Organ function requirements for patients with Ph-like ALL and a predicted TKI-sensitive mutation: patients identified as Ph-like with a TKI-sensitive kinase mutation must have assessment of organ function performed within  days of study entry onto the dasatinib arm of AALL
For Arm A: must have received  prior line of therapy with an EGFR TKI and confirmed TM negative
Receipt of an EGFR TKI within  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  or more next-generation ALK-TKI(s)\r\n* EGFR-mutant NSCLC (Cohorts A and C): Participants must have progressed on or after  or more third-generation, TM mutant-selective EGFR-TKI(s)
Phase :\r\n* Cohort A: RET-positive NSCLC subjects must have received at least one prior line of therapy, but must be RET TKI-naive\r\n* Cohort B: RET-positive NSCLC that has previously been treated with one RET TKI; subjects cannot have received more than one prior RET TKI and must not have received prior alectinib\r\n* Cohort C: RET-positive thyroid cancer, must be radioactive iodine refractory
Participant has had prior chemotherapy, targeted cancer therapy, immunotherapy, or treatment with an investigational anticancer agent within  weeks or  half-lives whichever is longer, before the first administration of JNJ-. For agents with long half-lives, the maximum required time since last dose is  weeks. Toxicities from previous anticancer therapies should have resolved to baseline levels or to Grade  or less, (except for alopecia [any grade] and Grade less than or equal to [=<]  peripheral neuropathy). For Part  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  insertions). Cohort C: Prior treatment with more than  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  insertions (such as poziotinib)
Acquired resistance to EGFR TKI (st or nd gnration)
Prior treatment with rd generation TKI
Has documented disease progression while receiving at least  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\ TM EGFR mutation).
Prior or ongoing treatment with any of the following:\r\n* EGFR targeted therapy (TKI or antibody) or any other targeted therapies targeting the ERBB family\r\n* Any cytotoxic chemotherapy, investigational agents, or anticancer drugs for the treatment of advanced NSCLC
Prior or ongoing treatment with any of the following:\r\n* EGFR targeted therapy (TKI or antibody) or any other targeted therapies targeting the ERBB family\r\n* Any cytotoxic chemotherapy, investigational agents, or anticancer drugs for the treatment of metastatic NSCLC
Progression on a first generation EGFR TKI (TM negative), or progression on a third generation TKI (if TM 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
Less than  days from prior treatment with EGFR TKI; patients with adverse events related to prior EGFR TKI must recover to Common Terminology Criteria for Adverse Events (CTCAE) =< grade  to be eligible
Radiological documentation of disease progression while on a previous continuous treatment with an EGFR TKI, e.g., gefitinib or erlotinib. In addition, other lines of therapy may have been given. All patients must have documented radiological progression on the last treatment administered, prior to enrolling in the study.
Confirmation that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity (including GX, exon  deletion, LR, LQ) 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  days or approximately  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
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
Cytotoxic chemotherapy, investigational agents, or any anticancer therapy for the treatment of advanced NSCLC (other than EGFR TKI) within  days of the first dose of study treatment
- days from prior TKI depending on half-life.
Previous treatment with osimertinib, or a rd generation EGFR TKI. NOTE: Patients who are receiving initial osimertinib (- 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
Patients must discontinue previous EGFR-TKI at least  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
Has acquired resistance to EGFR TKI according to the Jackman criteria (PMID: ):
Has experienced clinical benefit from an EGFR TKI, followed by systemic progression (Response Evaluation Criteria in Solid Tumors [RECIST version .] or World Health Organization [WHO]) while on continuous treatment with an EGFR TKI.
Any cytotoxic chemotherapy, immune checkpoint inhibitor therapy, investigational agent or other anticancer drug(s) from a previous cancer treatment regimen or clinical study (other than EGFR TKI), within  days of the first dose of study treatment.
Prior treatment with any pan-HER TKI (eg, lapatinib, afatinib, dacomitinib, neratinib).
Patients must be actively receiving treatment for their CML with a TKI: imatinib, dasatinib, nilotinib, or bosutinib\r\n* Patients must be on a stable dose of their TKI for at least  year prior to enrollment onto trial
Loss of MMR following a first TKI discontinuation trial
Known history of ABL-domain mutation that predicts resistance to the discontinued TKI
Unable to receive TKI for insurance reasons (uninsurable)
Prior treatment with neoadjuvant or adjuvant EGFR-TKI at any time
Phase : Subjects must not have received more than  prior line of therapy for locally advanced or metastatic NSCLC. First-line treatment must include an EGFR TKI, and subjects must have documented disease progression during or following treatment. Subjects with disease that progressed more than  months after completion of neoadjuvant/adjuvant chemotherapy or chemoradiation therapy are eligible if they received an EGFR TKI as first-line treatment for advanced NSCLC.
