Prior anticancer therapy is allowed (excluding approved or investigational Trk, ROS1, or ALK inhibitors in patients who have tumors that harbor those respective gene rearrangements)
Note: prior treatment with crizotinib is permitted only in ALK- or ROS1-rearranged NSCLC patients presenting with CNS-only progression. Other ALK inhibitors are prohibited.
Prior treatment with approved or investigational Trk, ROS1, or ALK inhibitors in patients who have tumors that harbor those respective gene rearrangements
Note: prior treatment with crizotinib is permitted only in ALK- or ROS1-rearranged NSCLC patients presenting with CNS-only progression. Other ALK inhibitors are prohibited.
Positive for translocation or inversion events involving the ALK gene locus (e.g. resulting in echinoderm microtubule associated protein like 4 [EML4]-ALK fusion) as determined by the Vysis Break Point fluorescence in situ hybridization (FISH) assay and defined by an increase in the distance between 5’ and 3’ ALK probes or the loss of the 5’ probe; this must have been performed:\r\n* By a local Clinical Laboratory Improvement Amendments (CLIA) certified laboratory: report must indicate the results as well as the CLIA number of the laboratory which performed the assay; tissue must be available for submission for central, retrospective confirmation of the ALK fusion status via ALCHEMIST-SCREEN (ALLIANCE A151216) OR\r\n* Patient registered to and the ALK fusion status performed centrally on the ALCHEMIST-SCREEN (ALLIANCE A151216)
No prior treatment with crizotinib or another ALK inhibitor
Patients whose biomarker profiling results indicate the presence of an EGFR mutation or echinoderm microtubule-associated protein-like 4 (EML4)/ALK fusion are not eligible
Non-squamous NSCLC histology with activating ALK and EGFR mutation
Tumors must harbor an alteration in ALK using a CLIA-certified laboratory, including, but not limited to, ALK^ATI, ALK fusions, or ALK mutations (for treatment phase)
Any prior ALK inhibition (for screening and treatment phases)
Cohort A1: Non-squamous NSCLC, with no activating EGFR mutations, ALK or ROS1 translocations/rearrangements. If monotherapy pembrolizumab is available as a standard of care treatment option, patients must have a tumor proportion score (TPS) <50% for PD L1 (via the 22C3 pharmDx or the Ventana (SP263) PD L1 IHC assay).
Tumors lack activating epidermal growth factor receptor (EGFR) mutations or ALK rearrangement (no EGFR or ALK testing is required if a subject has a KRAS mutation or squamous cell histology).
Histologically or cytologically confirmed advanced (stage IIIB or IV) non-small-cell lung cancer (NSCLC)\r\n* ALK-rearranged NSCLC: ALK rearrangement as assessed by ALK fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), or next-generation sequencing (NGS); for ALK FISH, rearrangements must be detected in > 15% of tumor cells\r\n* EGFR-mutant NSCLC: EGFR activating gene mutation (e.g., L858R, exon 19 deletion) as well as a T790M mutation per local testing
Presence of targetable EGFR mutations or ALK re-arrangements\r\n* All patients with adenocarcinoma histology must be tested for EGFR and ALK status, unless a KRAS mutation is detected in which case EGFR/ALK testing is not required
Patients are required to have an activating ALK aberration in their tumor detected by certified assay (i.e. CLIA in the US.) prior to registration. The report from this test is required to be submitted for eligibility. Patients with at least one of the following genetic features in their tumor will be considered to have an activating ALK aberration:
An ALK activating mutation;
ALK amplification (> 10 signals of the ALK gene);
Presence of any ALK fusion protein that arises from a chromosomal translocation.
NSCLC with EGFR or ALK mutation
ALCL, ALK negative
Participants with known EGFR mutations or ALK rearrangements; all subjects must have been tested for EGFR mutation and ALK rearrangement prior to study entry, unless they are known to have a KRAS mutation\r\n* Note: molecular testing is not required for squamous NSCLC
Patients whose tumour samples have targetable alterations in EGFR and/or ALK are excluded. In addition, patients whose tumour samples are known to have targetable alterations in ROS1, BRAF, MET or RET, are to be excluded.
