first dose of study treatment
Patients must have one of the following: \r\n* NSCLC which harbors EGFR exon 19 deletion or L858R mutation. This subset of patients must be TKI naive; OR\r\n* NSCLC which harbors an EGFR T790M mutation that was acquired following progression on erlotinib, gefitinib or afatinib. This subset of patients must have not received prior third generation TKI\r\n* NOTE: EGFR mutation must be documented by a Clinical Laboratory Improvement Amendments (CLIA) certified test
Previous treatment with osimertinib, or a 3rd generation EGFR TKI. NOTE: Patients who are receiving initial osimertinib (6-12 weeks) outside this study are not excluded
Progression after prior treatment with an EGFR TKI; in addition to this one prior line of therapy, any additional prior lines of therapy are permitted; prior treatment with a third-generation EGFR TKI is allowed for the dose escalation phase, but is not permitted for the expansion cohort
For the dose expansion portion only, patient must: 1) have a tumor which is EGFR-T790M positive and 2) be treatment naive to T790M-directed EGFR TKI (e.g. AZD9291, rociletinib, etc); T790M testing may be done locally or centrally on study, but if done locally, tissue must be available for central confirmation
Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment
Patients in the six patient safety run-in cohort may have had a prior EGFR TKI in the metastatic setting (to allow for patients who started initial therapy at an outside hospital), but treatment duration must have been less than three months; after the initial six-patient safety run-in, no prior EGFR TKI therapy in the metastatic setting is allowed; an EGFR TKI given in the adjuvant setting (i.e. with no measurable disease at the time of administration) is allowable provided the subject has been off of EGFR TKI therapy for at least six months at the time of enrollment
In dose expansion, patients must have received prior anti-EGFR therapy
Has acquired resistance to EGFR TKI according to the Jackman criteria (PMID: 19949011):
Has experienced clinical benefit from an EGFR TKI, followed by systemic progression (Response Evaluation Criteria in Solid Tumors [RECIST version 1.1] or World Health Organization [WHO]) while on continuous treatment with an EGFR TKI.
Demonstrates absence of EGFR T790M.
Patients with a known activating mutation in EGFR (exon 19 deletion, G719A, S768I, V769L, T790M, L833F, L858R, L861Q), must have progressed or been intolerant to treatment with a first-line EGFR TKI (erlotinib, afatinib, gefitinib, or osimertinib); patients whose tumors were found to have an EGFR T790M mutation must also have progressed or been intolerable to treatment with osimertinib
eGFR> 60% of mean age adjusted normal values
Patients must be previously treated with one or more regimens of systemic therapy for locally advanced or metastatic disease; previously untreated patients are eligible only if EGFR Exon 20 mutation is confirmed using an FDA approved device: cobas EGFR mutation test v2 or therascreen EGFR RGQ polymerase chain reaction (PCR) Kit prior to study enrollment
Prior erlotinib, gefitinib or lapatinib therapy or prior exposure to any investigational EGFR or panErbB reversible or irreversible inhibitor or any prior panitumumab or investigational EGFR-directed monoclonal antibody
Non-small cell lung cancer: 1) we will enroll non-small cell lung cancer patients with documented EGFR mutation who failed treatment with anti-EGFR therapy (e.g. erlotinib or afatinib) and tested negative for EGFR T790M mutation; we will allow patients with positive EGFR T790M mutation if they have progressed on third generation anti-EGFR therapy (e.g. CO-1686 or AZD9291) or medically not suitable/candidate for the third generation anti-EGFR therapy; failure from anti-EGFR therapy will be defined as progressive disease by RECIST (version 1.1) after at least two months of therapy
Phase 2 patients must have confirmed EGFR T790M mutation-positive NSCLC
Patients with histologically confirmed, by the National Cancer Institute (NCI) Laboratory of Pathology or by Clinical Laboratory Improvement Act (CLIA)-certified next generation sequencing or cobas EGFR mutation test v1/2 at an outside institution, advanced lung adenocarcinoma with EGFR-sensitizing somatic mutations or a germline T790M mutation (detected histologically or via ctDNA analysis using a CLIA assay) with:\r\n* No prior EGFR tyrosine kinase inhibitor (TKI) therapy (cohort 1)\r\nOR\r\n* Progressive disease after 1st or 2nd generation EGFR TKI therapy harboring somatic T790M mutation (cohort 2)\r\nOR\r\n* Progressive disease after treatment with osimertinib who are eligible for local ablative therapy (cohort 3)
Pathology consistent with EGFR-amplification of tumor (i.e. greater than 15% of cells exhibiting > 5 copies of EGFR loci); archival tissue may be tested for EGFR status in a separate consent
Confirmation by the central laboratory that the tumour harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either alone or in combination with other EGFR mutations including T790M.
Prior treatment with neoadjuvant or adjuvant EGFR-TKI at any time
Tumor tissue for determination and/or confirmation of genetic pre-requisites (i.e. EGFR T790M positivity post progression on EGFR TKI for Group 1; cMet status for Group 2) must be provided for analysis Group 1 patients:
Patients with EGFR T790M NSCLC (adenocarcinoma)
Patients with EGFR wild-type NSCLC
Patients who have received more than one prior line of EGFR TKI therapy1 (applies only to Group 1)
Patients who previously received agents targeting c-MET and/or EGFR T790M Note: Previous treatment with afatinib may be allowable after discussions between Novartis and Investigator.
The presence of an EGFR T790M mutation after progression on a first- or second-generation EGFR TKI; presence of an EGFR T790M mutation may be documented from biopsy material from any site of disease (intra- or extra-cranial) or from plasma testing if performed in a CLIA-certified laboratory; for patients who have disease progression in the CNS only (with otherwise stable disease systemically), T790M positivity is not required
Disease progression on a first- or second-generation EGFR TKI (i.e. erlotinib, gefitinib, or afatinib); patient may have also received prior chemotherapy or immunotherapy but this is not required
Prior treatment with a third-generation EGFR TKI (i.e. rociletinib)
Treatment with an EGFR TKI (i.e. erlotinib, gefitinib or afatinib) within 8 days or approximately 5 x half-life, whichever is longer, of the first dose of study treatment
For patients with a documented EGFR T790M mutation: have not received a TKI with activity against the EGFR T790M mutation.
Patients with an EGFR deletion or mutation known (from tumour biopsy or plasma) to be associated with EGFR TKI sensitivity
Patients who have received prior treatment with an EGFR TKI including in the adjuvant setting
eGFR > 45 mL/min
Patients whose tumors harbor an EGFR sensitizing mutation must have demonstrated progression on or intolerance to an Food and Drug Administration (FDA)-approved first-line EGFR tyrosine kinase inhibitor (TKI); patients with the EGFR T790M mutation, must also have demonstrated progression on or intolerance to osimertinib
Treatment with third generation EGFR inhibitors
Patients with known and documented EGFR mutation who have not received an EGFR inhibitor.