Have Chronic Phase Chronic Myeloid Leukemia (CP-CML) and have received at least two prior tyrosine-kinase inhibitor (TKI) therapies and have demonstrated resistance to treatment OR have documented history of presence of T mutation after receiving any number of prior TKI a. The diagnosis of CML will be made using standard hematopathologic and cytogenetic criteria; CP-CML will be defined by all of the following: i) < % blasts in bone marrow ii) < % blasts plus promyelocytes in bone marrow iii) < % basophils in peripheral blood iv) ?   /L platelets (? ,/mm^) v) No evidence of extramedullary disease except hepatosplenomegaly vi) No prior diagnosis of accelerated phase (AP-CML), and blastic phase (BP-CML) b. Cytogenetic assessment at screening must demonstrate the BCR-ABL fusion by presence of the t(;) Philadelphia chromosome i) Variant translocations are only allowed provided they are assessable for cytogenetic response utilizing conventional cytogenetic techniques c. Resistance to prior TKI therapy is defined as follows (participants must meet at least  criterion): i) Three months after the initiation of prior TKI therapy: No cytogenetic response (> % Ph+) or failure to achieve complete hematologic response (CHR) or new mutation ii) Six months after the initiation of prior TKI therapy: BCR-ABLIS >% and/or Ph+ >% or new mutation iii) Twelve months after the initiation of prior TKI therapy: BCR ABLIS >% and/or Ph+ >% or new mutation. iv) At any time after the initiation of prior TKI therapy, the development of a new BCR-ABL kinase domain mutation(s). v) At any time after the initiation of prior TKI therapy, the development of new clonal evolution vi) At any time after the initiation of prior TKI therapy, the loss of CHR, or complete cytogenic response (CCyR), or the confirmed loss of molecular response rate (MRR) in  consecutive tests, one of which has a BCR-ABLIS transcript level of ?% or new mutation d. > % of BCR-ABLIS as shown by real-time polymerase chain reaction
Patients who have received more than one prior line of EGFR TKI therapy (applies only to Group )
Participants must be within  months of initiating TKI treatment, which specifically targets the actionable mutation their tumor harbors (i.e., first-line TKI, or a next-line TKI that targets tumors with acquired resistance to first-line TKI)
Patients must be on continuous TKI therapy for management of their CML. Any commercially available and FDA- approved TKI can be used, i.e., imatinib mesylate (IM), nilotinib (NIL) or dasatinib (DAS). Patients may be receiving TKI at entry in the frontline or salvage setting, including patients currently on imatinib after alpha-interferon failure or on dasatinib or nilotinib after failure to prior therapy including imatinib.
Patients must have received the current TKI for at least  months and not have increased their dose in the last  months.
Patients must not have had a known interruption of TKI therapy of greater than  consecutive days or for a total of  weeks in the  months prior to enrollment.
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  days or approximately  x half-life, whichever is longer, of the first dose of study treatment
Have not received a TKI with pan-HER activity (eg, afatinib, neratinib, or dacomitinib).
Patients who have received prior treatment with an EGFR TKI including in the adjuvant setting
Investigator-determined radiographic disease progression per RECIST . after treatment with an EGFR TKI therapy: a) Participants previously treated with st or nd generation EGFR TKI (e.g. erlotinib/afatinib/gefitinib) are required to have confirmed documented absence of EGFR TM mutation; b) Participants with confirmed acquired TM mutation after st or nd 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 st line therapy are eligible regardless of their EGFR TM mutation status.
REGISTRATION TO TREATMENT (STEP ): The patient has to be on first-line TKI therapy (the same TKI) for at least  years prior to registration\r\n* Dasatinib:    mg per day\r\n* Imatinib:    mg per day\r\n* Nilotinib:    mg every - hours
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  days prior to planned\n             initiation of rociletinib
No intervening treatment between cessation of single agent EGFR TKI and planned\n             initiation of rociletinib
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
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 rd generation EGFR-TKI including AZD allowed for dose escalation)
Patients must discontinue previous EGFR-TKI at least  days prior to study enrollment
For the most recently received VEGFR-targeting TKI there must have been progression of disease as determined by the treating physician either (i) during treatment or (ii) within  mo following completion of at least  weeks of treatment with the TKI
Prior treatment with a VEGFR TKI (including pazopanib) (Phase  only)
Phase Ib only: documented progression of disease according to RECIST v. while on continuous treatment with EGFR TKI (e.g.: erlotinib, gefitinib or afatinib).