Non-small cell lung cancer (subjects in Part B must either lack EGFR sensitizing mutation or ALK translocation per local test results, or must have progressed on approved standard of care treatment for EGFR or ALK positive NSCLC)
Molecular testing results from CLIA-certified laboratories (using tissue and/or blood) demonstrating anaplastic lymphoma kinase (ALK) gene rearrangements, ALK mutations, ALK copy number gain or (for melanoma only) increased ALK expression or presence of ALK-alternative transcription initiation transcript (ALKATI) a) For participants screened using a blood assay: obtain tissue-based testing result confirming study eligibility (within first 4 weeks after enrolment) Atezolizumab
ALK-positive NSCLC, neuroblastoma, and childhood tumors
Previous treatment with alectinib or any other ALK inhibitor
Pts with NSCLC must have ALK wild-type, EGFR wild-type, and ROS1 fusion negative Part 3: Locally advanced (unresectable) and/or metastatic cancer as follows:
EGFR and ALK status must be known in all patients with adenocarcinoma histology; patients with activating EGFR mutations or ALK translocations are excluded from this study, unless disease has progressed on all available, approved therapies targeting these alterations
Histologically or cytologically confirmed diagnosis of metastatic NSCLC according to the 7th edition of the AJCC Cancer Staging Manual. In addition, the NSCLC must harbor an ALK rearrangement, as assessed using the FDA approved Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular Inc.) test and scoring algorithm (including positivity criteria). If documentation of ALK rearrangement as described above is not locally available, a test to confirm ALK rearrangement must be performed by a Novartis designated central laboratory. Patients must wait for the central laboratory result of the ALK rearrangement status before initiating treatment with ceritinib
Patients whose tumors harbor an anaplastic lymphoma kinase (ALK) translocation must have progressed on or had intolerance to an ALK inhibitor;
The tumor must carry a genetic alteration of ALK
PART II: Alk PO4 =< 3 x ULN (except for patients with documented metastatic disease to bone and/or liver)
Have undergone appropriate standard of care treatment options (in the opinion of the treating investigator); participants with non-small cell lung carcinoma (NSCLC) must have undergone EGFR and ALK testing and have received appropriate initial therapy
For Part B and Part C, patients with tumors bearing genetic abnormalities for which health authority-approved targeted therapies exist will not be enrolled; e.g, patients with mutations including but not limited to ROS rearrangements, BRAF V600E, EGFR mutations or ALK translocation patients will not be considered eligible
Subjects may not have genomic aberrations such as ALK, EGFR, or BRAF for which there are FDA-approved targeted therapies available. Subjects may not have ROS1 aberration in accordance with the pembrolizumab label.
For lung adenocarcinoma patients, patients must be wild-type for EGFR and ALK. For patients with histologies other than adenocarcinoma, EGFR and ALK status is not required. Adenocarcinoma patients may be consented prior to the EGFR and ALK status being known, but EGFR and ALK status must be determined prior to initiating therapy. EGFR and ALK status may be determined using either tumor- or plasma-based, Clinical Laboratory Improvement Amendments (CLIA)-certified assays. For patients with non-small cell lung cancer (NSCLC), not otherwise specified (NOS), EGFR/ALK testing is not required, as the frequency of alterations is exceedingly rare in this histology. Also, note that patients with ROS1/RET alterations can be enrolled, as tyrosine kinase inhibitors (TKIs)/crizotinib aren’t established as first line therapy for patients with these alterations.
Histological or cytological diagnosis of advanced/metastatic solid tumor. Measurable disease by RECIST 1.1 with at least 1 measurable lesion that has not been previously irradiated. Availability of tumor specimen taken within 1 year prior to study entry, with no intervening systemic anti-cancer therapy. No prior PD-1/PDL-1 therapy allowed. Combination A: Phase 1b, patients with NSCLC that have progressed on standard therapy or for which no standard therapy is available, and Phase 2, patients with NSCLC, melanoma, SCCHN, TNBC in any line of therapy, SCLC, 1st line NSCLC. 1st line NSCLC must demonstrate to express PD-L1. Activating EGFR mutation, ALK, ROS1 translocation/rearrangements are not permitted. Combination B: Phase 1b, patients with advanced solid tumors (NSCLC, SCCHN, melanoma) that have progressed on standard therapy or for which no standard therapy is available, and Phase 2, patients with NSCLC, melanoma, or SCCHN. Up to 2 lines of prior therapy in advanced/metastatic disease setting allowed. Activating EGFR mutation, ALK, ROS1 translocation/rearrangements are not permitted. Combination C: Ovarian cancer, SCCHN, NSCLC, gastric cancer, platinum resistant ovarian cancer. Up to 2 lines of prior therapy in advanced/metastatic disease setting allowed. TGCT/PVNS that is either inoperable or requires extensive resection. Prior treatment with agents targeting CSF-1/CSF-1R not allowed. NSCLC activating EGFR mutation, ALK, ROS1 translocation/rearrangements are not permitted. Combination D: NSCLC, melanoma, SCCHN, bladder cancer. NSCLC activating EGFR mutation, ALK, ROS1 translocation/rearrangements are not permitted. Up to 2 lines of prior therapy in advanced/metastatic disease setting allowed.