\Acquired\ resistance to commercially available anti-EGFR mAbs approved for the treatment of mCRC must have:
Received treatment with an anti-EGFR for ?16 weeks
Investigator-determined radiographic disease progression per RECIST 1.1 after treatment with an EGFR TKI therapy: a) Participants previously treated with 1st or 2nd generation EGFR TKI (e.g. erlotinib/afatinib/gefitinib) are required to have confirmed documented absence of EGFR T790M mutation; b) Participants with confirmed acquired T790M mutation after 1st or 2nd generation EGFR TKI (e.g. erlotinib/afatinib/gefitinib) are required to have osimertinib TKI treatment failure prior to enrollment; c) Participants previously failed osimertinib TKI treatment as 1st line therapy are eligible regardless of their EGFR T790M mutation status.
Disease progression confirmed by radiologic assessment while receiving treatment with\n             the first single agent EGFR-TKI
EGFR TKI treatment discontinued less than or equal to 30 days prior to planned\n             initiation of rociletinib
The washout period for an EGFR inhibitor is a minimum of 3 days
No intervening treatment between cessation of single agent EGFR TKI and planned\n             initiation of rociletinib
Prior treatment with rociletinib, or other drugs that target T790M positive mutant\n             EGFR with sparing of wild type EGFR
For Phase IB Extension Only:\r\n* Either or both of the following:\r\n** A tumor which harbors an activating epidermal growth factor receptor (EGFR)-mutation\r\n** History of objective response, or stable disease for at least 6 months, after treatment with erlotinib, afatinib, or gefitinib\r\n* Either or both of the following:\r\n** Progression or recurrence of disease after receiving prior continuous gefitinib, afatinib, or erlotinib\r\n** A tumor known to harbor a de novo T790M mutation, which is known to confer EGFR TKI resistance\r\n* Participants are allowed to have received systemic chemotherapy or investigational therapy in the intervening period prior to trial enrollment
Disease progression confirmed by radiologic assessment while on treatment with EGFR-\n             TKI Or
Disease progression confirmed by radiologic assessment while on treatment with the\n             first single agent EGFR TKI and
Documented evidence of T790M mutation in EGFR following disease progression on the\n             first single agent EGFR TKI.
No prior treatment with systemic anti-EGFR inhibitors or pemetrexed is permitted
Pathologically confirmed non-small cell lung cancer with documented EGFR mutation in tumor deoxyribonucleic acid (DNA) or complete/partial response to first line EGFR tyrosine kinase inhibitors with > or = to 6 months duration of response in patients who do not have a confirmed EGFR mutation
For participants receiving erlotinib group: prior treatment with any EGFR mutant-targeting TKI
For Dose escalation cohort - progressive disease on at least one prior EGFR-tyrosine kinase inhibitor (TKI) (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation)
For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies
For Dose Expansion Cohort B: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial)
For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial
For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naive to both EGFR-TKI and EGFR monoclonal antibody
Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment
Prior exposure to EGFR inhibitors.
Known tumor EGFR, KRAS, and/or Akt2 mutations or amplification
eGFR ? 50 mL/min/1.73 m2
History of NSCLC with EGFR mutation or an EGFR activating mutation that has had a clinical response to erlotinib, afatinib, or gefitinib in the patient being enrolled.
Patients who have had prior therapy that specifically and directly targets the EGFR/HER2 pathway.
Locally documented EGFR mutation L858R and/or ex19del, or a characterized de novo EGFR T790M mutation (or other rare activating mutations that confer sensitivity to 1st and 2nd generation EGFR inhibitors (e.g. L861Q, G719X, S768I)
Phase Ib only: documented progression of disease according to RECIST v1.1 while on continuous treatment with EGFR TKI (e.g.: erlotinib, gefitinib or afatinib).
Previous treatment with any investigational agent known to inhibit EGFR (mutant or wild-type)
Patients who have received more than three prior lines of antineoplastic therapies (including EGFR TKI) in advanced setting.
More than 3 prior lines of systemic antineoplastic therapies (including EGFR TKI) in the advanced setting
More than 1 previous treatment line with 1st or 2nd generation EGFR TKI (e.g. erlotinib, gefitinib, afatinib) in the advanced setting
Previous treatment with an investigational or marketed 3rd generation EGFR TKI (e.g. AZD9291, CO-1686, ASP8273, EGF816)
Previous treatment with an investigational or marketed agent known to inhibit EGFR (e.g. EGF monoclonal antibody therapy, dual TKI inhibitor).
Previous treatment with an investigational or marketed agent that inhibits EGFR. EGFR inhibitors include (but not limited to) all generations of EGFR TKI (e.g.erlotinib, gefitinib, afatinib, AZD9291, CO-1686, ASP8273, EGF816) or other anti-EGFR or EGFR monoclonal antibody therapy or dual TKI inhibitors.
De novo EGFR T790M mutation identified by central assessment
Previous treatment with an investigational or marketed 3rd generation EGFR TKI (e.g. AZD9291, CO-1686, ASP8273, EGF816)
Previous treatment with an investigational or marketed agent known to inhibit EGFR (e.g. EGF monoclonal antibody therapy, dual TKI inhibitor).
Inclusion Criteria:\n\n        All patients must meet all of the following inclusion criteria:\n\n          1. Histologically or cytologically confirmed metastatic or unresectable locally advanced\n             NSCLC with radiological progression on the most recent therapy received\n\n          2. Documented evidence of a tumor with 1 or more EGFR activating mutations excluding exon\n             20 insertion\n\n          3. Disease progression confirmed by radiological assessment while receiving treatment\n             with single agent EGFR-TKI (e.g., erlotinib, gefitinib, afatinib, or dacomitinib) or\n             EGFR-TKI in combination with other targeted therapy (e.g. bevacizumab, immunotherapy)\n\n          4. Multiple lines of prior treatment are permitted and there is no specified order of\n             treatment, but in the course of their treatment history, patients must have received\n             and have radiologically documented disease progression following:\n\n             At least 1 line of prior treatment with a single-agent EGFR-TKI (e.g., erlotinib,\n             gefitinib, afatinib, or dacomitinib)\n\n             If EGFR-TKI is a component of the most recent treatment line, the washout period for\n             the EGFR-TKI is a minimum of 3 days before the start of study drug treatment\n\n             AND\n\n             A platinum-containing doublet chemotherapy (either progressed during therapy or\n             completed at least 4 cycles without progression with subsequent progression after a\n             treatment-free interval or after a maintenance treatment).\n\n             If cytotoxic chemotherapy is a component of the most recent treatment line, treatment\n             with chemotherapy should have been completed at least 14 days prior to start of study\n             treatment. When an EGFR-TKI is given in combination with platinum-containing doublet\n             chemotherapy, treatment with the EGFR-TKI may continue until at least 3 days before\n             start of treatment.\n\n          5. Have undergone a biopsy of either primary or metastatic tumor tissue within 60 days\n             prior to start of treatment and have tissue sent to the central laboratory prior to\n             randomization\n\n          6. Measureable disease according to RECIST Version 1.1\n\n          7. Life expectancy of at least 3 months\n\n          8. ECOG performance status of 0 to 1\n\n          9. Age ? 