Patients must have had histologic verification of juvenile myelomonocytic leukemia (JMML) at original diagnosis and currently have relapsed or refractory disease; the diagnosis is made based on the following criteria\r\n* JMML category 1 (all of the following): the diagnostic criteria must include all features in category 1 and EITHER (i) one of the features in category 2 OR (ii) two features from category 3 to make the diagnosis\r\n** Splenomegaly\r\n** > 1000 (1 x 10^9/uL) circulating monocytes\r\n** < 20% blasts in the bone marrow or peripheral blood\r\n** Absence of the t(9;22) or BCR/ABL fusion gene\r\n* JMML category 2 (at least one of the following if at least two category 3 criteria are not present):\r\n** Somatic mutation in RAS or PTPN11\r\n** Clinical diagnosis of NF1 or NF1 gene mutation\r\n** Homozygous mutation in CBL\r\n** Monosomy 7\r\n* JMML category 3 (at least two of the following if no category 2 criteria are met):\r\n** Circulating myeloid precursors\r\n** White blood cell count, > 10 000 (10 x 10^9/ uL)\r\n** Increased hemoglobin F for age\r\n** Clonal cytogenetic abnormality\r\n** GM-CSF hypersensitivity
Patients who are known to have Lynch syndrome and have been found to carry a specific germline mutation in an MMR gene (MLH1, MSH2, MSH6, PMS2) are eligible to participate
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 3 days of study entry onto the dasatinib arm of AALL1131
Patient must have enrolled onto APEC1621SC and must have been given a treatment assignment to Molecular Analysis for Therapy Choice (MATCH) to APEC1621H based on the presence of an actionable mutation
Patient must have enrolled onto APEC1621SC and must have been given a treatment assignment to molecular analysis for therapy choice (MATCH) to APEC1621B based on the presence of an actionable mutation
Patient must have enrolled onto APEC1621SC and must have been given a treatment assignment to Molecular Analysis for Therapy Choice (MATCH) to APEC1621G based on the presence of a BRAF V600 mutation
Patient must have enrolled onto APEC1621SC and must have been given a treatment assignment to Molecular Analysis for Therapy Choice (MATCH) to APEC1621F based on the presence of an actionable mutation
APEC1621SC: Patient must have enrolled onto APEC1621SC and must have been given a treatment assignment to molecular analysis for therapy choice (MATCH) to APEC1621A based on the presence of an actionable mutation
History of malignancy with confirmed activating RAS mutation at any time; Note: prospective RAS testing is not required; however, if the results of previous RAS testing are known, they must be used in assessing eligibility
Prospectively determined eligible PTEN alteration determined by next generation sequencing, protein deficient determined by IHC or PIK3CB mutation/amplification. Part D2
For Phase 2a, subjects with one of the following tumor types will be enrolled: i. Urothelial cancer with HER2 or HER3 mutation ii. Biliary tract cancer with HER2 or HER3 mutation iii. Breast cancer with HER2 or HER3 mutation iv. Breast cancer with HER2 amplification or overexpression v. NSCLC with HER2 or HER3 mutation vi. CRC with HER2 mutation or amplification vii. Other tumors with HER2 mutation/amplification/overexpression or HER3 mutation (gastric/GEJ, endometrial).
ER+ breast cancer patients harboring the AKT1 E17K mutation (patient population tested in MSK IRB# 14-214, study D3610C00001 part E, ClinicalTrials.gov NCT01226316)
Patients with unknown BRAF mutation status may enroll so long as mutation testing is planned to be performed within 30 days of Cycle 1 Day 1 First-line NSCLC (pembrolizumab only)
Known mutation of Rb in tumor tissue
Has documented evidence of an activating EGFR mutation in the tumor tissue determined by either sequencing or PCR-based technique (Part 1).
For Part 1 only: subjects with a positive T790M mutation are preferred, but not required. Confirmation of T790M mutation status will be determined from an archived tumor tissue sample or fresh tumor tissue sample obtained via biopsy if archived tissue is not available. In Part 2, subjects must have a confirmed, positive T790M EGFR mutation (acquired T790M EGFR mutation or \de novo\ T790M EGFR mutation).
BRAFV600 mutation positive
NRAS codon 12, 13, or 61 mutation
Is willing to undergo tumor genotyping for TP53 mutation, insertion, or deletion at screening. Confirmation of TP53 nonmutant status is encouraged, but not required prior to DS-3032b dosing.
PIK3CA MUTANT COHORT (closed 03/17/2016): Tumor PIK3CA mutation present
Participants must have a lung cancer harboring an EGFR mutation
Must have RAS mutation and microsatellite stability status results as part of medical history
Able to provide a sufficient amount of representative tumor specimen for central laboratory testing of RAS mutation status and microsatellite stable (MSS).
RAS mutation per local assay at any time prior to Screening or by the central laboratory.
Molecular testing results from CLIA-certified laboratories (using tissue and/or blood) demonstrating hedgehog pathway relevant mutation (activating mutation of smoothened [SMO] or loss-of-function mutation of protein patched homolog-1 [PTCH-1]) a) For participants screened using a blood assay: obtain tissue-based testing result confirming study eligibility (within first 4 weeks after enrollment)
Prior or concurrent malignancy with known RAS mutation
Patients with histologically confirmed diagnosis of a primary central nervous system tumor will be eligible; patient tumors must test positive for the BRAFV600E or the BRAF Ins T mutation at a Clinical Laboratory Improvement Act (CLIA)-approved laboratory; if either mutation cannot be confirmed from a prior test and archival tumor is not available to confirm presence of either mutation, patients must have tumor biopsy to collect tumor sample for mutation confirmation
Note: HER2 mutation testing may be performed while the patient is receiving active systemic therapy for metastatic breast cancer so that the result can be used to determine eligibility for study drug therapy in the future
INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASHINGTON UNIVERSITY [WASH U] GENOMICS AND PATHOLOGY SERVICES [GPS] LABORATORY): Tumor tissue tested positive for HER2 mutation; mutations outside the list will be assessed on a case-by-case basis by the study team to determine eligibility\r\n* Note: HER2 mutations listed and detected by Guardant360 are also eligible
INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASH U GPS LABORATORY): Agree to provide archival tumor material for research
INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASH U GPS LABORATORY): ECOG performance status =< 2
INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): Tumor tissue or circulating tumor deoxyribonucleic acid (DNA) tested positive for HER2 mutation; mutations outside the list will be assessed on a case-by-case basis by the study team to determine eligibility
INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): ECOG performance status =< 2
Cohort A: Histologically confirmed locally advanced or metastatic solid tumor malignancy other than clear cell renal cell carcinoma with progression on at least one prior systemic therapy and presence of biallelic loss of SETD2 detected in tumor tissue detected using a Clinical Laboratory Improvement Act (CLIA)-certified next generation sequencing panel (e.g. UCSF500, FoundationOne); biallelic loss will be defined by one or more of the following:\r\n* Pathogenic or likely pathogenic loss-of-function SETD2 mutation with mutant allele frequency (MAF) > 50%\r\n* Pathogenic or likely pathogenic loss-of-function SETD2 mutation with MAF > 2 times the MAF of other oncogenic mutations detected in the tumor sample\r\n* Pathogenic or likely pathogenic loss-of-function SETD2 mutation with concomitant loss of chromosome 3p\r\n* Pathogenic or likely pathogenic loss-of-function SETD2 mutation with copy-neutral loss of heterozygosity
Participant has presence of the FLT3/ITD activating mutation in the BM or PB as determined by the local institution at diagnosis.