Histologically or cytologically confirmed diagnosis of advanced solid tumor malignancy. Patients may be ALK TKI-naive or may have received prior crizotinib and/or second generation ALK TKIs. In addition, patients with a known ALK 1198 mutation will be allowed. -For the expanded cohort portion of the study, patients must have NSCLC with ALK genomic alterations; however, patients will be allowed to enroll based on local FDA-approved ALK results.
For phase I trial portion, treatment naive or patients previously treated with chemotherapy, immunotherapy or targeted therapy for NSCLC are allowed; patient who underwent curative intent chemotherapy and/or radiation in the neoadjuvant or adjuvant setting are allowed to enroll if tumor recurrence occurred greater than 6 months from completion of that therapy (and will be considered treatment naïve in the stage IV setting); patients with NSCLC tumor known to harbor a genomic aberration for which Food and Drug administration (FDA) approved treatment is available (i.e, non-resistant EGFR mutations, EGFR T790M mutation, ALK rearrangement, ROS rearrangement, BRAF V600E mutation) are allowed to enroll if they have received prior treatment with the FDA approved targeted therapy
For phase II trial portion, patients will be enrolled as two parallel cohorts:\r\n* Arm A (treatment naive): patients who are newly diagnosed and treatment naive; patient who underwent curative intent chemotherapy and/radiation in the neoadjuvant or adjuvant setting are allowed to enroll if tumor recurrence occurred greater than 6 months from completion of therapy; patients with NSCLC tumor known to harbor a genomic aberration for which FDA approved treatment is available (i.e, non-resistant EGFR mutations, EGFR T790M mutation, ALK rearrangement, ROS rearrangement, BRAF V600E mutation) are allowed to enroll if they have received prior treatment with the FDA approved targeted therapy\r\n* Arm B (pre-treated group): patients who have received prior immunotherapy; patients who are primary refractory to immunotherapy (i.e., patients who were previously treated with immunotherapy and did not at least achieve stable disease on first imaging assessment on immunotherapy) or have relapsed disease (i.e., patients that were treated with immunotherapy, achieved at least stable disease on first imaging assessment and subsequently developed disease progression or relapse); patients with NSCLC tumor known to harbor a genomic aberration for which FDA approved treatment is available (i.e, non-resistant EGFR mutations, EGFR T790M mutation, ALK rearrangement, ROS rearrangement, BRAF V600E mutation) are allowed to enroll if they have received prior treatment with the FDA approved targeted therapy
EGFR or ALK activating alteration
Subjects with EGFR or ALK genomic tumor aberrations should have documented disease progression on FDA-approved therapy for these aberrations; subjects with EGFR or ALK genomic tumor aberrations who develop isolated brain metastases with good response outside the central nervous system (CNS) while on FDA-approved therapy for these aberrations may be included at the discretion of the treating oncologist
If tumor demonstrates EGFR or ALK genomic tumor aberrations, subject should have documented disease progression on FDA-approved therapy for these aberrations
Patients with a known targetable EGFR mutation or ALK rearrangement
Patients with lung cancers harboring sensitizing EGFR or ALK mutations for whom tyrosine kinase inhibitors (TKIs) are approved for first line therapy
Patients with a known ALK-rearrangement must have progressed or been intolerant to treatment with at least one ALK TKI: crizotinib, ceritinib, alectinib, brigatinib, or loralatinib
Patients with PDL1 level of >= 50%, who do not have an ALK-rearrangement or EGFR-mutation, must have progressed or been intolerant to treatment with anti-PD1/PDL1 therapy (pembrolizumab, nivolumab, or atezolizumab)
Confirmation of the presence or absence of EGFR mutations and ALK gene fusions prior to study enrollment in all subjects. Subjects with known EGFR sensitizing mutational status or ALK fusion must have been treated and progressed on EGFR tyrosine kinase inhibitors (TKIs) or ALK-directed therapy, or with tumors harboring EGFR T790M mutation to have received and progressed on therapy directed at the T790M mutation (e.g. osimertinib). Subjects with known ROS1 translocation must have been treated and progressed on ROS1-directed therapy
Patients whose tumors contain activating EGFR mutations or ALK rearrangement should be excluded from this study, unless disease has progressed on all available, approved therapies targeting the EGFR mutation or ALK rearrangement
Prior treatment with an ALK, ROS1 or MET inhibitor
PHASE II DOSE EXPANSION COHORTS: \r\n* Documented ALK-­rearranged stage IIIB or IV NSCLC and:\r\n** Cohort A: No prior ALK inhibitor therapy (prior chemotherapy or immunotherapy is allowed)\r\n** Cohort B: Prior treatment with crizotinib and documented disease progression by RECIST 1.1 criteria\r\n** Cohort C: Prior treatment with 2nd generation ALK inhibitor (ALKi) (e.g. ceritinib, alectinib, loratinib, or brigatinib) and documented disease progression by RECIST 1.1 criteria