18 years (in certain territories, the minimum age requirement may be higher\n             e.g., age ? 20 years in Japan and Taiwan, age ? 21 years in Singapore)\n\n         10. Patients should have recovered to National Cancer Institute (NCI) Common Terminology\n             Criteria for Adverse Events (CTCAE) Grade ? 1 from any significant\n             chemotherapy-related toxicities\n\n         11. Adequate hematological and biological function\n\n         12. Written consent on an Institutional Review Board (IRB)/Independent Ethics Committee\n             (IEC)-approved ICF before any study specific evaluation\n\n        Exclusion Criteria:\n\n        Any of the following criteria will exclude patients from study participation:\n\n          1. Any other malignancy associated with a high mortality risk within the next 5 years and\n             for which the patients may be (but not necessarily) currently receiving treatment\n\n             Patients with a history of malignancy that has been completely treated, with no\n             evidence of that cancer currently, are permitted to enroll in the trial provided all\n             chemotherapy was completed > 6 months prior and/or bone marrow transplant > 2 years\n             prior\n\n          2. Known pre-existing interstitial lung disease\n\n          3. Tumor small cell transformation by local assessment, irrespective of presence of\n             T790M+ component\n\n          4. Patients with leptomeningeal carcinomatosis are excluded. Other central nervous system\n             (CNS) metastases are only permitted if treated, asymptomatic, and stable (not\n             requiring steroids for at least 2 weeks prior to randomization and the patient is\n             neurologically stable i.e. free from new symptoms of brain metastases)\n\n          5. Patients who are currently receiving treatment with any medications that have the\n             potential to prolong the QT interval and that treatment cannot be either discontinued\n             or switched to a different medication (known to have no effect on QT) before starting\n             protocol-specified treatment (see http://crediblemeds.org/ for a list of QT-prolonging\n             medications)\n\n          6. Prior treatment with rociletinib, or other drugs that target T790M+ mutant EGFR with\n             sparing of WT-EGFR including but not limited to osimertinib, HM61713, and TAS-121\n\n          7. Any contraindications for therapy with pemetrexed, paclitaxel, gemcitabine or\n             docetaxel unless a contraindication with respect to one of these drugs will not affect\n             the use of any of the others as a comparator to rociletinib\n\n          8. Any of the following cardiac abnormalities or history:\n\n               1. Clinically significant abnormal 12-lead ECG, QT interval corrected using\n                  Fridericia's method (QTCF) > 450 msec\n\n               2. Inability to measure QT interval on ECG\n\n               3. Personal or family history of long QT syndrome\n\n               4. Implantable pacemaker or implantable cardioverter defibrillator\n\n               5. Resting bradycardia < 55 beats/min\n\n          9. Non-study related surgical procedures ? 7 days prior to randomization. In all cases,\n             the patient must be sufficiently recovered and stable before treatment administration\n\n         10. Females who are pregnant or breastfeeding\n\n         11. Refusal to use adequate contraception for fertile patients (females and males) while\n             on treatment and for 6 months after the last dose of study treatment (rociletinib and\n             chemotherapy irrespective of single cytotoxic agent used)\n\n         12. Presence of any serious or unstable concomitant systemic disorder incompatible with\n             the clinical study (e.g., substance abuse, uncontrolled intercurrent illness including\n             uncontrolled diabetes, active infection, arterial thrombosis, and symptomatic\n             pulmonary embolism)\n\n         13. Any other reason the investigator considers the patient should not participate in the\n             study\n\n         14. Treatment with live vaccines initiated less than 4 weeks prior to randomization
In Part B-BM expansion, patients must have not received any EGFR TKI and have asymptomatic brain metastasis, either found during screening process which does not require local treatment in the opinion of the investigator or local treatment has been given (surgery or radiation), patient must be stable without corticosteroid and/or anti-convulsants treatment for at least 2 weeks before study enrollment. For Part B-LM expansion, patients who received previous EGFR TKI treatment must have stable extracranial disease;EGFR TKI treatment naïve patients can also be enrolled into AZD9291 cohorts, or AZD3759 cohorts if efficacy signal seen in Part A and agreed by Safety Review Committee.
In Part B-AZD9291 LM expansion (sub-cohort of T790M+ LM patients), patients must have central confirmation of T790M+ mutation status from a sample taken after documented progression on the last treatment administered prior to enrolling in the study. Patients must have received prior therapy with an EGFR TKI and may also have received additional lines of treatment. Stable extracranial disease is not required.
Treatment with an EGFR TKI (e.g., erlotinib or gefitinib) within 8 days or approximately 5 x half-life, whichever is the longer, of the first dose of study treatment.
Response expansion/RP2D expansion/ FE Cohort subjects: disease progression on or was intolerant to prior EGFR TKI; activating mutation as above AND T790M mutation; tumor sample subsequent to EGFR TKI is available for central testing; at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Inclusion Criteria for Exon 20 cohort:
CKD 1 to 3 (eGFR > 30)
Previous treatment with osimertinib or third generation EGFR TKIs.
Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI
Previous treatment with anticancer therapies, EGFR-TKI, HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, investigational agent(s) within 28 days prior to the first administration of study drug, radiotherapy
Confirmation from a previous archival sample that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity
Histologically or cytologically confirmed metastatic or unresectable locally advanced NSCLC with known sensitive EGFR mutations; patients with mutations in T790M are eligible if they have progressed after treatment with a third generation EGFR tyrosine kinase inhibitor (osimertinib), but otherwise patients must have EGFR T790M negative or unknown status; patients previously treated with third generation EGFR tyrosine kinase inhibitor must have achieved a treatment benefit of at least 4 months
For EGFR mutant cohort, patients must have: a) documented EGFR mutation by Clinical Laboratory Improvement Amendments (CLIA)-certified test b) documented disease progression on treatment with erlotinib, gefitinib, afatinib, or other EGFR-targeted tyrosine kinase inhibitor c) tissue available from a biopsy or surgical procedure performed after progression on an EGFR targeted tyrosine kinase inhibitor; if tissue is not available, the patient must have biopsy accessible disease and must be willing to undergo a biopsy
For HER2 mutant cohort, patients must have: a) documented EGFR mutation by CLIA-certified test b) documented disease progression on treatment with erlotinib, gefitinib, afatinib, or other EGFR-targeted tyrosine kinase inhibitor c) tissue available following progression on most recent systemic therapy; if tissue is not available, the patient must have biopsy accessible disease and must be willing to undergo a biopsy
The tumour harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R).
Prior treatment with an EGFR-TKI.