For the dose expansion and extension cohorts, patients also must have confirmation of tumor T790M+ mutation status from a biopsy sample taken after disease progression on the most recent treatment regimen with an EGFR TKI. Prior to entry, a result from the central analysis of the patient's T790M mutation status must be obtained.
Documentation of BRAFv600 mutation-positive status in melanoma tumor tissue (archival or newly obtained) through use of a clinical mutation test approved by the local health authority
Participants must have one of the following (confirmed via targeted NextGen Sequencing using the DFCI/BWH OncoPanel or another Clinical Laboratory Improvement Act [CLIA]-certified method):\r\n* For the replicative stress cohort: MYC amplification, CCNE1 amplification, Rb loss, FBXW7 mutation, or another genomic abnormality indicative of replicative stress as agreed upon with the principal investigator -OR-\r\n* For the HR deficiency cohort: genomic or somatic mutation in BRCA1, BRCA2, PALB2, RAD51C, RAD51D, ATR, ATM, CHK2, the Fanconi anemia pathway genes, or another genomic or somatic mutation in a known HR gene as agreed upon with the principal investigator.\r\n* For enrollment to the CCNE1 cohort: CCNE1 amplification of 6-fold or greater. Patients with borderline amplification levels may be considered following approval from the overall principal investigator.
Part B4: Have metastatic melanoma carrying NRAS mutation
Part C: Have advanced unresectable cancer (dose escalation) and advanced/unresectable/metastatic NSCLC carrying BRAF or RAS mutation and colorectal cancer carrying RAS mutation (dose expansion)
PID deemed to be of sufficient past severity to warrant allo BMT, by meeting the two criteria below:\r\n* PID as defined by monogenetic mutation or, in the absence of a PID-associated genetic mutation, patients with an immune defect potentially amenable to allo BMT who meet the clinical history criteria below may be eligible upon discussion with the principal investigator (PI)\r\n** Mutations should be confirmed in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory, if such testing is available\r\n** Patients without a mutation must be deemed eligible and appropriate for allo BMT by the PI; some patients may meet the clinical history criteria listed below, but will not be eligible if it is thought that their clinical history is due to a condition apart from an immune defect; in addition, patients with a PID of mild severity, such as those with selective immunoglobulin A (IgA) deficiency, may meet at least two of the clinical history criteria, but may be deemed inappropriate for allo BMT by the PI if it is felt that the risks of the procedure outweigh the severity of the disease\r\n** All mutation testing will be performed on National Institute of Allergy and Infectious Diseases (NIAID) protocols (such as 07-I-0033 – Detection and Characterization of Infections and Infection Susceptibility; PI: Steve Holland, with genetic counseling and education through these established protocols)\r\n* Clinical history of at least two of the following:\r\n** Life-threatening, organ-threatening, or severely disfiguring infection\r\n** Protracted or recurrent infections requiring unusually long or repeated courses of antibiotics\r\n** Infection with an opportunistic organism\r\n** Chronic elevation in the blood (>= 2 documented elevations over a period of 6 months or longer) of a latent virus (EBV, CMV, human herpesvirus [HHV]6, HHV8, etc.)\r\n** Evidence of immune dysregulation, as manifested by autoimmune disease, atopy, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, granulomas, splenomegaly, or lymphadenopathy\r\n*** Patients with hemophagocytic lymphohistiocytosis or macrophage activation syndrome related to an underlying lymphoma with no other clinical history suggestive of a primary immunodeficiency will not be eligible\r\n** Hypogammaglobulinemia, dysglobulinemia, or impaired response to vaccination\r\n** Hematologic malignancy or lymphoproliferative disorder\r\n*** Tissue diagnosis should be confirmed by National Cancer Institute (NCI) Department of Pathology, if prior biopsies are available\r\n** Virus-associated solid tumor malignancy or pre-cancerous lesion\r\n*** Tissue diagnosis should be confirmed by NCI Department of Pathology, if prior biopsies are available
Activating mutation in EGFR
Patients’ tumors will need to tested for the RAS mutation status; only those patients with wild-type or unmutated RAS oncogene are eligible to participate in this study
Pathologically confirmed diagnosis of IDH2-mutant acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML)\r\n* IDH2 mutations will include any IDH2 R140 or R172 alterations\r\n* Eligibility and enrollment will be based on local IDH2 mutational testing performed at any center. The presence of an IDH2 mutation at the time of initial diagnosis or any other time thereafter is necessary and sufficient. The presence of an IDH2 mutation at time of enrollment is not necessary for the purposes of eligibility
Documentation of BRAFV600 wild-type status in melanoma tumor tissue through use of a clinical mutation test approved by the local health authority
Patient must have enrolled onto APEC1621SC and must have been given a treatment assignment to MATCH to APEC1621I based on the presence of an actionable mutation\r\n* Positive Rb expression by immunohistochemistry is required for study enrollment
Patients with history of RAS mutation-positive tumors are not eligible regardless of interval from the current study. Prospective RAS testing is not required. However, if the results of previous RAS testing are known, they must be used in assessing eligibility.
Has previously documented evidence of ALK fusion, ROS1 fusion, BRAF V600E mutation, RET rearrangement, HER2 mutation, MET amplification, or MET exon 14 skipping mutation. No new testing for these genomic alterations is required for Screening.
Known mutation in KRAS at position G12, G13, or Q61
Any known concurrent RAF or PIK3CA mutation
The presence of a TP53 mutation should be determined by Genoptix (or institutional preferred equivalent assay) for all patients; detection of a TP53 mutation at the time of initial diagnosis is sufficient for enrollment; detection of a TP53 mutation in either the peripheral blood or bone marrow is adequate for enrollment
Documented HER2 mutation.
Patients with previously documented BCR-ABL Kinase Domain mutations that confer resistance to nilotinib; this includes, but is not limited to, the T315I mutation
Patients with T315I mutation will not be excluded, but their response will be analyzed separately.
Known drug-related, inherited, or acquired procoagulant disorder including prothrombin gene mutation 20210, antithrombin III deficiency, protein C deficiency, protein S deficiency and antiphospholipid syndrome but not including heterozygosity for the Factor V Leiden mutation or the presence of a lupus anticoagulant in the absence of other criteria for the antiphospholipid syndrome
CML with BCR-ABL mutation consistent with poor response to tyrosine kinase inhibition (e.g. T351I mutation)
Have an EGFR mutation (sensitizing or non-sensitizing)
Newly diagnosed AML patients who are identified with FLT3-ITD or tyrosine kinase domain (TKD) point mutation in the codon for an aspartate (D835) or an isoleucine (I836) residue
Known non-synonymous mutation in the following genes: Raf, PDGFR, VEGFR, Flt-3, KIT, JAK, STAT, RAS, MEK, or ERK; genomic sample preferably from relapse, but may be from other stage of treatment if relapse sample is not reasonably obtainable; genetic analysis for determination of eligibility occurs as part of routine care and is not being performed specifically for the purposes of this study
Known history of ABL1-domain mutation that predicts resistance to the discontinued TKI
Patients with del(17p) by FISH (or known tumor protein p53 [TP53] mutation)
Subjects must be willing to undergo malignancy genotyping for tumor protein 53 (TP53) mutation, insertion, or deletion at screening
Documented mutation in gBRCA1 or gBRCA2 that is predicted to be deleterious or suspected deleterious
Patient must have enrolled onto APEC1621SC and must have been given a treatment assignment to molecular analysis for therapy choice (MATCH) to APEC1621E based on the presence of an actionable mutation\r\n* Note: patients with BRAF V600 actionable mutations of interest (aMOIs) will be preferentially assigned to APEC1621G (vemurafenib) if that study is open and they are otherwise eligible for it
Subjects must have evidence of a T790M mutation in tumor tissue or plasma obtained after disease progression during or after treatment with an EGFR TKI. T790M mutation status from a local laboratory is acceptable; however, a tumor tissue sample or plasma sample suitable for centralized T790M mutation analysis must be available.