Subjects whose tumors harbor a mutation in EGFR exon 19 or 21 or have gene rearrangements in ALK or ROS1 must have already been treated with standard targeted therapies; NOTE: Subjects must also have progressed on or after platinum containing combination chemotherapy
Patients who are known to be EGFR- or ALK-positive must have received prior EGFR- or ALK-targeted therapy, respectively\r\n* NOTE: in such cases, documentation of EGFR mutation or ALK translocation status should be provided if available
Part D: Relapsed or refractory non-neuroblastoma, extracranial solid tumors with NTRK1/2/3, ROS1, or ALK gene fusions documented by a CLIA-approved lab prior to enrollment;
Patients with advanced (metastatic) NSCLC, whose disease progressed during or after platinum-based chemotherapy; patients with EGFR or ALK genomic tumor aberrations should have disease progression on Food and Drug Administration (FDA)- approved therapy for these aberrations prior to receiving nivolumab
Patients must have histologically or cytologically confirmed incurable non-small cell lung cancer that harbors an activating mutation in EGFR, MET, BRAF, V600E, RET, HER2, translocation in Alk, or translocation in ROS-1
Patients with advanced (metastatic) NSCLC, whose disease progressed during or after platinum-based chemotherapy; patients with EGFR or ALK genomic tumor aberrations (testing required for adenocarcinoma patients) should have disease progression on Food and Drug Administration (FDA) approved therapy for these aberrations prior to receiving nivolumab; these patients are eligible regardless of line of therapy
Patients with known activating EGFR mutations or ALK rearrangements should have progressed after appropriate targeted treatment in addition to progressing during or after platinum-based doublet chemotherapy
Sensitizing mutations in EGFR or rearrangements in ALK or ROS1
Treatment-naive systemic ALK-positive ALCL patients
Molecular confirmation of an anaplastic lymphoma kinase (ALK) rearrangement using ALK fluorescence in situ hybridization (FISH), immunohistochemistry (IHC) or next-generation sequencing (NGS); for ALK FISH, rearrangements must be detected in > 15% of tumor cells; if an ALK rearrangement has been detected by IHC or NGS, archival tissue must be available to confirm ALK positivity by FISH
Patients with no prior ALK-inhibitor therapy will be placed in cohort A, those treated with one prior line of ALK-inhibitor (at any time) will enter cohort B
Patients with characterized ALK-positive rearrangement
Known ALK mutation
Known actionable mutations, (e.g. EGFR, ALK, ROS1), against which there is an established effective targeted therapy
NSCLC subjects with EGFR mutations or ALK translocations should have previously received appropriate Food and Drug Administration (FDA) approved therapies in addition to prior chemotherapy
Patients whose tumors are positive for the sensitizing ALK fusion
Presence of activating EGFR mutations or ALK re-arrangement unless previously treated with standard TKI therapy; all patients with adenocarcinoma histology must be tested for EGFR and ALK status
For dose expansion cohort: patients with stage IIIB or IV ALK + NSCLC who have failed at least one line of therapy and are progressing on an ALK inhibitor; for dose expansion, patients who have ROS1 rearrangement testing by either next generation sequencing (NGS) or fluorescence in situ hybridization (FISH) will be eligible
Patients with epidermal growth factor receptor (EGFR) or transforming fusion gene EML4-ALK variant 4 (EML4-ALK) mutations
Inclusion:\n\n          1. Histologically or cytologically confirmed diagnosis of stage IIIB (and is not a\n             candidate for definitive multimodality therapy) or IV ALK-positive NSCLC.\n\n          2. Patients may have received one prior treatment regimen with crizotinib (all other ALK\n             inhibitors are excluded).\n\n          3. Patients may have received prior chemotherapy, biologic therapy, or other\n             investigational agents. ALK inhibitors other than crizotinib are excluded.\n\n          4. Patient has a World Health Organization (WHO) performance status 0-2.\n\n        Exclusion:\n\n          1. Prior treatment with an ALK inhibitor other than crizotinib.\n\n          2. History of carcinomatous meningitis.\n\n          3. Presence or history of a malignant disease other than an ALK-positive advanced tumor\n             that has been diagnosed and/or required therapy within the past 3 years.\n\n        5. Clinically significant, uncontrolled heart disease and/or recent cardiac event (within 6\n        months) 6. Patient has history of interstitial lung disease or interstitial pneumonitis,\n        including clinically significant radiation pneumonitis (i.e., affecting activities of daily\n        living or requiring therapeutic intervention).\n\n        7. Patient has other severe, acute, or chronic medical conditions 8. Patient is currently\n        receiving treatment with warfarin sodium (Coumadin®) or any other coumarin-derivative\n        anticoagulants.