Treatment with an approved EGFR-TKI (e.g.,erlotinib, gefitinib, afatinib) within 8 days or approximately 5x half-life of the first dose of study treatment
Previous treatment with AZD9291, or a 3rd generation EGFR TKI For subjects who cross-over to AZD9291:
Inclusion:\n\n          -  Aged at least 18 years. Japan patients aged at least 20 years.\n\n          -  Locally advanced/metastatic NSCLC not amenable to curative surgery or radiotherapy\n\n          -  Radiological documentation of disease progression:\n\n        following 1st line EGFR TKI treatment but who have not received further treatment OR\n        following prior therapy with an EGFR TKI and a platinum-based doublet chemotherapy.\n        Patients who received prior EGFR TKI and platinum-based doublet chemotherapy may have also\n        received additional lines of treatment. All patients must have documented radiological\n        progression on the last treatment administered prior to enrolling in the study.\n\n          -  Disease progression following 1st line EGFR TKI treatment or following prior EGFR TKI\n             and platinum-containing doublet chemotherapy.\n\n          -  Confirmation that the tumour harbours an EGFR mutation known to be associated with\n             EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). Patients must\n             have central confirmation of tumour T790M mutation positive status from a biopsy\n             sample taken after confirmation of disease progression on the most recent treatment\n             regimen.\n\n          -  World Health Organisation (WHO) performance status 0-1 with no deterioration over the\n             previous 2 weeks and a minimum life expectancy of 12 weeks.\n\n          -  At least one lesion, not previously irradiated and not chosen for biopsy during the\n             study screening period, that can be accurately measured at baseline as ? 10mm in the\n             longest diameter (except lymph nodes which must have short axis ? 15mm) with\n             computerised tomography (CT) or magnetic resonance imaging (MRI) which is suitable for\n             accurate repeated measurements.\n\n          -  Females of child-bearing potential using contraception; negative pregnancy test.\n\n        Exclusion:\n\n          -  Treatment with an EGFR-TKI within 8 days of study entry; any cytotoxic chemotherapy,\n             investigational agents or other anticancer drugs within 14 days of study entry;\n             previous treatment with AZD9291 (or 3rd generation TKIs); major surgery within 4\n             weeks; radiotherapy treatment to more than 30% of the bone marrow or with a wide field\n             of radiation within 4 weeks; current treatment with potent inhibitors of CYP2C8 and\n             potent inhibitors/inducers of CYP3A4.\n\n          -  Unresolved toxicities from prior therapy.\n\n          -  Unstable spinal cord compression/brain metastases.\n\n          -  Severe/uncontrolled systemic diseases, including uncontrolled hypertension, bleeding\n             diatheses or infection.\n\n          -  Refractory nausea/vomiting, chronic gastrointestinal diseases or bowel resection.\n\n          -  Cardiac disease.\n\n          -  Past history of ILD, drug-induced ILD, radiation pneumonitis which required steroid\n             treatment, or any evidence of clinically active interstitial lung disease.\n\n          -  Inadequate bone marrow reserve or organ function.
Subjects must have a. In the escalation phase, locally advanced or metastatic NSCLC subjects who have either failed to respond or relapsed following any line of standard treatment, were unable to tolerate, or were not eligible for standard treatment b. In the expansion phase, histologically or cytologically confirmed locally advanced or metastatic NSCLC that is EGFR mutation positive, naïve to EGFR TKI therapy, and sensitive to EGFR TKIs therapy
Must have experienced clinical benefit from EGFR TKI, according to the Jackman criteria (Jackman et al 2010) followed by systemic objective progression (RECIST or WHO) while on continuous treatment with EGFR TKI.
Previous treatment with a single-agent EGFR TKI (e.g. gefitinib or erlotinib).
Treatment with an EGFR TKI (erlotinib or gefitinib) within 8 days (approximately 5x half-life) of the first dose of study treatment.
For the expanded cohort only, patient must not have had prior therapy with an EGFR-specific monoclonal antibody or EGFR-specific tyrosine kinase inhibitor (TKI) for treatment of incurable HNSCC; prior therapy with an EGFR-specific monoclonal antibody as part of the definitive treatment of curable HNSCC is acceptable if this occurred more than 3 months prior to study enrollment; for the dose-finding cohorts, prior EGFR-specific therapy in the incurable setting is allowed
Histologically or cytologically confirmed stage IV EGFR-mutant NSCLC or, in the absence of availability of EGFR testing (for example, inadequate tissue), clinical response overwhelmingly consistent with EGFR mutation (partial response [PR] plus at least 6 months free of progressive disease as a consequence of EGFR-TKI therapy)
History of previous response to EGFR-TKI, defined as either a PR by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria, or at least six months without progressive disease as a result of EGFR-TKI therapy
Progressive disease as measured via RECIST 1.1 following EGFR-TKI therapy (with =< 5 sites of disease amenable to SRS or other locally-ablative treatment)
Treatment with any Food and Drug Administration (FDA) approved or experimental cancer treatment following progression on EGFR-TKI (e.g., radiation or chemotherapy; supportive regimens such as denosumab or zoledronic acid will not result in exclusion)
Somatic activating mutation in EGFR radiographic progression during treatment with erlotinib or any other EGFR tyrosine kinase inhibitor (TKI) therapies
Any type of systemic therapy (chemotherapy or experimental drugs) within 2 weeks of starting treatment on protocol except for a EGFR TKI
Confirmed stage IV or recurrent EGFR Mutation (MT)+ NSCLC with disease progression after 1 prior EGFR TKI therapy
Subject has received a prior treatment with a therapeutic agent targeting EGFR (e.g., afatinib, dacomitinib, ASP8273, etc).
eGFR > 30 ml/min/1.73 m^2
Prior treatment with EGFR TKIs (e.g. erlotinib, gefitinib, neratinib, afatinib, AZD9291, or dacomitinib), rociletinib or other drugs that target mutant EGFR
Progression within 6 weeks following their last dose of anti-EGFR therapy
Treatment with a non-EGFR targeting regimen following progression on anti-EGFR plus irinotecan-based therapy
History of severe anti-EGFR toxicity requiring drug discontinuation or dose-modification within the first 4 months of prior anti-EGFR therapy
Intervening anticancer treatment subsequent to the EGFR TKI is allowed (but not required).
Subject has a NSCLC tissue sample obtained after subject developed resistance to EGFR TKI therapy that is available for central testing.
Subject's baseline tumor specimen (obtained after subject developed resistance to EGFR TKI therapy) is T790M negative.
Subject received an EGFR TKI for at least 6 months and progressed on this therapy within the past 28 days.
Subject has not had any intervening anticancer treatment subsequent to the EGFR TKI with the exception of radiotherapy which is allowed if it occurred at least 14 days prior to the first dose of study drug.