For Cohort 3, 5 and 7 (subjects with INI1-negative/aberrant tumors or any solid tumor with EZH2 GOF mutation only), the following test results must be available by local laboratory: Morphology and immunophenotypic panel consistent with INI1-negative tumors (not applicable for solid tumors with EZH2 GOF mutation), and loss of INI1 confirmed by IHC, or molecular confirmation of tumor bi-allelic INI1 loss or mutation when INI1 IHC is equivocal or unavailable, or molecular evidence of EZH2 GOF mutation
Documented/locally determined AKT1 or PIK3CA mutation
Patients whose tumors are positive for the sensitizing EGFR mutation
Patients with history of activating RAS mutation positive tumors regardless of interval from current study; however, patients may have concurrent BRAFV600 and RAS mutations in the tumor to be treated with protocol therapy
Patient’s tumor must have documentation of the presence of an IDH-1 and/or IDH-2 mutation of any type
For Phase I Only: Patients are eligible regardless of their FLT3 mutation status.
MATCHED RELATED DONOR: No mutation in GATA2, or in the case where the mutation in GATA2 has not been identified, but the recipient has the clinical syndrome of MonoMAC, the donor is required to have no clinical evidence of MonoMAC
HAPLOIDENTICAL RELATED DONOR: No mutation in GATA2, or in the case where the mutation in GATA2 has not been identified, but the recipient has the clinical syndrome of MonoMAC, the donor is required to have no clinical evidence of MonoMAC
MATCHED RELATED DONOR: Mutation in GATA2, or evidence of loss of expression of one allele of GATA2 by cDNA analysis performed by a CLIA certified laboratory, or in the case where the mutation in GATA2 has not been identified, but the recipient has the clinical syndrome of MonoMAC, the donor is excluded if he or she has the clinical syndrome of MonoMAC
HAPLOIDENTICAL RELATED DONOR: Mutation in GATA2, or evidence of loss of expression of one allele of GATA2 by cDNA analysis performed by a CLIA certified laboratory, or in the case where the mutation in GATA2 has not been identified, but the recipient has the clinical syndrome of MonoMAC, the donor is required to have no clinical history of MonoMAC
Patient with confirmed del11q mutation may be included if untreated
Colorectal cancer patients with known v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation (for the arm combining bevacizumab, temsirolimus and cetuximab)
Known drug-related, inherited, or acquired procoagulant disorder including prothrombin gene mutation 20210, antithrombin III deficiency, protein C deficiency, protein S deficiency and antiphospholipid syndrome but not including heterozygosity for the factor V Leiden mutation or the presence of a lupus anticoagulant in the absence of other criteria for the antiphospholipid syndrome
Qualifying HRR mutation in tumor tissue.
Immunohistochemically negative for IDH1 R132H mutation
An activating point mutation in HER2 including, but not limited to, L755S, G776V, and V777L.
An activating point mutation in HER2 including, but not limited to, L755S, G776V, and V777L.
For patients with an uncommon activating mutation in EGFR: have not received a TKI with activity against the specific documented uncommon activating mutation.
tumor that carries a missense HRAS mutation
FLT3 mutation positive (ITD, TKD or other)
Sufficient tumor available to determine if expresses a mutation in KIT
Documentation of tumor activating EGFR mutation, specifically either DEL19 or L858R.
Presence of FLT3-ITD and/or D835 mutation(s) in bone marrow or peripheral blood
Presence of FLT3-ITD and/or D835 mutation(s)
In cohort 1, must have EGFR S492R or other ectodomain mutation detected from circulating tumor DNA from plasma collected after progression to prior cetuximab; may have a concomitant mutation in KRAS, NRAS, or BRAF, if there is at least a 5-fold higher allele frequency of the most prevalent EGFR mutation than the most prevalent KRAS/NRAS/BRAF mutation
Patient must have enrolled onto APEC1621SC and must have been given a treatment assignment to Molecular Analysis for Therapy Choice (MATCH) to APEC1621C based on the presence of an actionable mutation
Documented RAS-mutated tumor without activating PIK3CA mutations or PTEN mutation (loss of PTEN or silencing)
Have an isocitrate dehydrogenase 1 (IDH1) mutation
Patient has a PIK3CA mutation confirmed by Novartis designated central lab or patient has a pathology report confirming PIK3CA mutant status by certified laboratory (using validated PI3KCA mutation assay) either from tissue or blood and must (mandatory) send tumor tissue to Novartis designated central lab for confirmation of mutational status
IDH1/2 mutation in any prior biopsy
Subjects must be willing to undergo myeloma genotyping for TP53 mutation, insertion, or deletion at screening
Subjects with a malignancy that contains a non-synonymous mutation, insertion, or deletion in the TP53 gene determined prior to screening; TP53 mutation status at screening is NOT required prior to AMG-232 dosing; however, subjects found to have TP53 mutation and/or deletion from screening bone marrow biopsy as assessed by central deoxyribonucleic acid (DNA) sequencing conducted at Dr. Jeffrey Sklar’s laboratory at Yale University Cancer Center, will be removed from study after C1 and continue on standard-of-care KRd alone
Patients with history of rat sarcoma (RAS) mutation-positive tumors are not eligible regardless of interval from the current study; Note: RAS testing and absence of RAS mutation are required for eligibility
Patients with a history of RAS mutation-positive tumors are not eligible regardless of interval from the current study; Note: prospective RAS testing is not required; however if the results of previous RAS testing are known, they must be used in assessing eligibility
Patients with history of rat sarcoma (RAS) mutation-positive tumors are not eligible regardless of interval from the current study; Note: prospective RAS testing is not required; however, if the results of previous RAS testing are known, they must be used in assessing eligibility
Patients must not have a known thrombophilic condition (i.e. protein S, protein C or antithrombin III deficiency, Factor V Leiden, Factor II G20210A mutation, homocysteinemia or antiphospholipid antibody syndrome); testing is not required in patients without thrombophilic history
All potential subjects should be evaluated for whether breast cancer (BRCA)1-2 testing is medically appropriate; individuals who have a 10% or higher risk of having a BRCA1-2 mutation (Myriad tables at www.myriad.com) are encouraged (but not required) to have mutation testing and results known; information regarding mutation status (positive [including specific mutation], negative, or unknown) and projected risk of having a mutation (as determined by Myriad tables) will be collected at the time of diagnosis
Subject is positive for FLT3 mutation in bone marrow or whole blood as determined by the central lab. A subject with rapidly proliferative disease and unable to wait for the central lab results can be enrolled based on a local test performed after completion of the last interventional treatment. Subjects can be enrolled from a local test result if they have any of the following FLT3 mutations: FLT3 internal tandem duplication (ITD), FLT3 tyrosine kinase domain (TKD)/D835 or FLT3- TKD/I836.
Subject has an FLT3 mutation other than the following: FLT3-ITD, FLT3-TKD/D835 or FLT3-TKD/I836.
Molecular confirmation of tumor bi-allelic INI1 loss/mutation when INI1 IHC is equivocal or unavailable
Presence of the FLT3-ITD activating mutation in bone marrow or peripheral blood (allelic ratio as determined by a central laboratory with a cutoff of ?3% FLT3-ITD/total FLT3). If a specimen has been sent for FLT3-ITD testing at the central laboratory but the subject requires treatment for AML before the central FLT3-ITD test result is available, a local test result may be acceptable for randomization after consultation with the Medical Monitor.