Patients with EGFR mutations or ALK rearrangements must have disease progression on appropriate Food and Drug Administration (FDA)-approved therapy for these genomic aberrations prior to enrollment
Histologically or cytologically confirmed diagnosis of anaplastic thyroid cancer or undifferentiated thyroid cancer that demonstrates mutation in the ALK gene as assessed by sequencing of the tumor specimen for Arm A; other ALK abnormalities as detected by the approved fluorescence in situ hybridization (FISH) test (Abbott Molecular Inc), using Vysis breakapart probes (defined as 15% or more positive tumor cells); or the Ventana immunohistochemistry (IHC) test will also be seen as evidence of ALK abnormality and meeting eligibility requirement
Arms 1E, 2E and 3E: solid tumor that demonstrate anaplastic lymphoma kinase (ALK) positivity; ALK positivity can be assessed using the assays below, and documentation of ALK positivity using one of the tests below is required\r\n* Fluorescence in situ hybridization (FISH) test for ALK positivity using the Food and Drug Administration (FDA)-approved FISH test (Abbott Molecular Inc), using Vysis breakapart probes (defined as 15% or more positive tumor cells); OR\r\n* Harboring a confirmed ALK positivity, as determined by positivity to the Ventana immunohistochemistry (IHC) assay
Histologically-confirmed stage 4 NSCLC that: has not been treated with prior chemotherapy for metastatic disease and has high PD-L1 expression (ie, a TPS ? 50%), as determined by an FDA-approved test. Previous neoadjuvant/adjuvant chemotherapy is allowed if completed ? 6 months before diagnosis of metastatic disease.The subject's tumor must not harbor an EGFR sensitizing (activating) mutation or ALK translocation. EGFR sensitizing mutations are those mutations that are amenable to treatment with tyrosine kinase inhibitors including erlotinib, gefitinib, or afatinib. Investigators must be able to produce the source documentation of the EGFR mutation and ALK translocation status in all subjects with non-squamous histologies AND for subjects in whom testing is clinically recommended. If either an EGFR sensitizing mutation of ALK translocation is detected, additional information regarding the mutation status of the other molecule is not required. If unable to test for these molecular changes, formalin fixed paraffin embedded tumor tissue of any age should be submitted to a central laboratory designated by the Sponsor for such testing. Subjects with non-squamous histologies will not be randomized until the EGFR mutation status and/or ALK translocation status is available in source documentation at the site. For patients enrolled who are known to have a tumor of predominantly squamous histology, molecular testing for EGFR and ALK translocation will not be required as this is not standard of care and is not part of current diagnostic guidelines.
Have an EGFR or ALK genomic tumor aberrations for which targeted therapy with an EGFR or ALK inhibitor is indicated. Additional Exclusion Criteria for Cohort 2:
The patient must have failed at least one line of standard treatment, with the following exceptions in which a PD-1 antibody is Food and Drug Administration (FDA) approved in the first-line setting: \r\n* Melanoma patients\r\n* Non-small cell lung cancer patients without EGFR or ALK genomic tumor aberrations whose tumors have high PD-L1 expression (tumor proportion score [TPS] >= 50%) as determined by an FDA-approved test
Patients with sensitizing EGFR mutations and/or ALK gene rearrangements.
Patients with EGFR, ALK or ROS-1 mutations who are eligible for treatment with a TKI and who have not received such treatment
Patients with tumors having actionable genomic alterations should have received prior therapy with Food and Drug Administration (FDA) approved agents targeting these aberrations (ie EGFR, ALK, ROS1, BRAF V600E)
Patient has NSCLC with a targetable mutation in EGFR, ALK, or ROS1.
Prior therapies:\r\n* Patients without activating mutations and gene rearrangements should have received at least one prior chemotherapy regimen; any number of prior therapies is allowed except for immunotherapy (e.g. anti PD-1, PD-L1, vaccines, CTLA-4 etc.)\r\n* Patients with activating mutations and gene rearrangements with known documented benefit from tyrosine kinase inhibitors should have received and demonstrated progression with that inhibitor (e.g. EGFR del 19 mutation should have been treated with gefitinib, erlotinib or afatanib etc); ALK rearrangements should have been treated with an ALK inhibitor; patients who have progressed on these agents should be assessed, if appropriate, for resistance mutations susceptible to approved agents and treated with that agent\r\n* No prior gemcitabine treatment
DOSE EXPANSION COHORT: Subjects with metastatic or recurrent NSCLC who progressed on at least one line of systemic therapy for metastatic or recurrent disease, which must include anti PD-1 or PD-L1 inhibitor, and must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and accessible tumor for biopsy; molecular status of EGFR and ALK must have been assessed for nonsquamous NSCLC; those with activating EGFR mutation or ALK gene arrangement must have progressed on at least one kinase inhibitor
Subjects whose tumors express EGFR mutations on exons 19 and 21, ALK rearrangement, or ROS1 rearrangement who still have other Food and Drug Administration (FDA) approved targeted agents available for treatment.