Phase II Group  (EGFRmut, any TM, any c-MET, /L antineoplastic, EGFR TKI resistant) only: Patients demonstrated a documented clinical benefit (CR (any duration), PR (any duration), or SD for at least  months) on prior EGFR TKI (e.g. erlotinib, gefitinib or afatinib, and subsequently demonstrated progression according to RECIST v..
Patients who have received more than three prior lines of antineoplastic therapies (including EGFR TKI) in advanced setting.
Phase II Group  (EGFRmut, any TM, any c-MET, /L antineoplastic, EGFR TKI resistant):
More than  prior lines of systemic antineoplastic therapies (including EGFR TKI) in the advanced setting
More than  previous treatment line with st or nd generation EGFR TKI (e.g. erlotinib, gefitinib, afatinib) in the advanced setting
Previous treatment with an investigational or marketed rd generation EGFR TKI (e.g. AZD, CO-, ASP, EGF)
Previous treatment with an investigational or marketed agent known to inhibit EGFR (e.g. EGF monoclonal antibody therapy, dual TKI inhibitor).
Phase II Group  (EGFRmut, de novo TM, any c-MET, /L antineoplastic, EGFR TKI nave):
Previous treatment with an investigational or marketed rd generation EGFR TKI (e.g. AZD, CO-, ASP, EGF)
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          . Histologically or cytologically confirmed metastatic or unresectable locally advanced\n             NSCLC with radiological progression on the most recent therapy received\n\n          . Documented evidence of a tumor with  or more EGFR activating mutations excluding exon\n              insertion\n\n          . 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          . 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  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  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  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  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  days before\n             start of treatment.\n\n          . Have undergone a biopsy of either primary or metastatic tumor tissue within  days\n             prior to start of treatment and have tissue sent to the central laboratory prior to\n             randomization\n\n          . Measureable disease according to RECIST Version .\n\n          . Life expectancy of at least  months\n\n          . ECOG performance status of  to \n\n          . Age ?  years (in certain territories, the minimum age requirement may be higher\n             e.g., age ?  years in Japan and Taiwan, age ?  years in Singapore)\n\n         . Patients should have recovered to National Cancer Institute (NCI) Common Terminology\n             Criteria for Adverse Events (CTCAE) Grade ?  from any significant\n             chemotherapy-related toxicities\n\n         . Adequate hematological and biological function\n\n         . 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          . Any other malignancy associated with a high mortality risk within the next  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 >  months prior and/or bone marrow transplant >  years\n             prior\n\n          . Known pre-existing interstitial lung disease\n\n          . Tumor small cell transformation by local assessment, irrespective of presence of\n             TM+ component\n\n          . 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  weeks prior to randomization and the patient is\n             neurologically stable i.e. free from new symptoms of brain metastases)\n\n          . 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          . Prior treatment with rociletinib, or other drugs that target TM+ mutant EGFR with\n             sparing of WT-EGFR including but not limited to osimertinib, HM, and TAS-\n\n          . 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          . Any of the following cardiac abnormalities or history:\n\n               . Clinically significant abnormal -lead ECG, QT interval corrected using\n                  Fridericia's method (QTCF) >  msec\n\n               . Inability to measure QT interval on ECG\n\n               . Personal or family history of long QT syndrome\n\n               . Implantable pacemaker or implantable cardioverter defibrillator\n\n               . Resting bradycardia <  beats/min\n\n          . Non-study related surgical procedures ?  days prior to randomization. In all cases,\n             the patient must be sufficiently recovered and stable before treatment administration\n\n         . Females who are pregnant or breastfeeding\n\n         . Refusal to use adequate contraception for fertile patients (females and males) while\n             on treatment and for  months after the last dose of study treatment (rociletinib and\n             chemotherapy irrespective of single cytotoxic agent used)\n\n         . 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         . Any other reason the investigator considers the patient should not participate in the\n             study\n\n         . Treatment with live vaccines initiated less than  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  weeks before study enrollment. For Part B-LM expansion, patients who received previous EGFR TKI treatment must have stable extracranial disease;EGFR TKI treatment nave patients can also be enrolled into AZD cohorts, or AZD cohorts if efficacy signal seen in Part A and agreed by Safety Review Committee.