Subjects must have tested positive for FLT3-ITD and/or other FLT3 activating mutations
KRAS or NRAS mutation detected in tumor specimen
KRAS or NRAS mutation detected in tumor tissue specimen
Evidence of common EGFR mutation (Del 19 and/or L858R)
Part 2: Molecular evidence of BAP1 loss of function mutation present on local pathology, e.g., lack of nuclear BAP1 staining by immunohistochemistry (IHC) or evidence of loss of function by gene sequencing
A valid cobas PIK3CA mutation result by central testing is required
Part B only: 5. Histologically or cytologically confirmed, molecularly selected (i.e. BRAFV600 positive and/or PI3K mutation positive) advanced solid tumors. Prior molecular characterization should be based using a regulatory approved assay or analytically validated assay.
Known KRAS or NRAS mutations:\r\n* All patients must have molecular testing performed in a clinical lab which includes codon 12 and 13 of KRAS; patients with any mutation in codon 12 and 13 of KRAS are not eligible for the protocol\r\n* Testing for additional codons in KRAS or testing for NRAS is not required; however, if such testing has been performed in a clinical lab and any mutation in codons 61 or 146 in KRAS, or codons 12, 13, 61, or 146 in NRAS is detected, the patient is not eligible for the protocol
Patients must have BRAFV600E mutation
Determined to have detectable mutations in codons 12 or 13 of the kirsten rat sarcoma (KRAS) oncogene by an investigational assay at the study JPBK central laboratory. A KRAS positive mutation result in codons 12 or 13 of the KRAS oncogene from tumor tissue per local laboratory will be permitted in no more than 10% of randomized participants.
Patients must have a tumor protein (p)53 mutation which is defined as cytoplasmic positivity by immunohistochemistry and/or next gene mutation sequencing
Subject is positive for FLT3 mutation (internal tandem duplication [ITD] or tyrosine kinase domain [TKD] [D835/I836] mutation) in bone marrow or whole blood as determined by central laboratory. Note: Only applicable to the randomization portion.
Presence of T315I mutation by ABL1 sequencing
Patients who have a known dasatinib-resistant ABL-kinase mutation such as T315I are not eligible; for confirmation, please contact PI
Untreated, histological confirmed acute myeloid leukemia (AML) based on World Health Organization (WHO) 2008 criteria with either/or both:\r\n* FLT3 ITD mutation\r\n* FLT3 TKD mutation
Presence of a RAS mutation in exons 2, 3, or 4 of KRAS or NRAS (patients with mutations in exons 2, 3, or 4 of KRAS and/or NRAS are excluded)
Known T315I or V299L mutation.
Central confirmation of T790M+ mutation status
Known Abl-kinase mutation resistant to Dasatinib (e.g. T315I or T315A)
Documented presence of EGFR mutation confirmed by MSKCC or a local facility
History of malignancy with confirmed activating RAS mutation at any time. Prospective RAS testing is not required. However, if the results of previous RAS testing are known, then those results must be used in assessing eligibility.
KRAS mutation positive tumour sample as determined by the designated testing laboratory
Subject must be known to be RET positive (known KIF5B-RET translocation, or other confirmed RET translocations (e.g., CCDC6-RET)) or have an available tumor sample for local or central testing obtained prior to consent (Screen 1). Subjects whose samples need to be submitted for central laboratory testing must be current non-smokers and not known to have mutation in EGFR, KRAS, or ALK.
Confirmed FLT3-ITD mutation, measured on peripheral blood or bone marrow aspirate prior to study enrollment (patients may also have a concurrent FLT3-tyrosine kinase domain [TKD] mutation)
For dose expansion and extension cohorts, patients must also have confirmation of tumour T790M mutation status (confirmed positive or negative) from a biopsy sample taken after disease progression on the most recent treatment regimen (irrespective of whether this is EGFR TKI or chemotherapy). Prior to entry a result from the central analysis of the patient's T790M mutation status must be obtained.
A minimum of 10 patients in the trial (~50%) will need to have a PIK3CA mutation in their cancer
Presence of NRAS Q61 mutation in tumor tissue prior to randomization as determined by a Novartis designated central laboratory
Prospective confirmation of KRAS mutation negative status as determined via an AZ approved laboratory
T315I mutation
If archived tissue is unavailable for KRAS, NRAS, or BRAF mutation testing, or patient refuses a fresh biopsy for mutation analysis
History of malignancy with confirmed activating RAS mutation at any time; Note: prospective RAS testing is not required; however, if the results of previous RAS testing are known, they must be used in assessing eligibility
CML treatment resistant mutation(s) (T315I, E255K/V, Y253H, F359C/V) detected if a testing was done in the past (there is no requirement to perform mutation testing at study entry if it was not done in the past)
Patients must have tested positive for FLT3-ITD and /or other FLT3 activating mutations within 30 day screening period
Absence of a FLT3 activating mutation
High risk cytogenetics (-5, -7, del(5q), abnormal 3q, 11q23 translocations, complex cytogenetics) or if cytogenetics are normal the presence of a FLT3 mutation without a NPM1 mutation
Genotype: APC mutation (with or without family history) required
High Tumor Mutation Burden
Somatic activating mutation in EGFR
Patients with a known mutation in p53 (Li Fraumeni syndrome)
For gastrointestinal stromal tumors (GIST), patients must have failed previous therapy with imatinib and sunitinib. Patients with known PDGFR mutations are excluded, but mutation testing is not required for study entry.
Known procoagulant disorder including prothrombin gene mutation 20210, antithrombin III deficiency, protein C deficiency, protein S deficiency and antiphospholipid syndrome but not including heterozygosity for the Factor V Leiden mutation or the presence of a lupus anticoagulant in the absence of other criteria for the antiphospholipid syndrome
The melanoma must harbor a c-KIT mutation determined by PCR and sequencing
Assessment of FLT3 mutation status;
Cohort A: Subjects with a FLT3 mutation (e.g. ITD or D835) with prior FLT3 inhibitor treatment
Cohort B: Subjects with a FLT3 mutation (e.g. ITD or D835) without prior FLT3 inhibitor treatment
Cohort C: Subjects without a FLT3 mutation at the time of enrollment
Subject has an EGFR activating mutation based on local testing.
Histological diagnosis of unresectable or metastatic colorectal cancer which is KRAS and NRAS mutation negative (wild type); patients with any known mutation in KRAS or NRAS codons 12, 13, 59, 61, 117, or 146 will be excluded; mutations of KRAS and NRAS codons not listed above are allowed; biopsy of metastatic lesion is not required
Any known mutation in KRAS or NRAS codons 12, 13, 59, 61,117, or 146
Solid tumors that meet the following criteria: Measurable disease by Response Evaluation Criteria In Solid Tumors 1.1 (RECIST) in at least 1 site. For Castrate Resistant Prostate Cancer (CRPC) measurable disease can also include Prostate Specific Antigen (PSA) level. Disease progression with the last line of therapy and at least one prior standard of care regimens, or tumor for which there is no approved therapy, or for which standard therapy is unsuitable or refused. Mutation Status: Solid tumor types, other than prostate, must have a one of the following EZH2 inhibitor sensitizing mutations as determined via local testing: An activating mutation in EZH2 (Y641F/C/S/H/N, A677V/G, and/or A687V; Loss of a component of the SWI/SNF complex, including, but not limited to, ARID1A, SMARCB1 (aka SNF5/INI1/BAF47), SMARCA4 (aka BRG1), or PBRM1 (aka PB1) as determined by molecular testing (bi-allelic loss or mutation) or immunohistochemistry; Loss of BAP1 (ubiquitin carboxy-terminal hydrolase) as determined by molecular testing (bi-allelic loss or mutation) or immunohistochemistry
Lymphoma subjects will be required to undergo EZH2 mutation testing. This will require availability of archival tissue, or willingness to undergo fresh biopsy, for central testing of EZH2 mutation status.