Known sensitizing EGFR mutations or ALK gene rearrangement; if patient’s biopsy did not allow EGFR or ALK gene analysis (e.g., inconclusive, not enough tissue, etc.), the patient is considered eligible for study; enrollment on this clinical trial after progression on targeted therapy is allowed
Patients with EGFR/ALK/ROS-1+ lung adenocarcinoma
* Phase 1 (Part A2) - COMPLETE: Patients with confirmed ALK fusion proteins, ALK mutations, ALK amplification (defined as greater than 4-fold increase in the ALK signal number as compared to reference signal number on chromosome 2q arm) or MET proto-oncogene, receptor tyrosine kinase (MET) mutation or amplification; testing to confirm the presence of ALK fusion proteins, ALK mutations, ALK amplification or evidence of MET mutation or amplification for eligibility purposes must be performed as a Clinical Laboratory Improvement Act (CLIA)-certified assay; ALK immunohistochemistry can be used as a surrogate for fluorescent in situ hybridization (FISH) for patients with inflammatory myofibroblastic tumors (IMT) or ALCL
* Phase 2 (Part A2): Patients with diagnoses other than neuroblastoma or ALCL with confirmed ALK fusion proteins, ALK mutations, ALK amplification (defined as greater than 4-fold increase in the ALK signal number as compared to reference signal number on chromosome 2q arm) or MET mutation or amplification; testing to confirm the presence of ALK fusion proteins, ALK mutations, ALK amplification or evidence of MET mutation or amplification for eligibility purposes must be performed as a CLIA-certified assay; ALK immunohistochemistry can be used as a surrogate for FISH for patients with IMT
Prior positive test for EGFR mutation or ALK gene rearrangement
Evidence of histologically or cytologically confirmed diagnosis of metastatic NSCLC (Stage IV, AJCC v7.0) that carries an ALK rearrangement, as determined by the Food and Drug Administration (FDA) approved FISH assay (Abbott Molecular Inc) or by Immunohistochemistry (IHC) (Ventana Inc), or a ROS1 rearrangement as determined by FISH or RT PCR or Next Generation Sequencing (NGS) via a local diagnostic test (LDT). All patients (ALK positive and ROS1 positive) must have archival tissue sample available and collected prior to enrollment.
Disease Status Requirements: Phase 1: ALK-positive NSCLC and ROS1-positive patients must either be treatment naïve in the advanced setting or have had disease progression after at least 1 previous ALK/ROS1 inhibitor therapy(ies). Phase 2: ALK-positive NSCLC patients must either be or have had:
Any prior treatment with dalantercept or any other agent targeting ALK1 pathway.
Absence of known translocation or inversion events involving the ALK gene locus (resulting in EML4-ALK fusion)
Must have documented ALK rearrangement.
Previously received any prior TKI, including ALK-targeted TKIs.
Histologically or cytologically confirmed diagnosis of advanced non-small cell lung cancer (stage IIIB or IV) or recurrent disease. Subjects with known EGFR mutations or ALK or ROS1 gene rearrangements must have also failed prior EGFR or ALK or ROS1 tyrosine kinase inhibitor, respectively (PD or unacceptable toxicity). Subjects may have received PD-1 or PDL-1 inhibitors. There is no limit on lines of prior anti-cancer therapy.
EGFR sensitizing mutation and/or ALK translocation
A patient with non-squamous NSCLC must have been tested for relevant EGFR mutations, ALK translocation or other genomic aberrations (e.g. ROS rearrangement, BRAF V600E mutation) for which FDA-approved targeted therapy is available and, if positive, the patient should have received such therapy prior to study entry.
In the absence of relevant EGFR mutation, ALK translocation, ROS rearrangement or BRAF V600E mutation, the patient must have received first-line therapy with a platinum-based regimen, be intolerant to, or refused such treatment.
A patient with a tumor with an EGFR mutation, ALK translocation, ROS rearrangement, or BRAF V600E mutation may have received appropriate inhibitors of EGFR, ALK, ROS or BRAF in addition to 3 prior lines of therapy for metastatic disease.