Key Eligibility Criteria:\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-1\n\n          -  Confirmed recurrent Stage IV NSCLC which progressed while on treatment with EGFR TKI\n\n          -  Measurable disease according to Response Evaluation Criteria in Solid Tumors version\n             1.1 (RECIST 1.1)\n\n          -  Documented evidence of an EGFR mutation known to be associated with an EGFR TKI\n             sensitivity\n\n          -  No T790M mutation or small cell transformation including an assessment from tumor\n             biopsy obtained while on or subsequent to the most recent EGFR TKI therapy\n\n          -  Acceptable laboratory results as indicated by protocol\n\n          -  Acceptable cardiac function as indicated by protocol\n\n        Key Exclusion Criteria:\n\n          -  Receiving medication that prolongs QT interval, with a risk of causing Torsades de\n             Pointes (TdP) unless ECG meets inclusion criteria while on a stable dose of the\n             medication\n\n          -  Family history of long QTc syndrome\n\n          -  Symptomatic central nervous system (CNS) lesions\n\n          -  Radiation therapy within 2 weeks prior to the first dose of study medication\n\n          -  Major surgery within 4 weeks or minor surgery within 2 weeks prior to the first dose\n             of study medication\n\n          -  Concurrent active malignancy requiring systemic treatment\n\n          -  Any other serious uncontrolled medical disorders or psychological conditions that may\n             interfere with study conduct including but not limited to: clinically significant\n             active infection (e.g., tuberculosis, viral hepatitis, human immunodeficiency virus\n             [HIV]), recent (within 6 months) myocardial infarction or unstable angina, congestive\n             heart failure, poorly-controlled hypertension or diabetes, concurrent active\n             malignancy, or psychiatric condition that may interfere with the patient's ability to\n             follow study procedures\n\n          -  Pregnant or breast-feeding
Received prior EGFR TKI therapy for recurrent or metastatic SCC (e.g., oral EGFR TKIs such as erlotinib, gefitinib, or afatinib)
Prior monotherapy with an EGFR inhibitor except as maintenance therapy
In countries where EGFR TKIs are available for the treatment of NSCLC, subjects need to have been screened for EGFR mutations and excluded if positive, unless previously treated and progressed on an appropriate TKI therapy
Patients with previous anti-cancer chemotherapy, immunotherapy or investigational agents =< 3 weeks prior to the first day of study defined treatment; NSCLC patients with EGFR mutation can enroll within 7 days of discontinuing EGFR-TKI; palliative radiation < 1 week before the start of treatment (lesions subjected to radiotherapy may not be used as target lesions); patients who receive gamma knife radiosurgery for brain metastases within 1 week prior to treatment start
Patients must have documented clinical benefit (CR, PR, or patients with SD for 6 months or greater) on prior EGFR TKI (e.g. erlotinib or gefitinib) followed by documented progression according to RECIST.
Documented EGFR activating mutations (if already tested)
ERLOTINIB HYDROCHLORIDE ARM: Previous anti-EGFR TKI therapy
ERLOTINIB HYDROCHLORIDE ARM: Patients with a known EGFR TKI resistant mutation
FOR PHASE II COHORT B: (EGFR exon 20 insertions): Prior EGFR-TKIs including erlotinib is allowed; if patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to initiation of erlotinib and onalespib
Patients with tumors confirmed to have EGFR-activating mutations who are suitable for anti-EGFR therapy (e.g. gefitinib or erlotinib), as determined by the investigator, unless that treatment is unavailable or refused by the patient
Prior treatment with an EGFR TKI; in Phase 2, prior treatment with a T790M-directed EGFR TKI for patients in Group B. Previous chemotherapy is allowed; in Phase 2, immediate prior therapy must be EGFR TKI
Presence of EGFR activating mutation and absence of EGFR T790M in the tumour associated with the latest disease progression. Only applicable in Part B
Part A: Progression of disease (RECIST 1.1) while on continuous treatment with single EGFR TKI or for histology other than adenocarcinoma and without prior EGFR TKI treatment: progression of disease (RECIST v1.1) on platinum-based chemotherapy. Part B: Progression of disease (RECIST v1.1) while on continuous treatment with single agent of the second generation irreversible EGFR TKI (e.g. afatinib or dacomitinib)
No intervening systemic therapy between cessation of EGFR TKI and study treatment
Patient whose disease progressed on insufficient dose of EGFR TKI immediately prior to study in the opinion of the investigator
More than 2 prior EGFR TKI treatment regimens for Part B
Use of previous EGFR TKIs except afatinib within 3 days
Previous treatment with EGFR TKI which cannot be documented as either reversible or irreversible (Part B only)
Part B only: Prior treatment with third generation irreversible EGFR TKI (e.g. AZD9291 or CO-1686)
Any type of systemic therapy (chemotherapy or experimental drugs) within 3 weeks of starting treatment on protocol except for erlotinib or other EGFR TKI
Acquired resistance to marketed anti-EGFR mAbs as defined in the protocol
Exposure to an investigational or marketed agent that can act by EGFR inhibition
Eligibility is restricted to subjects with confirmed EGFR amplification in the EGFR amplified cohort
(summarized due to limitation of characters)\n\n        Inclusion Criteria:\n\n          1. Written informed consent\n\n          2. Aged at least 18 years (20 years for Japan)\n\n          3. Histological or cytological confirmation diagnosis of EGFRm+ NSCLC. Confirmation from\n             a previous archival sample that the tumour harbours an EGFRm+ known to be associated\n             with EGFR TKI sensitivity.\n\n          4. Radiological documentation of disease progression while on a previous continuous\n             treatment with an EGFR TKI (on the last treatment administered prior to enrolling in\n             the study)\n\n             Part B cMET+ve patients:\n\n               -  No prior treatment with a 3rd generation TKI: at least one prior line of therapy\n                  with 1st or 2nd generation EGFR TKI, but not a 3rd generation (T790M-directed)\n                  EGFR TKI.\n\n               -  Prior treatment with a 3rd generation TKI: at least one prior line of therapy\n                  with a 3rd generation (T790M-directed) EGFR TKI for EGFRm or T790M+ NSCLC.\n\n             Part B cMET-ve patients:\n\n               -  T790M directed EGFR TKI patients only: their immediate prior therapy before entry\n                  into this study must be a T790M directed EGFR TKI.\n\n               -  ?2nd line cohort: patients must have progressed while on treatment with an EGFR\n                  TKI (T790M directed EGFR TKIs are permitted). Other prior lines of therapy may\n                  have been given.\n\n             Part D cMET-ve patients:\n\n             No prior treatment with a 3rd generation TKI, T790M negative:\n\n             Patients must have received at least one prior line of therapy with 1st or 2nd\n             generation EGFR TKI, but not a 3rd generation (T790M directed) EGFR TKI.\n\n          5. cMET status: Prior to study entry, local confirmation of tumour cMET status is\n             acceptable, a central result will be confirmed retrospectively. If a local test is not\n             available, central confirmation of tumour cMET status must be obtained prior to study\n             entry.\n\n             T790M status: Local confirmation of tumour T790M status is acceptable, a central\n             result will be confirmed retrospectively. If local testing is performed with the\n             Cobas® EGFR Mutation Test, the central confirmation is not required.\n\n          6. At least one lesion, not previously irradiated, not biopsied during the screening\n             period, that can be accurately measured at baseline as ?10 mm in the longest diameter\n             (except lymph nodes which must have short axis ?15 mm) with CT or MRI which is\n             suitable for accurate repeated measurements\n\n          7. WHO performance status 0-1 with no deterioration over the previous 2 weeks and minimum\n             life expectancy of 12 weeks\n\n          8. Females should be using adequate contraceptive measures, must not be breast feeding\n             and must have a negative pregnancy test prior to start of dosing if of child-bearing\n             potential or must have evidence of non-child-bearing potential.\n\n        Exclusion Criteria (summary):\n\n          -  Treatment with an EGFR TKI within approximately 5x half-life of the first dose of\n             study treatment. Any cytotoxic chemotherapy, investigational agents or other\n             anticancer drugs for the treatment of advanced NSCLC from a previous treatment regimen\n             or clinical study within 14 days of the first dose of study treatment. Patients\n             currently receiving (or unable to stop use) medications or herbal supplements known to\n             be potent inducers of CYP3A4 (at least 3 weeks prior). For AZD6094 patients currently\n             receiving (or unable to stop use at least 2 weeks) prior to receiving the first dose,\n             medications known to be strong inhibitors of CYP1A2. Prior AZD9291 dosing in the\n             present study. Prior or current treatment with AZD6094 or another cMET inhibitor (if\n             allocated to AZD9291 + AZD6094). Radiotherapy with a limited field of radiation for\n             palliation within 1 week of the first dose of study treatment, with the exception of\n             patients receiving radiation to more than 30% of the bone marrow or with a wide field\n             of radiation which must be completed within ?4 weeks of the first dose of study\n             treatment. Major (or anticipated major) surgical procedure (excluding placement of\n             vascular access) or significant traumatic injury within 4 weeks of the first dose of\n             study treatment. Currently receiving treatment with warfarin sodium.\n\n          -  With the exception of alopecia and Grade 2, prior platinum-therapy related neuropathy,\n             any unresolved toxicities from prior therapy and/or pre-study biopsies greater than\n             CTCAE Grade 1 at the time of starting study treatment.\n\n          -  Spinal cord compression or brain metastases unless asymptomatic, stable and not\n             requiring steroids for at least 2 weeks prior to start of study treatment.\n\n          -  Severe or uncontrolled systemic diseases; known serious active infection; active\n             hepatitis B or C; cardiac disease; inadequate bone marrow reserve or organ function or\n             coagulation parameters; inadequate liver or renal function; GI events that would\n             preclude adequate absorption, distribution, metabolism or excretion of AZD9291,\n             AZD6094 or selumetinib; hipersensitivity to IP or similar drugs\n\n          -  Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation\n             pneumonitis which required steroid treatment, or any evidence of clinically active\n             ILD.