Confirmed RAS mutation (neuroblastoma RAS viral [v-ras] oncogene homolog [NRAS] or Kirsten rat sarcoma viral oncogene homolog [KRAS]) or confirmed PTPN11 mutation, measured on peripheral blood or bone marrow aspirate as part of screening prior to study enrollment; mutation status must be confirmed within 45 days of initiation of therapy
The institution’s pre-enrollment biomarker screening at a CLIA certified lab documents absence of T790M mutation in the EGFR TK domain
Positive for PIK3CA mutation based on central laboratory testing
Patients must have EGFR gene mutation in their tumors. This can be source - documented by one of the following: • Provide a pathology report that indicates the patient's tumor had EGFR activating mutation in the past. Or: • Perform testing (local or central) in an archival tumor or a fresh baseline biopsy tumor tissue to show the presence of EGFR activating mutation.
Poor-risk (monosomy 5,7) or complex cytogenetics profile (3 or more cytogenetic abnormalities), or deletion of chromosome 5 (-5), or deletion of chromosome 7 (-7), or positive FLT3-ITD mutation
Patients must have melanoma that is documented to contain a BRAFV600E or BRAFV600K mutation by a FDA-approved test.
Known Abl-kinase T315I or T315A mutation
Individuals who meet the eligibility criteria for EGFR germline mutation testing but who do not have advanced cancer may enroll for EGFR germline mutation testing only and will not be eligible for the treatment or not otherwise specified (NOS) arms
Patients with advanced cancer must meet one of the following criteria (does not apply to first-degree relatives or individuals with pre-invasive histology enrolling only for EGFR germline mutation testing):\r\n* Patients must have biopsiable disease and be willing to undergo biopsy for molecular profiling or\r\n* Patients must have enough and adequate archival material from a previous biopsy to perform molecular profiling analyses; the adequacy of the material provided will be determined by the principal investigator in conjunction with the laboratories performing the molecular profiling analyses or\r\n* Patients must have previously undergone a successful molecular profiling of their tumor with mutation analysis of any of the genes described or anaplastic lymphoma receptor tyrosine kinase (ALK) break apart fluorescence in situ hybridization, as part of this protocol (crossover patients) or other molecular profiling protocols such as the Lung Cancer Mutation Consortium protocol among others
SELUMETINIB ARM: Patients must have one of the following as determined by analysis of the primary tumor or a metastatic site in a CLIA certified laboratory:\r\n* Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation or\r\n* Neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) mutation or\r\n* Harvey rat sarcoma viral oncogene homolog (HRAS) mutation or\r\n* V-raf murine sarcoma viral oncogene homolog B (BRAF) mutation
AKT INHIBITOR MK2206 ARM: Patients must have one of the following as determined by analysis of the primary tumor or a metastatic site in a CLIA certified laboratory:\r\n* Phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PI3KCA) mutation or\r\n* PI3KCA gene amplification by fluorescent in situ hybridization (FISH) (gene to chromosome ration > 2) or\r\n* V-akt murine thymoma viral oncogene homolog 1 (AKT) mutation or\r\n* Phosphatase and tensin homolog (PTEN) mutation
SUNITINIB MALATE ARM: Patients must have one of the following as determined by analysis of the primary tumor or a metastatic site in a CLIA certified laboratory:\r\n* Platelet derived growth factor receptor alpha (PDGFR-A) mutation or\r\n* PDGFR-A gene amplification by FISH (gene to chromosome ratio > 2) or\r\n* V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) mutation
Patients with known concurrent activating retrovirus-associated DNA sequence (RAS)/v-RAF-1 murine leukemia viral oncogene homolog (RAF) mutation or loss of function mutation or deletion in neurofibromin (NF)1 of NF2 resulting in mitogen-activated protein (MAP) kinase pathway activation; patients are not required to be evaluated for these alterations if not already performed
has 17p- and/or TP53 mutation; or
For Part 1 (phase 1, single agent): Patients with a known or presumed pathogenic KIT exon 13 or 14 resistance mutation.
Written documentation of KRAS wild-type status and BRAFV600-mutation with RNF43 mutation and/or RSPO fusion
No known potentially targetable mutation other than IGF signaling pathway or EGFR or no available treatment for potentially targetable mutation
Patient must have been pre-identified as having a tumor with CDK4 amplification or mutation, CDK6 amplification or mutation, Cyclin D1 (CCND1) amplification, Cyclin D3 (CCND3) amplification, or p16 (CDKN2A) mutation
BRAFV600 mutation positive.
History of another active malignancy within the past 5 years, or any malignancy with a confirmed activating RAS mutation. The prospective RAS mutation testing is not required, however, if results of previous RAS testing are known, they must be used in assessing eligibility. Subjects with a history of completely resected non-melanoma skin cancer are eligible.
For expansion cohort only: Subjects with histologically or cytologically proven metastatic breast cancer (with and without AKT1 E17K (G49A) mutation) or subjects with known AKT1 E17K (G49A) mutation in any other advanced solid tumor with at least one line of chemotherapy in the metastatic setting and not amenable to surgery with curative intent
Patients with a known germline mutation of PTPN11 (Noonan’s Syndrome) are not eligible
Tumor must be wild type for the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and BRAF oncogenes, and must have known PIK3CA, AKT mutation status and PTEN expression status
Documented presence\r\n* GROUP A: kinesin family member 5B (KIF5B)-RET or related variant RET fusions\r\n* GROUP B: any of the following aberrations\r\n** NTRK fusion\r\n** MET overexpression, amplification, or mutation\r\n** AXL overexpression, amplification, or mutation\r\n* GROUP C: ROS1 fusion
Have documented IDH1 R132H gene mutation by local testing and known 1p19q or ATRX mutation status by local testing.
Patients with colorectal carcinoma with tumors that demonstrate a Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation
Positive for Flt3-ITD activating mutations during Screening. Local laboratory results must be received prior to enrollment. Patients with a history of Flt3-ITD positive disease may be considered after discussion with the Medical Monitor.
Patients should have a FLT3 mutation, either internal tandem duplication (ITD) or kinase domain mutation or activation loop mutation
Histologically confirmed diagnosis of metastatic melanoma with the presence of the B-Raf proto-oncogene, serine/threonine kinase (BRAFV600) mutation
Presence of FLT3-ITD activating mutation in bone marrow (allelic ratio of ?3% FLT3-ITD/total FLT3);
Group 1: Patients must have a confirmed diagnosis of unresectable GIST that has progressed following imatinib and at least 1 of the following: sunitinib, regorafenib, sorafenib, dasatinib, pazopanib, or an experimental kinase-inhibitor agent, and the patient does not have a D842V mutation in PDGFR?.
Group 2: Patients must have a confirmed diagnosis of unresectable GIST with a D842V mutation in the PDGFR? gene. The PDGFR? mutation will be identified by local or central assessment, either in an archival tissue sample or a new tumor biopsy obtained prior to treatment with avapritinib.
Group 3: Patients must have a confirmed diagnosis of unresectable GIST that has progressed and/or patients must have experienced intolerance to imatinib and not received additional kinase-inhibitor therapy. Patients must not have a known D842V mutation in PDGFR?.
Patients with known risk factors for thromboembolism (e.g. Factor V Leiden mutation, antithrombin III (ATIII) deficiency, Protein C and S deficiency, antiphospholipid syndrome, portal hypertension, etc.)
Should generally be between the ages of 30 and 55; can be older or younger than this range depending on family history, genetic mutation status, or other factors; or as specified by separate protocols for approved intervention trials
Patients must have a documented FLT3 ITD mutation, determined by local laboratory for eligibility (historical tissue will be requested for central analysis confirmation)
Have personally received genetic testing for the CDKN2A/p16 genetic mutation and/or has one or more family members who received CDKN2A/p16 testing
All TP53 germline mutation positive adult patients will be eligible for this study; all patients must have a documented TP53 germline mutation
Individuals with “Li Fraumeni syndrome” defined as one of the following:\r\n* Carriers of a germline protein 53 (p53) mutation\r\n* Members of families meeting classic Li-Fraumeni syndrome (LFS) criteria by family history without an identifiable p53 mutation\r\n* Obligate carrier by pedigree (these individuals can be offered testing but are still eligible if they defer); the following examples describe “obligate carriers by pedigree”\r\n** A child of a parent with known p53 mutation that is diagnosed with cancer\r\n** An individual with a sibling and a child who are p53 positive OR\r\n* Individuals with an inherited cancer predisposition syndrome as defined by one of the following:\r\n** Hereditary retinoblastoma with a germline retinoblastoma (Rb) mutation\r\n** Diagnosis of hereditary paraganglioma/pheochromocytoma syndrome with a germline succinate dehydrogenase (SDH) mutation\r\n** Diagnosis of multiple endocrine neoplasia, type 1 or 2, with a germline multiple endocrine neoplasia (MEN) mutation\r\n** New diagnosis of opsoclonus-myoclonus with a negative cancer work-up upon presentation of symptoms\r\n** Familial neuroblastoma with a germline anaplastic lymphoma kinase (ALK) mutation\r\n** Rapid-onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation (ROHHAD syndrome) or congenital central hypoventilation syndrome (CCHS) with or without a germline paired–like homeobox 2B (PHOX 2B) mutation\r\n** Von Hippel-Lindau with a Von Hippel-Lindau (VHL) mutation\r\n** Women with an abnormal cell-free deoxyribonucleic acid (DNA) test (i.e. a non-invasive prenatal test [NIPT] to detect chromosomal abnormalities) and no cancer diagnosis\r\n** Other rare cancer predisposition syndromes at the discretion of the treating physician and study physicians\r\n* IF APPLICABLE: individuals with any of the above-listed cancer predisposition syndromes (apart from Li Fraumeni syndrome) are likewise eligible in the absence of a known mutation if they are an obligate carrier by pedigree
Individuals with “Li Fraumeni syndrome” defined as one of the following:\r\n* Carriers of a germline p53 mutation OR\r\n* Members of families meeting classic LFS criteria by family history without an identifiable p53 mutation OR\r\n* Obligate carrier by pedigree (these individuals can be offered testing but are still eligible if they defer); the following examples describe “obligate carriers by pedigree”\r\n** A child of a parent with known p53 mutation that is diagnosed with cancer\r\n** An individual with a sibling and a child who are p53 positive OR\r\n* Individuals with an inherited cancer predisposition syndrome as defined by one of the following:\r\n** Hereditary retinoblastoma with a germline Rb mutation\r\n** Diagnosis of hereditary paraganglioma/pheochromocytoma syndrome with a germline SDH mutation\r\n** Diagnosis of multiple endocrine neoplasia, type 1 or 2, with a germline MEN mutation\r\n** New diagnosis of opsoclonus-myoclonus with a negative cancer work-up upon presentation of symptoms\r\n** Familial neuroblastoma with a germline ALK mutation\r\n** Rapid-onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation (ROHHAD syndrome) or congenital central hypoventilation syndrome (CCHS) with or without a germline PHOX 2B mutation\r\n** Von Hippel-Lindau with a VHL mutation\r\n** Other rare cancer predisposition syndrome at the discretion of the treating physician and study physicians\r\n* IF APPLICABLE: individuals with any of the above-listed cancer predisposition syndromes (apart from Li Fraumeni syndrome) are likewise eligible in the absence of a known mutation if they are an obligate carrier by pedigree
Patient must not have a known thrombophilic condition (i.e. protein S, protein C or antithrombin III deficiency, Factor V Leiden, Factor II G20210A mutation, homocysteinemia, or antiphospholipid antibody syndrome); testing is not required in patients without a thrombophilic history
Has previously documented evidence of ALK fusion, ROS1 fusion, BRAF V600E mutation, RET rearrangement, HER2 mutation, MET amplification, or MET exon 14 skipping mutation. No new testing for these genomic alterations is required for Screening.
or mutation, including any deletions and any met fusions
or mutation, including any deletions and any met fusions
Patients with advanced AML that harbors IDH1 mutation
Documentation of IDH1 or IDH2 mutation in any tumor specimen
Subject has had presence of the FLT3/ITD activating mutation in the bone marrow or peripheral blood as determined by the local institution at diagnosis.
A tumor that is known to have a v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (K-ras) mutation
Family history of Leber Hereditary Optic Neuropathy, Autosomal Dominant Optic Atrophy, Late-Onset Retinal Degeneration, Familial Dysautonomia or other hereditary mitochondrial disease, unless the causative mutation(s) in the family have been determined and the participant has tested negative for the mutation(s).
Patients must have a potential germline mutation, as determined by the NCI-MATCH tumor profiling assay
Received HBOC genetic counseling or mutation testing prior to diagnosis; if the patient was previously tested only for a variant of uncertain clinical significance (i.e., not for known familial mutation, Jewish ethnicity panel/multisite 3 or comprehensive sequencing) and documentation is provided, they remain eligible
Tumor must harbor an IDH1-R132X mutation
Mutation results:\r\n* All patients must have molecular testing performed in a Clinical Laboratory Improvement Act (CLIA) certified lab which includes which includes KRAS and NRAS gene and exon 15 of BRAF gene (BRAF V600E mutation); patients with any known activating mutation in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61) and exon 4 (codons 117 and 146) of KRAS/NRAS genes and in exon 15 (BRAFV600E mutation) of BRAF gene are not eligible
Tumors must be tested and known negative for EGFR tyrosine kinase inhibitor (TKI) sensitizing mutations (EGFR exon 19 deletions, L858R, L861Q, G719X) and ALK gene rearrangements by routine Clinical Laboratory Improvement Act (CLIA)-certified clinical testing methods; negative circulating tumor DNA results alone are not acceptable; prior testing for tumor PD-L1 status is not required
An EGFR exon 20 insertion mutation must be detected in the tumor tissue; patients may be enrolled in the study based on an exon 20 insertion EGFR mutation detected by any Clinical Laboratory Improvement Act (CLIA)-certified tissue assay\r\n* NOTE: Testing results are to be submitted via Medidata Rave and the study chair or delegate will review the reports
Participants with known epidermal growth factor receptor (EGFR) mutations which are sensitive to available targeted inhibitor therapy (including, but not limited to, deletions in exon 19 and exon 21 [L858R] substitution mutations) are excluded
For Part 2 only: Participants must also have disease with a previously diagnosed activating epidermal growth factor receptor (EGFR) mutation (includes both inhibitor sensitive primary mutations such as Exon 19 deletion and L858R, as well as marketed tyrosine kinase inhibitor [TKI] -resistant mutations such as Exon 20 insertion). Documentation of EGFR mutation eligibility by CLIA-certified laboratory (or equivalent) testing is required
EGFR mutation (L858R and /or ex19del)
Eligible for first-line treatment with erlotinib based on documented evidence of tumor harboring an activating EGFR mutation [exon 19 deletion or exon 21 (L858R) substitution mutation].
Non-small cell lung cancer (NSCLC) or pancreatic cancer identified by exon 19 deletions or exon 21 L858R substitution mutations
Cancers with exon 20 mutations
Presence of sensitizing EGFR mutations (deletion in exon 19, L858R in exon 21, G719X, and L861Q); patients with the T790M mutation will also be eligible
EGFR mutations as performed on a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory demonstrating EGFR exon 18 G719X, exon 20 S768I, or exon 21 L861Q. Patients with compound (also referred to as multiple mutations) will be eligible provided the non-small cell lung cancer [NSCLC] demonstrates one of these mutations)
Detection of concurrent EGFR mutation with exon 20 T790M, exon 19 deletion, exon 21 L858R mutation or exon 20 insertion. Patients with compound (also referred to as multiple mutations) will be excluded if the molecular testing includes one of these mutations
Documented activating EGFR mutation (Exon 19 deletion, T790M, or L858R) on tumor samples by Food and Drug Administration (FDA)-approved test
Prior genotyping positive for an EGFR activating mutation (L858R, exon 19 deletion, G719X, L861Q)
An EGFR sensitizing mutation must be detected in tumor tissue; specifically, patients harboring the most common mutations, deletions in exon 19 or the L858R mutation in exon 21 are eligible; other EGFR sensitizing mutations may be eligible after discussion with the principal investigator; patients may be enrolled in the study based on an activating EGFR mutation detected by a Clinical Laboratory Improvement Act (CLIA) certified tissue or plasma-based assay, but will be required to undergo a mandatory tumor biopsy during study screening
Patients must have tumors that lack sensitizing EGFR mutation (e.g. exon 19 deletion or exon 21 L858R) or ALK rearrangement; if a patient has squamous histology, then EGFR and ALK testing is not required
Historical confirmation that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q).
Patients whose tumors known to harbor an exon 19 deletion or exon 21 L858R EGFR mutation must have progressed on or had intolerance to an EGFR TKI; patients whose tumors are known to harbor an ALK translocation must have progressed on or had intolerance to an ALK inhibitor
Cohort 1 specific inclusion criteria: Documented EGFR exon 20 mutation by one of the following Clinical Laboratory Improvement Act (CLIA) certified tests: OncoMine Comprehensive Assay (OCA), Guardant360 Assay (using plasma), or FoundationOne Assay or by a Food and Drug Administration (FDA) approved device using cobas EGFR mutation test version (v)2 or therascreen EGFR RGQ PCt kit; eligible mutations include D770_N771insSVD, D770_N771insNPG, V769_D770insASV, H773_V774insNPH, or any other exon 20 in-frame insertion or point mutation excluding T790M
Cohort 2 specific inclusion criteria: documented HER2 exon 20 mutation by a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory; eligible mutations include A775_G776insYVMA, G776_V777insVC, or P780_Y781insGSP, or any other in-frame exon 20 insertion mutation or point mutation including, but not limited to, L755S, G776V, and V777L
EGFR T790M mutation or any other acquired EGFR exon 20 mutation; patients with coexisting primary EGFR exon 20 and T790M mutations are eligible
Documented EGFR exon 20 insertion mutation
Documented HER2 exon 20 insertion mutation
Patient has had previous treatment with poziotinib or any other EGFR or HER2 exon 20 insertion mutation tyrosine kinase inhibitor prior to study participation
Phase 2 patients are also excluded if they had prior treatment with CK-101 or other third generation TKIs that target EGFR T790M mutation-positive NSCLC, or have evidence that the tumor harbors an exon 20 insertion mutation
Tumor sample confirmed as KRAS or NRAS [codons 12 and 13 (exon 2), 59 and 61 (exon 3), and 117 and 146 (exon 4)] or BRAF [codon 600 (exon 15)] mutation positive
Patients with characterized EGFR mutations that predict sensitivity to EGFR therapy, including, but not limited to exon 19 deletions and exon 21 mutations
Documented evidence of somatic activating mutation in EGFR (eg, G719X, exon 19 deletion, L858R, L861Q) in a tumor tissue sample. If a tissue sample is not available, then EGFR mutation status may be determined from circulating tumor DNA obtained from a blood sample using a validated or approved test kit.
Presence of exon 19 deletion or exon 21 (L858R) substitution of the EGFR gene
EGFR mutation with exon 19 deletion or L858R mutation (Exon 21) or ALK rearrangement positive must have failed prior TKI therapy
Incurable, advanced or metastatic/recurrent non-small cell lung cancer with EGFR activating mutations (exon 19 del, exon 21 L858R, L861Q, G718X); who have radiologic and/or clinically progressive disease on erlotinib at any point during the patient's cancer treatment as determined by the Investigator
Non-small cell lung cancer (NSCLC) with an activating EGFR mutation (exon 19 deletion, L858R point mutation, or any other mutation known to be associated with EGFR TKI sensitivity); presence of an activating EGFR mutation may be documented in tumor tissue or by plasma testing if performed in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory; AND
Have a documented EGFR in-frame exon 20 insertion by a local test, including A763_Y764insFQEA, V769_D770insASV, D770_N771insNPG, D770_N771insSVD, H773_V774insNPH, or any other in-frame exon 20 insertion mutation.
A HER2 exon 20 insertion including A775_G776insYVMA, G776_V777insVC, or P780_Y781insGSP, or any other in-frame exon 20 insertion mutation.
An EGFR exon 20 insertion: A763_Y764insFQEA, V769_D770insASV, D770_N771insNPG, D770_N771insSVD, H773_V774insNPH, or any other in-frame exon 20 insertion mutation.
A HER2 exon 20 insertion: A775_G776insYVMA, G776_V777insVC, P780_Y781insGSP, or any other in-frame exon 20 insertion mutation.
For patients with an EGFR exon 20 insertion: have not received a TKI with activity against the specific documented EGFR exon 20 insertion.
For patients with a HER2 exon 20 insertion or HER2 activating point mutation: have not received a TKI with pan-HER activity (eg, afatinib, neratinib, or dacomitinib).
Have one of the following documented by a local test: an activating mutation in EGFR including exon 19 deletions or exon 21 L858R substitution (with or without T790M), or an uncommon activating mutation other than exon 20 insertion including, but not limited to, G719X (where X is any other amino acid), S768I, L861Q, or L861R.
For patients with a documented EGFR exon 19 deletion or exon 21 L858R substitution: resistant to at least one prior EGFR inhibitor (eg, erlotinib, gefitinib, or afatinib).
Patients with an EGFR exon 20 insertion
Absence of an activating mutation (Exon 19 deletion or Exon 21 L858R mutation) in the epidermal growth factor receptor (EGFR) in the pre-treatment biopsy of the tumor. Patients with activating EGFR mutations are eligible if they have progressed following treatment with erlotinib. A pretreatment tumor biopsy must be available for analysis. If a biopsy has not been performed prior to entry, then a biopsy will be required.
In cohort 2, must have one or more mutations found in KRAS exon 2, 3, or 4; NRAS exon 2, 3, or 4; BRAF codon 600; may have a concomitant EGFR ectodomain mutation, if the most prevalent EGFR ectodomain mutation does not have over a 5-fold higher allele frequency than the most prevalent KRAS/NRAS/BRAF mutation
All patients must have a somatic PIK3CA gene mutation (i.e., R88Q in exon 1, N345K in exon 4, C420R in exon 7, E542K, E545X [E545A, E545D, E545G, and E545K], Q546X [Q546E, Q546K, Q546L, and Q546R] in exon 9, and M1043I, H1047X [H1047L, H1047R, and H1047Y], or G1049R in exon 20) in a representative primary or metastatic tumor sample confirmed by the Roche COBAS PIK3CA Mutation Test at Q^2 Solutions
Documented evidence of a tumor with 1 or more EGFR mutations excluding exon 20\n             insertion
-  Documented evidence of an exon 20 insertion activating mutation in the EGFR gene
Presence of JAK2 exon 12 mutation
Patients must have documented presence of an EGFR exon 19 deletion or exon 21 (L858R) substitution mutation; T790M mutation or other molecular abnormality will be allowed as long as it accompanies one of the mutations listed above; EGFR testing must be performed using a Food and Drug Administration (FDA)-approved test or in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory.