Subjects with characterized Anaplastic Lymphoma Kinase (ALK) rearrangements that predict sensitivity to anti-ALK therapy
There should be a minimum of 4 weeks from any prior investigational drug, chemotherapy, immunotherapy, with the exception of hormonal therapy for prostate and breast cancers, HER2-directed therapy for HER2+ breast or stomach cancer (3+ immunohistochemistry [IHC] or fluorescence in situ hybridization [FISH]+), drugs targeting EGFR, ALK or ROS1 in EGFR, ALK, ROS1-mutated lung cancer, respectively, or standard maintenance therapies for any solid tumor under the condition that subjects are on these therapies for at least two months before start of trial treatment
The participant must have progressed after 1 platinum-based chemotherapy regimen for Stage IV NSCLC. Prior therapy with VEGF/VEGFR targeting agents is permitted. Prior neoadjuvant/adjuvant therapy is permitted. Prior treatment with EGFR-TKI and ALK inhibitors is mandatory in participants with NSCLC whose tumor has EGFR-activating mutations or ALK translocations, respectively.
Known EGFR TK activating mutations or ALK rearrangements
Patients must be diagnosed with ALK-positive advanced NSCLC. The tumor must be ALK-positive as determined by ALK rearrangement in ?15% of cells (as measured by FISH using the Vysis break-apart ALK probe) or by using the Ventana ALK IHC test. The analysis may be performed locally.
For Phase I part: o Patients who have not previously received at least one line of therapy for ALK-positive NSCLC
Group A: prior therapy with any ALK inhibitor is not permitted.
Have documented ALK rearrangement by a positive result from the Vysis® ALK Break-Apart fluorescence in situ hybridization (FISH) Probe Kit; or
Received any prior ALK-targeted TKI other than crizotinib.
Patients with documented EGFR or ALK mutations must have been treated with prior EGFR or ALK therapy as well as a platinum containing doublet
PART A: Known EGFR mutation and/or ALK rearrangement in NSCLC with adenocarcinoma histology
Known to be wild-type for mutations in EGFR, KRAS, and ALK
STEP 1 ENROLLMENT: standard induction chemotherapy planned defined as: at least 4 cycles of platinum doublet chemotherapy for metastatic disease (with or without bevacizumab); if the patient is known to be EGFR mutation positive, erlotinib, afatinib, or gefitinib for >= 3 months, or for patients with known EML4-ALK fusions, crizotinib for >= 3 months
STEP 2 ENROLLMENT AND RANDOMIZATION: completion of standard induction chemotherapy planned defined as: at least 4 cycles of platinum doublet chemotherapy for metastatic disease (with or without bevacizumab); if the patient is known to be EGFR mutation positive, erlotinib, afatinib, or gefitinib for >= 3 months, or for patients with known EML4-ALK fusions, crizotinib; note that it is not mandatory to check EGFR mutation or EML4-ALK status prior to entry, but patients that receive options 2 or 3 should have had these molecular tests performed
Previously tested for presence of EGFR and ALK mutations in lung cancer tissue confirmed in a CLIA-certified laboratory (or equivalent). Subjects with EGFR or ALK mutation are eligible if they have previously received EGFR or ALK inhibitor(s) respectively.
Confirmation of the presence or absence of EGFR mutations and ALK gene fusions prior to study enrollment in all subjects; subjects with unknown EGFR sensitizing mutational status or ALK fusion must have been treated and progressed on EGFR tyrosine kinase inhibitors (TKIs) or ALK-directed therapy
positive for ALK amplification events
positive for ALK activating point mutations
prior therapy specifically directed against ALK
No prior systemic anticancer therapy (including EGFR and ALK inhibitors)
Alk-positive NSCLC as determined by a test that is approved or validated for use as a companion diagnostic test.
Patients with known EGFR-activating mutations or ALK rearrangements should have received treatment with a targeted kinase inhibitor (e.g., erlotinib, crizotinib) and no longer be considered as a candidate for such treatment
Never-smokers if EGFR/ALK testing results are unknown
Patients with NSCLC that harbors an ALK rearrangement, or sensitizing EGFR mutation
Subjects with known ALK translocations which are sensitive to available targeted inhibitor therapy are excluded; if tested, use of an FDA-approved test is strongly encouraged; subjects with unknown or indeterminate ALK status may be enrolled
Treatment on this protocol may begin as long as the patient has recovered from toxicities of prior therapy at the discretion of the treating physician; patients with non-small cell lung cancer (NSCLC) harboring an EGFR, ALK or ROS-1 alteration must have progressed through at least one prior therapy with appropriate molecularly targeted agents
Must have progressed following treatment with platinum-based combination chemotherapy for metastatic disease, and patients with an EGFR or ALK/ROS1 genetic aberration must have received appropriately targeted treatment.
Subjects known to be anaplastic lymphoma kinase (ALK)-fusion/rearrangement mutation positive must have received an ALK inhibitor.