More than 30 days of exposure to an investigational or marketed agent that can act by EGFR inhibition, or a known EGFR-related toxicity resulting in dose modifications (EGFR inhibitors including but not limited to gefitinib, erlotinib and cetuximab)
Prior treatment of NSCLC with EGFR TKIs or monoclonal antibodies targeting EGFR
Prior or other EGFR inhibiting agents.
Prior EGFR tyrosine kinase inhibitor (TKI) therapy with progression, and documented EGFR T790M mutation on tumor biopsy; however, this need not be only second line
Progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including osimertinib [AZD9291] allowed for dose escalation only)
For the dose expansion portion ONLY, patient must: 1) have progression of disease with erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) tumors must be EGFR T790M negative confirmed by central testing prior to treatment (If EGFR-T790M status is unknown, patient may consent for trial for biopsy and testing for EGFR T790M will be performed as part of the initial biopsy for the trial: patients who test positive for EGFR T790M by central testing will be ineligible for the dose expansion), 3) be treatment naive for 3rd generation EGFR-TKI (CO-1686 and osimertinib [AZD9291]) and mTOR inhibitors
Known EGFR mutation status
Any prior treatment with erlotinib or other agent whose primary mechanism of action is known to inhibit EGFR
Any prior treatment with erlotinib or other agent whose primary mechanism of action is known to inhibit EGFR
For Phase 1 and Phase 2 Group B, progression after prior 1st or 2nd generation EGFR TKI (eg, erlotinib, gefitinib, afatinib). Previous chemotherapy for NSCLC is allowed.
For Phase 2 Group A, EGFR TKI treatment-naïve and chemotherapy-naïve
Previous EGFR-directed therapy
All subjects providing written informed consent will complete the subject history and screening form prior to MR imaging; the form will be reviewed to determine whether the subject is at risk as defined above and the availability of an estimated glomerular filtration rate (eGFR) within six weeks of anticipated MR imaging; an eGFR result greater than six weeks prior to the MRI imaging date will be repeated and evaluated for renal function; subjects with an eGFR of < 30 mL/min/1.73 m^2 will be excluded from the study
Has acquired resistance to EGFR TKI according to the Jackman criteria (PMID: 19949011)
Has experienced clinical benefit from an EGFR TKI, followed by systemic progression of disease [Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1] or World Health Organization (WHO)] while on continuous treatment with an EGFR TKI
Demonstrates absence of EGFR T790M mutation if treated with erlotinib, gefitinib, or afatinib. No EGFR mutation testing is required if treated with osimertinib.
Any cytotoxic chemotherapy, investigational agent or other anticancer drug(s) from a previous cancer treatment regimen or clinical study (other than EGFR TKI), within 14 days of the first dose of study treatment
Prior treatment with a VEGF receptor TKI within a time period equivalent to 5 half-lives of the prior TKI (e.g., there should be no substantial amount of TKI remaining in the patient)
Patients should be potential candidates for therapy with an EGFR tyrosine kinase inhibitor or with an anti-EGFR monoclonal antibody by clinical criteria
Patients should have clinical characteristics that would suggest an increased probability of benefit from an EGFR inhibitor; specifically, they should have known EGFR mutations or high gene copy number
EGFR genotype must not be known; however, pending EGFR tumor genotyping is allowed\r\n* Participants with positive or pending EGFR mutation on plasma genotyping performed at the central lab are eligible for enrollment, and will not need to repeat initial plasma genotyping on study
Participants must not have had prior treatment with an EGFR kinase inhibitor, EGFR directed therapy or investigational agent
Patients with EGFR mutations expected to be sensitive to EGFR inhibitors and patients with EML4/ALK translocations are excluded, unless all available Food and Drug Administration (FDA)-approved targeted therapy options have been utilized; for example, a patient with exon 19 EGFR mutation who has never been treated with an EGFR inhibitor would be excluded; patients with other sensitizing mutations that become actionable with FDA-approved targeted therapies during the course of this trial (e.g., crizotinib for MET deletion 14) will also be expected to have utilized all available FDA-approved targeted therapy options prior to eligibility\r\n* Note: In contrast to the above, a patient with an EGFR mutation who has been treated with a first-generation and third generation tyrosine kinase inhibitors (TKIs) and then with four cycles of carboplatin plus pemetrexed would be eligible
BCR-ABL1-rearranged (Ph+) ALL
Negativity for the Philadelphia chromosome must be established by conventional cytogenetics, fluorescence in situ hybridization (FISH) and/or polymerase chain reaction (PCR); patients who are negative for the Philadelphia chromosome by conventional cytogenetics must have FISH or PCR performed for BCR/ABL to exclude occult translocations
Patients with BCR-ABL1 fusion are not eligible for post-induction therapy on this study but may be eligible to enroll in a successor Children's Oncology Group (COG) Philadelphia positive (Ph+) ALL trial by day 15 Induction
Patients with Philadelphia chromosome positive/breakpoint cluster region protein (BCR)-Abelson murine leukemia viral oncogene homolog 1 (ABL1)+ ALL are not eligible
Patients must have a new morphologic diagnosis of precursor B cell acute lymphoblastic leukemia (ALL) (non T cell) based on World Health Organization (WHO) criteria; patients with Burkitt's (L3) are excluded; patients with Ph-positive or Ph-like ALL with dasatinib-sensitive mutations or kinase fusions may have relapsed or refractory diagnoses\r\n* NOTE: Relapsed/refractory Ph-positive patients or Ph-like patients with dasatinib-sensitive mutations or kinase fusions who have previous exposure to either dasatinib or another 2nd or 3rd generation TKI will begin protocol therapy with Cohort 2: re-induction cycle 1
Patients must have a diagnosis of Philadelphia chromosome negative ALL or Ph chromosome positive ALL by cytogenetics, fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR); patients will be registered to receive treatment in either Cohort 1 (ph-) or Cohort 2 (Ph+ or Ph-like DSMKF) based on these results; diagnostic specimens must be submitted to the site’s local Clinical Laboratory Improvement Amendments (CLIA)-approved cytogenetics laboratory and results of tests (cytogenetics, FISH or PCR) must confirm Ph status prior to registration; if not already known, breakpoint cluster region- abelson murine leukemia viral oncogene homolog 1 (BCR-ABL) status (p190 or p210) must be evaluated in Ph-positive patients by PCR\r\n* For Cohort 2, Ph-like testing is not required specifically for this study; however, to be registered to Cohort 2 under the Ph-like DSMKF criterion, the patient must have a known or presumed activating Ph-like signature and dasatinib-sensitive mutation or kinase fusion, such as: ABL1, ABL2, colony stimulating factor 1 receptor (CSF1R), platelet derived growth factor receptor beta (PDGFRB), platelet derived growth factor receptor alpha (PDGFRA), or fibroblast growth factor receptor (FGFR)s that was otherwise identified as part of normal standard of care; prior to registering any patients with a known or presumed activating Ph-like signature and dasatinib-sensitive mutations or kinase fusions (DSMKF) treating physicians must confirm eligibility with the study chairs via email; the study chairs must respond via email with confirmation of patient eligibility prior to patient registration
Cohort 2, Ph-positive and Ph-like DSMKF Patients Only
Pretreatment cytogenetics must be performed on all patients; collection of pretreatment specimens must be completed within 28 days prior to registration to S1318; specimens must be submitted to the site’s preferred CLIA-approved cytogenetics laboratory; BCR-ABL status must be verified in Ph-positive patients by FISH, cytogenetics, and/or PCR prior to enrollment; if a patient is Ph-positive, PCR for both p190 and p210 must be sent
Patients known to have Philadelphia chromosome positive (Ph+) ALL must have either failed treatment or been intolerant to treatment with at least one second or third generation tyrosine kinase inhibitor
Patients known to have Philadelphia (Ph) positive (+) ALL are not eligible; leukemia cell samples will be obtained from all patients enrolled before starting protocol treatment and submitted for Philadelphia chromosome testing by either karyotyping, or breakpoint cluster region (bcr)/Abelson murine leukemia viral oncogene homolog 1 (abl1) translocation by fluorescent in situ hybridization (FISH) or by PCR; patients who are later found to have Ph+ ALL should have treatment on this trial discontinued and will not be considered in the evaluation
Patients with Philadelphia chromosome (Ph)+ ALL or blast crisis of CML must be refractory (not intolerant) to at least 2 second/third generation ABL kinase inhibitors (TKI)
Patients with Philadelphia chromosome (Ph)-positive ALL or Burkitt leukemia
Philadelphia chromosome (Ph)-positive ALL
Philadelphia chromosome positive (Ph+) patients must be refractory to or intolerant of standard tyrosine kinase inhibitor therapy
Patients may not be receiving any other investigational agents, or concurrent biological, chemotherapy, or radiation therapy; maintenance therapy with Food and Drug Administration (FDA)-approved targeted therapies (e.g. tyrosine kinase inhibitors for Philadelphia chromosome [Ph] positive [+] acute lymphoblastic leukemia [ALL], and FLT inhibitors for FLT3+ patients) will be allowed after day 60 disease assessment
Philadelphia-positive (Ph+) ALL
World Health Organization (WHO)-defined acute lymphoblastic leukemia and either:\r\n* Relapsed after achieving remission\r\n* Refractory to therapy\r\n* Newly diagnosed and ineligible for intensive chemotherapy induction\r\nNote: patients with T lineage and B lineage ALL are eligible for this trial; likewise, patients with Philadelphia chromosome positive (Ph+) (as long as they are not candidate for other therapies for Ph+) and Ph- ALL are eligible
Philadelphia chromosome/BCR-ABL1-positive B-lineage acute lymphoblastic leukemia (ALL) must have failed at least 1 second or third generation tyrosine kinase inhibitor (TKI) or be intolerant to TKIs
Patients >= 60 years of age with previously untreated Ph-positive ALL [either t(9;22) and/or BCR-ABL positive] (includes patients initiated on first course of hyper-CVAD before cytogenetics known).
PHASE I: Philadelphia chromosome positive ALL must have failed at least 1 TKI
PHASE II: Philadelphia chromosome positive ALL must have failed at least 1 TKI
Pediatric patients with acute lymphoblastic leukemia (ALL) that is t (9,22) positive in first remission are not eligible unless there is evidence of minimal residual disease after initial induction and/or consolidation treatment or the pediatric Philadelphia chromosome positive (Ph+) ALL is clinically refractory to available therapies with evidence of persistence in the bone marrow or peripheral blood.
Philadelphia chromosome (Ph)+ ALL
CELL PROCUREMENT: Subjects with Philadelphia chromosome (Ph)+ ALL will be eligible if they have failed >= 2 ABL tyrosine kinase inhibitors; subjects with the T315I ABL kinase point mutation will be eligible if they have failed ponatinib-containing therapy, regardless of the number of prior ABL tyrosine kinase inhibitors
Patients must have a diagnosis of Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase by having met all of the following criteria at the time of their initial diagnosis\r\n* Cytogenetic confirmation of Philadelphia chromosome or variants of the t(9;22) translocations; patients may have secondary chromosomal abnormalities in addition to the Philadelphia chromosome\r\n* Peripheral blood or bone marrow blast count < 10%\r\n* Peripheral blood basophil count < 20%\r\n* Platelet count >= 100,000 x 10^9/L\r\n* If the peripheral blood counts are unavailable from the time of their original diagnosis, but there is no evidence of accelerated or blast-phase disease from prior clinical or other medical records, then they will be allowed to participate
Philadelphia chromosome (Ph)-positive ALL
Diagnosis of Philadelphia chromosome positive (Ph+) (by cytogenetics or FISH) or BCR-ABL+ (by polymerase chain reaction [PCR]) CML in CP (cohort 1), AP (cohort 2) or BP (cohort 2)
Patients with a diagnosis of Philadelphia chromosome (Ph)+ ALL are not eligible
For patients with Philadelphia chromosome positive (Ph+) disease, have previously received treatment with >= 1 Abelson (ABL) kinase inhibitor (e.g., imatinib, dasatinib, etc.) or are ineligible for such treatment
Philadelphia chromosome positive acute lymphoblastic leukemia
Diagnosis of Philadelphia chromosome (Ph)-positive or BCR-ABL positive CML in early chronic phase CML (i.e., time from diagnosis is 12 months); except for hydroxyurea, patients must have received no or minimal prior therapy, defined as < 1 month (30 days) of prior Food and Drug Administration (FDA) approved tyrosine kinase inhibitor (TKI)
Patients with Philadelphia chromosome positive (Ph+) ALL are eligible if they are intolerant to or have failed tyrosine kinase inhibitor therapy
Participants with ALL with Philadelphia chromosome or with an ABL class targetable fusion are eligible.