JAK2 exon 12 mutation: PV that lacks the JAK2V617F mutation but is characterized by the exon 12 mutation
Pathologically confirmed diagnosis of non-small cell lung cancer with either EGFR exon 19 deletion mutation, EGFR exon 21 L858R point mutation, exon 18 G719X, and exon 21 L861Q; other rare EGFR mutations may be eligible after discussion with the overall principal investigator; mutations detected at outside laboratories are acceptable for enrollment
NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test
Dose escalation subjects: Epidermal Growth Factor Receptor (EGFR) activating mutation by local testing: exon 18 G719X, exon 19 deletion, exon 21 L861Q, exon 21 L858R or exon 20 insertion; and received prior treatment with EGFR Tyrosine Kinase Inhibitor (TKI)
Subject on any line of treatment and has an EGFR exon 20 insertion mutation on examination of an NSCLC tissue or cellular specimen. Local testing may determine eligibility and a tumor sample should also be sent for central testing.
Known EGFR exon 19 or 21 mutation or ALK rearrangement
Subjects with characterized Epidermal Growth Factor Receptor (EGFR) activating mutations that predict sensitivity to anti-EGFR-therapy, including, but not limited to exon 19 deletions and exon 21 alterations
At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q)
Subject has squamous NSCLC, or an untreated known EGFR mutation of exon 19 deletion or L858R mutation in exon 21, or a known ALK gene rearrangement.
Subject has non-squamous NSCLC, or a known Epidermal Growth Factor Receptor (EGFR) mutation of exon 19 deletion or L858R mutation in exon 21, or a known Anaplastic Lymphoma Kinase (ALK) gene rearrangement.
All adenocarcinoma patients will be tested for ALK rearrangements and EGFR (exon 19 deletion and exon 21 L8585R substitution) mutations and must have been treated with prior EGFR or ALK therapy as well as a platinum containing doublet
Participants must have histologically or cytologically confirmed stage IV or recurrent non-small cell lung cancer with a documented exon 20 insertion mutation in EGFR (exon 20 insertion/deletion and deletion mutations will also be allowed)
Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) OR
Histologic documentation of primary lung carcinoma, non-squamous histology with activating epidermal growth factor receptor (defined as deletion 19 or exon 21 L858R mutation); Note: EGFR mutation testing must be performed at a Clinical Laboratory Improvement Amendments (CLIA) certified lab; either institutional or through a commercial laboratory (e.g. Genzyme, Response Genetics, etc); the laboratory report from the commercial laboratories report the specific mutations detected, and the method of detecting the exon 19 and exon 21 L858R point mutations must be available
Evidence of either EGFR gene amplification by fluorescence in situ hybridization (FISH) or EGFR activating mutation in the most recent tumor specimen prior to enrollment; results of EGFR gene amplification will be confirmed by Dr. John Lafrate's laboratory at Massachusetts General Hospital (MGH) post hoc; gene amplification is defined as EGFR to Cen7 (centromere 7 copy number control) ratio of at least 2 to 1; for EGFR activating mutation, any one of the following EGFR mutations is eligible: extracellular domain mutation: EGFRvIII, R108K, T263P, A289V, A289D, A289T, G598V; or kinase domain mutation: G719X, T790M, exon19 deletions/insertions (at/near/within codons 744-759), exon 20 insertions/deletions/mutations (insertions/deletions at or near 766-769, S768I, R776C), L858R, L861Q
Subject has an EGFR activating mutation (exon 19 deletion or exon 21 L858R), with or without T790M mutation, by local or central testing on examination of a NSCLC FFPE specimen (archival or fresh biopsy). Subjects harboring both exon 19 deletion and exon 21 L858R mutations are not eligible. A tissue sample from the same block used to determine eligibility by local testing should be available to send to the central lab for confirmatory testing. Subjects randomized based on local results indicating presence of EGFR mutation may remain on study if central results are discordant.
Documented evidence of a tumor with activating EGFR mutations by local testing. Patients with exon 20 insertions are not eligible with the exception of patients with documented evidence of the exon 20 insertion A763_Y764insFQEA in the EGFR gene
Documented evidence of an exon 20 insertion activating mutation other than A763_Y764insFQEA in the EGFR gene
Subjects with known EGFR mutations which are sensitive to available targeted inhibitor therapy (including, but not limited to, deletions in exon 19 and exon 21 [L858R] substitution mutations) are excluded; all subjects with non-squamous histology must have been tested for EGFR mutation status; use of a Food and Drug Administration (FDA)-approved test is strongly encouraged
Subject has a documented exon 19 deletion or exon 21 L858R EGFR activating mutation.
Patients with tumors that harbor either EGFR sensitizing mutations or ALK rearrangement\r\n* EGFR sensitizing mutations include: \r\n** Exon 19 deletion or insertion\r\n** L858R (c.2573 T>G)\r\n** G719X (c.2156 G>C, G>T, or G>A)\r\n** L861Q (c.2582 T>A)
Metastatic NSCLC with documented EGFR exon 19 deletion or exon 21 (L858R) substitution mutation
If tumor histology is adenocarcinoma, must have wild-type EGFR genotype as assessed by a validated assay that includes exon 19 deletion and exon 21 (L858R) substitution.
PHASE I: Patients must have metastatic/recurrent, histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with progressive disease by RECIST 1.1 on a previous EGFR-tyrosine kinase inhibitor (TKI); OR patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on platinum containing chemotherapy
PHASE II COHORT A: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with stable disease by RECIST 1.1 as best response on erlotinib compared to pre-treatment erlotinib imaging by RECIST 1.1 or progressive disease compared to pre-treatment imaging by RECIST 1.1 after a minimum duration of treatment on erlotinib of 12-weeks; patients must be enrolled within 6 months of initiation of erlotinib
PHASE II COHORT B: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on or after platinum doublet chemotherapy
Documented evidence in tumor of exon 20 insertion, small cell transformation, or MET amplification
Patients with activating but not sensitizing mutations (exon 20 insertions, EGFR T790M)
Activating EGFR mutation (exon 19 deletion, L858R, G719X, L861X)
A documented somatic activating mutation in epidermal growth factor receptor (EGFR) (including but not limited to exon 19 deletion or L858R)
For the MTD expansion cohort, patients will be eligible if they meet one of the following criteria:\r\n* Have an EGFR-sensitive mutation (as G719C in exon 18, E746-A750 in exon 90, L858R in exon 21) and have been previously treated with EGFR inhibitor therapy but have subsequently developed resistance, OR\r\n* Have an EGFR-resistant mutation (as T790M in exon 20), OR\r\n* Do not have an EGFR mutation, but have benefited from EGFR inhibitor therapy (including either >= 4 months of stable disease [SD] OR a >= partial response [PR])
Histologically or cytologically confirmed metastatic stage IIIB/IV lung adenocarcinoma with known activating mutations in the EGFR TK domain (including exon 19 deletion and L858R)
NSCLC must harbor an EGFR activating mutation (Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q)
Histologically or cytologically documented metastatic or unresectable, locally advanced or metastatic NSCLC, with one or more activating EGFR mutation (eg, G719X, exon 19 deletion, L858R, L861Q) and absence of exon 20 insertion
Historical confirmation that the tumor harbors an epidermal growth factor receptor (EGFR) mutation known to be associated with EGFR tyrosine kinase inhibitor (TKI) sensitivity (including G719X, exon 19 deletion, L858R, L861Q)
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.