Subjects with a known EGFR mutation must have received previous treatment with an EGFR tyrosine kinase inhibitor; and subjects with a known ALK translocation must have received previous treatment with an ALK inhibitor.
NSCLC with known EGFR mutation or anaplastic lymphoma kinase (ALK) gene translocation (such as EML4-ALK)
ALK-rearrangement confirmed by FDA approved test
Prior therapy with ALK inhibitor other than crizotinib
Patient must have been pre-identified as having a tumor with an ALK or ROS1 positive mutation, translocation, rearrangement or amplification. The qualifying alteration must be assessed and reported by a CLIA-certified laboratory. ALK positivity as assessed by IHC or FISH are allowed.
Patients must have documented ALK positivity at the time of initial crizotinib monotherapy using the Vysis Break-Apart FISH assay (or other Food and Drug Administration [FDA]-approved diagnostic test); samples are deemed to be FISH-positive if greater than or equal to 15% of scored tumor cells had split ALK 5? and 3? probe signals or had isolated 3? signal; FISH status must be documented on the Onstudy Form and a copy of the pathology report from the Vysis Break-Apart FISH assay (or other FDA-approved diagnostic test) must be submitted
Prior treatment with dalantercept or other agent targeting the ALK1 pathway.
Documented ALK rearrangement based on FDA approved test
Receipt of any other ALK inhibitors in addition to crizotinib
Known EGFR (exon 19 and 21) mutations, ALK translocations, and/or ROS-1 translocations
For NSCLC, an ALK translocation must be detected by FISH in ? 15% of tumor cells.
In patients with diseases other than NSCLC, ALK translocation is not required and overexpression of ALK protein may be considered indicative of a genetic abnormality in ALK.
Patients with EGFR- or ALK-positive disease are not eligible for this study
Patients with an Alk+ relapsed/refractory hematologic malignancy including but not limited to ALK+ ALCL or ALK+ large B cell lymphoma
No known presence of known EGFR or EML4-ALK driver mutations in the tumor
Known sensitizing mutation in the EGFR gene or ALK fusion oncogene
Patients with NSCLC (adenocarcinoma, squamous, or adenosquamous histopathology) must also meet the following criteria: a. Must have disease that is stage IIIB, not curable by surgery or radiotherapy, or stage IV; b. Must have received at least one prior chemotherapy regimen for locally advanced or metastatic disease; c. EGFR-positive or ALK-positive patients must have received at least one line of EGFR-directed or ALK-directed therapy, respectively; d. Must have received prior taxane therapy.
Chemotherapy naive NSCLC patients; for NSCLC patients with lung adenocarcinoma, tumors must be EGFR and ALK wild-type; if a KRAS mutation is detected, EGFR and ALK testing is not required
Histologically or cytologically confirmed diagnosis of NSCLC that is EGFR Wild-type, ALK-negative rearrangement and ROS1-negative rearrangement
Patients with histological- or cytological-confirmed, advanced unresectable breast, gastric, or non-small cell lung cancer, who have progressed on (or not been able to tolerate) standard therapy or for whom no standard anticancer therapy exists. a. Part C: Only the following subtype of tumors with the molecular/genetic alterations will be enrolled: HER2 positive MBC Advanced NSCLC, harboring EGFR mutations after progression on osimertinib Advanced NSCLC, harboring ALK translocations after treatment with alectinib or at least 2 ALK inhibitors
ALK positive NSCLC patients must either be treatment naive in the advanced setting or have had disease progression on or intolerance to at least 1 previous ALK inhibitor; ROS1 positive NSCLC patients must either be treatment naive in the advanced setting or have had disease progression on or intolerance to at least 1 previous ROS1 inhibitor
After progression on or intolerance to prior ALK or ROS inhibitor therapy:\r\n* A minimum washout period of at least 5 days between the last dose of ALK or ROS tyrosine kinase therapy (TKI) therapy and the first dose of study treatment is required; a shorter washout period may be considered in the event of disease flare, after discussion with the sponsor\r\n* Patients must have recovered from treatment toxicities to =< grade 1 or to their pretreatment levels except for adverse events (AEs) that in the investigator’s judgment do not constitute a safety risk for the patient
Histologically or cytologically confirmed diagnosis of stage IIIB (and is not a candidate for definitive multimodality therapy) or stage IV NSCLC demonstrated ALK-positive or an advanced tumor, other than NSCLC, that carries an ALK genetic alteration (mutation, translocation or amplification) and/or ALK overexpression that has progressed despite standard therapy, or for which no effective standard therapy exists.
The test to confirm ALK-positivity may be performed in archival tumor (obtained at or since the time of diagnosis), or in a newly obtained tumor sample taken prior to the first day of study drug. Results confirming ALK-positive status must be available before initiating treatment with ceritinib.