Treatment with an EGFR TKI (e.g., erlotinib or gefitinib) within  days or approximately  x half-life, whichever is the longer, of the first dose of study treatment.
Patients are not eligible if they have an intolerance to most recent prior TKI (other than dasatinib) at the lowest possible effective dose, defined as a grade >=  toxicity considered at least possibly related to that TKI; patients are also excluded if they are intolerant or allergic to dasatinib and discontinued prior therapy due to a >= grade  treatment related adverse event
Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI
Prior treatment with an EGFR-TKI.
Patient has been on TKI therapy for at least  years
Patients who have been resistant to previous TKI therapy are not eligible
Radiological documentation of disease progression following st line EGFR TKI Treatment without any further treatment
Treatment with an approved EGFR-TKI (e.g.,erlotinib, gefitinib, afatinib) within  days or approximately x half-life of the first dose of study treatment
Previous treatment with AZD, or a rd generation EGFR TKI For subjects who cross-over to AZD:
Inclusion:\n\n          -  Aged at least  years. Japan patients aged at least  years.\n\n          -  Locally advanced/metastatic NSCLC not amenable to curative surgery or radiotherapy\n\n          -  Radiological documentation of disease progression:\n\n        following st 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 st 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 GX, exon  deletion, LR, LQ). Patients must\n             have central confirmation of tumour TM 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 - with no deterioration over the\n             previous  weeks and a minimum life expectancy of  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 ? mm in the\n             longest diameter (except lymph nodes which must have short axis ? mm) 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  days of study entry; any cytotoxic chemotherapy,\n             investigational agents or other anticancer drugs within  days of study entry;\n             previous treatment with AZD (or rd generation TKIs); major surgery within \n             weeks; radiotherapy treatment to more than % of the bone marrow or with a wide field\n             of radiation within  weeks; current treatment with potent inhibitors of CYPC and\n             potent inhibitors/inducers of CYPA.\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.
Previous therapy with any HER TKI (such as trastuzumab, lapatinib, neratinib, etc.) for any malignancy.
Radiological documentation of disease progression while on a previous continuous treatment with an EGFR TKI e.g. gefitinib or erlotinib (with the exception of st line expansion cohort). In addition other lines of therapy may have been given. All patients must have documented radiological progression on the last treatment administered prior to enrolling in the study.
Must have experienced clinical benefit from EGFR TKI, according to the Jackman criteria (Jackman et al ) 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  days (approximately x half-life) of the first dose of study treatment.
History of previous response to EGFR-TKI, defined as either a PR by Response Evaluation Criteria in Solid Tumors (RECIST) . criteria, or at least six months without progressive disease as a result of EGFR-TKI therapy
Progressive disease as measured via RECIST . following EGFR-TKI therapy (with =<  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)
Participants may have received prior TKI therapy, however must be on a stable dose of their current TKI for at least one month prior to enrollment
Any type of systemic therapy (chemotherapy or experimental drugs) within  weeks of starting treatment on protocol except for a EGFR TKI
Patient may not have been resistant to any other prior TKI therapy; prior TKI therapy must only have been discontinued due to intolerance
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 TM negative.
Subject received an EGFR TKI for at least  months and progressed on this therapy within the past  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  days prior to the first dose of study drug.
Received prior EGFR TKI therapy for recurrent or metastatic SCC (e.g., oral EGFR TKIs such as erlotinib, gefitinib, or afatinib)
Patients must have documented clinical benefit (CR, PR, or patients with SD for  months or greater) on prior EGFR TKI (e.g. erlotinib or gefitinib) followed by documented progression according to RECIST.
ERLOTINIB HYDROCHLORIDE ARM: Previous anti-EGFR TKI therapy
ERLOTINIB HYDROCHLORIDE ARM: Patients with a known EGFR TKI resistant mutation
For Part , the patient has not received prior treatment with a TKI.