Confirmation of Philadelphia chromosome positivity by cytogenetics (karyotype/fluorescence in situ hybridization [FISH]) and/or molecular tests (BCR-ABL1 transcripts)
Ph-negative ALL
Patients with Philadelphia chromosome positive (Ph+) ALL can be enrolled in CR1 or CR2 and beyond; a tyrosine kinase inhibitor (TKI) will be added at the discretion of the treating physician; MRD for these patients will be defined by PCR of 0.1% and above (International Scale).
Patients 18 years or older with Philadelphia chromosome (Ph)-positive or BCR/ABL-positive CML (as determined by cytogenetics, FISH, or PCR).
Patients with previously untreated ALL of pre-B, Philadelphia chromosome (Ph-) negative ALL; minimal prior therapy (less than 1 week of steroids, vincristine, and/or 1 dose of anthracycline or alkylating agents) are allowed
Philadelphia chromosome negative myeloproliferative disease
Philadelphia chromosome positive (Ph+) B-cell ALL eligible for tyrosine kinase inhibitor therapy
Philadelphia chromosome-positive (Ph+) ALL
For patients with Philadelphia chromosome positive (Ph+) ALL, they must not have progressed within 3 months of receiving imatinib or have a documented ABL kinase mutation known to confer resistance to imatinib (e.g., T315I)
Patients with Philadelphia chromosome (Ph)+ ALL must have had two prior therapy attempts including two different tyrosine kinase inhibitors (TKIs)
All previous immunologic or molecularly targeted therapy must be completed at least 2 weeks prior to study entry; any prior non-hematologic toxicity of any previous therapy must have resolved to grade 1 or less, unless specified elsewhere, or except breakpoint cluster region/tyrosine-protein kinase ABL1 (BCR-ABL) tyrosine kinase in patients who have Philadelphia chromosome positive (Ph+) ALL, where there will be no washout period
Patients with Philadelphia chromosome positive (Ph+) ALL are eligible if they are intolerant to or have failed 2 lines of tyrosine kinase inhibitor therapy (TKI), or if TKI therapy is contraindicated OR
Patients with Philadelphia chromosome positive (Ph+) ALL are eligible if they are intolerant to or have failed 2 lines of tyrosine kinase inhibitor therapy (TKI), or if TKI therapy is contraindicated OR.
AML participants who are Philadelphia chromosome positive must have received ? 2 lines of therapy, including 2 bcr-abl tyrosine-kinase (TK) inhibitors (among imatinib, nilotinib and dasatinib), or only 1 line including 1 TK inhibitor if the relapse/refractoriness is associated with the detection of a resistance mutation to these inhibitors
Confirmed Philadelphia Chromosome positive Chronic Myeloid Leukemia or Confirmed BCR-ABL1 (Abelson-break point cluster) Positive if Philadelphia Chromosome negative Chronic Myeloid Leukemia (from initial diagnosis).
Prior treatment with 1 or more tyrosine kinase inhibitor drugs (imatinib, dasatinib and/or nilotinib) for Philadelphia Chromosome positive Chronic Myeloid Leukemia (CML).
Philadelphia chromosome (Ph)+ ALL
Ph+ CML; the diagnosis of chronic phase CML based on cytogenetic detection of the Ph chromosome and/or detection of the breakpoint cluster region (BCR)-Abelson (ABL) rearrangement by molecular analysis (recombinant deoxyribonucleic acid [DNA] analysis of the BCR-ABL fusion gene, fluorescence in situ hybridization, or polymerase chain reaction detection of the BCR-ABL hybrid messenger ribonucleic acid [mRNA])
Confirmed new diagnosis of Philadelphia chromosome-positive or BCR-ABL1 positive precursor B cell acute lymphoblastic leukemia (B-ALL) based on >= 20% lymphoblasts in bone marrow or blood; outside specimens will be subject to central review at the Huntsman Cancer Institute (HCI) Department of Pathology; BCR-ABL1 or Philadelphia-chromosome positivity may be determined by polymerase chain reaction (PCR), conventional cytogenetics and/or fluorescence in situ hybridization (FISH)
Presence of the Philadelphia chromosome t(9;22)
Relapsed or refractory B-ALL due to receive salvage 1, 2, 3, 4, 5, or 6; half of the patients, i.e. 5 out of the first 10 patients, and 5 out of 10 patients thereafter, need to be in earlier line of salvage therapy, defined as 1st, 2nd, or 3rd line of salvage therapy; Philadelphia chromosome-positive (Ph+) B-ALL patients must have failed treatment with at least 1 second generation tyrosine kinase inhibitor; patients in salvage 1 with late relapse should be deemed poor candidates for reinduction with initial therapy; patients with ALL of T cell origin (T-ALL) can not be treated
Chromosome 5q deletion
Philadelphia chromosome negative myeloproliferative disease (including myelofibrosis)
Patients with Philadelphia chromosome (Ph) positive (+) pre-B cell ALL OR Ph+ MPAL will be eligible if they have been refractory to or intolerant of treatment with at least 1 second-generation or third-generation tyrosine kinase inhibitor (TKI)
Phase II Group 1 (EGFRmut, any T790M, any c-MET, 2/4L antineoplastic, EGFR TKI resistant) only: Patients demonstrated a documented clinical benefit (CR (any duration), PR (any duration), or SD for at least 6 months) on prior EGFR TKI (e.g. erlotinib, gefitinib or afatinib, and subsequently demonstrated progression according to RECIST v1.1.
Phase II Group 2 (EGFRmut, de novo T790M, any c-MET, 1/3L antineoplastic, EGFR TKI naïve) only: Advanced NSCLC patients who have not been previously treated with any therapy known to inhibit EGFR and harbor de novo T790M mutation .
Phase II Group 3 (EGFRmut, T790M negative, any c-MET, 1L antineoplastic) only: patients must harbor an EGFR activating mutation and must be naïve from any line of systemic antineoplastic therapy in the advanced setting.
Phase II Group 4 (EGFRmut, any T790M, any c-MET, 1L (treatment-naïve), 2//3L antineoplastic): All patients must harbor an EGFR activating mutation and 2/3L patients must have failed (defined as intolerance to treatment or documented disease progression) a maximum of 2 prior lines of antineoplastic therapy in the advanced setting
Phase II Group 1 (EGFRmut, any T790M, any c-MET, 2/4L antineoplastic, EGFR TKI resistant):
Phase II Group 2 (EGFRmut, de novo T790M, any c-MET, 1/3L antineoplastic, EGFR TKI naïve):
Phase II Group 3 (EGFRmut, T790M negative, any c-MET, 1L antineoplastic):
Phase II Group 4 (EGFRmut, any T790M, any c-MET, 1/3L antineoplastic):