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