Part d: Patients with non GIST solid tumors with KIT mutations, who are TKI nave or have been previously treated with KIT directed TKI therapy who are appropriate for KIT directed TKI therapy
Prior treatment with an EGFR TKI; in Phase , prior treatment with a TM-directed EGFR TKI for patients in Group B. Previous chemotherapy is allowed; in Phase , immediate prior therapy must be EGFR TKI
Part A: Progression of disease (RECIST .) while on continuous treatment with single EGFR TKI or for histology other than adenocarcinoma and without prior EGFR TKI treatment: progression of disease (RECIST v.) on platinum-based chemotherapy. Part B: Progression of disease (RECIST v.) 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  prior EGFR TKI treatment regimens for Part B
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. AZD or CO-)
Any type of systemic therapy (chemotherapy or experimental drugs) within  weeks of starting treatment on protocol except for erlotinib or other EGFR TKI
(summarized due to limitation of characters)\n\n        Inclusion Criteria:\n\n          . Written informed consent\n\n          . Aged at least  years ( years for Japan)\n\n          . 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          . 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 rd generation TKI: at least one prior line of therapy\n                  with st or nd generation EGFR TKI, but not a rd generation (TM-directed)\n                  EGFR TKI.\n\n               -  Prior treatment with a rd generation TKI: at least one prior line of therapy\n                  with a rd generation (TM-directed) EGFR TKI for EGFRm or TM+ NSCLC.\n\n             Part B cMET-ve patients:\n\n               -  TM directed EGFR TKI patients only: their immediate prior therapy before entry\n                  into this study must be a TM directed EGFR TKI.\n\n               -  ?nd line cohort: patients must have progressed while on treatment with an EGFR\n                  TKI (TM 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 rd generation TKI, TM negative:\n\n             Patients must have received at least one prior line of therapy with st or nd\n             generation EGFR TKI, but not a rd generation (TM directed) EGFR TKI.\n\n          . 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             TM status: Local confirmation of tumour TM 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          . At least one lesion, not previously irradiated, not biopsied during the screening\n             period, that can be accurately measured at baseline as ? mm in the longest diameter\n             (except lymph nodes which must have short axis ? mm) with CT or MRI which is\n             suitable for accurate repeated measurements\n\n          . WHO performance status - with no deterioration over the previous  weeks and minimum\n             life expectancy of  weeks\n\n          . 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 x 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  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 CYPA (at least  weeks prior). For AZD patients currently\n             receiving (or unable to stop use at least  weeks) prior to receiving the first dose,\n             medications known to be strong inhibitors of CYPA. Prior AZD dosing in the\n             present study. Prior or current treatment with AZD or another cMET inhibitor (if\n             allocated to AZD + AZD). Radiotherapy with a limited field of radiation for\n             palliation within  week of the first dose of study treatment, with the exception of\n             patients receiving radiation to more than % of the bone marrow or with a wide field\n             of radiation which must be completed within ? 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  weeks of the first dose of\n             study treatment. Currently receiving treatment with warfarin sodium.\n\n          -  With the exception of alopecia and Grade , prior platinum-therapy related neuropathy,\n             any unresolved toxicities from prior therapy and/or pre-study biopsies greater than\n             CTCAE Grade  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  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 AZD,\n             AZD 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.
New onset or worsening of fatigue since starting TKI
Progressive disease on at least one prior EGFR-TKI (previous treatment with rd generation EGFR-TKI including osimertinib [AZD] allowed for dose escalation only)
Grade >=  thrombocytopenia (platelets <  x ^/L) after the first  months of therapy with the TKI for patients with CML and platelets <  x ^/L for patients with MF after the first  months of therapy; thrombocytopenia must be either recurrent (i.e., second or greater episode of thrombocytopenia) or having required dose reductions of the TKI
Subject is anticipated to have therapy with TKI continued for >=  months
Thrombocytopenia that is considered to be unrelated to treatment with TKI or accelerated phase as defined above
For Phase  and Phase  Group B, progression after prior st or nd generation EGFR TKI (eg, erlotinib, gefitinib, afatinib). Previous chemotherapy for NSCLC is allowed.
For Phase  Group A, EGFR TKI treatment-nave and chemotherapy-nave
Has acquired resistance to EGFR TKI according to the Jackman criteria (PMID: )
Has experienced clinical benefit from an EGFR TKI, followed by systemic progression of disease [Response Evaluation Criteria in Solid Tumors (RECIST) version .] or World Health Organization (WHO)] while on continuous treatment with an EGFR TKI
Any cytotoxic chemotherapy, investigational agent or other anticancer drug(s) from a previous cancer treatment regimen or clinical study (other than EGFR TKI), within  days of the first dose of study treatment
Prior treatment with a VEGF receptor TKI within a time period equivalent to  half-lives of the prior TKI (e.g., there should be no substantial amount of TKI remaining in the patient)
TKI treatment failure will be defined as  of the following: