M6620 (VX-970) in Selected Solid Tumors

Inclusion Criteria

• •Participants Enrolling to the Translational Lead-in Study:
• •For enrollment to cohort T1: participants must have metastatic or progressive LMS with a) treatment with at least one prior systemic therapy b) ATRX mutation by NGS
• •For enrollment to cohorts T2 or T3: participants must have a histologically or cytologically confirmed advanced solid tumor for which no standard curative therapy is available.
• •For enrollment to cohort T2: participants must have a truncating ATM mutation. Testing may be completed via the DFCI/BWH OncoPanel, MGH SNaPshot, or any other CLIA-certified method.
• •For enrollment to cohort T3, participants must have one of the following (testing may be completed via the DFCI/BWH OncoPanel, MGH SNaPshot, or any CLIA-certified laboratory):
• •* Germline mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function).
• •* A somatic mutation in BRCA1 or BRCA2, or another mutation within a known HR gene including BARD1, BRIP1, CDK12, CHEK2, FANCA, FANCC, FANCE, FANCF, FANCM, MRE11A, NBN, PALB2, RAD51B, RAD51C, or RAD51D.
• •* A MYC amplification of greater than 6-fold.
• •* FBXW7 truncating or missense mutation designated as deleterious.
• •* CCNE1 amplification of greater than 8-fold.
• •* An ARID1A mutation as determined by the DFCI/BWH OncoPanel or any other CLIA-certified method.
• •* Other (unlisted) mutations within known HR genes may be considered with approval from the site principal investigator.
• •For enrollment to cohort T4: participants must have GIST with known mutation in SDHX genes or loss of expression of SDHX protein(s), as determined by standard pathology assays. Prior therapy is not required.
• •Age ≥ 18 years
• •ECOG performance status ≤ 2 (Karnofsky \[KPS\] ≥ 60%; KPS of 50 is not permitted)
• •Participants must have tumor amenable to biopsy, and be a candidate for tumor biopsy according to the treating investigator. The patient must be willing to undergo a fresh tumor biopsy for this study.
• •Participants must have archival tissue available for analysis. Participants without available archival tissue enrolling to the translational lead-in study may instead use tissue from the fresh pre-treatment biopsy.
• •Participants Enrolling to the Phase II:
• •For enrollment to cohort 1A: participants must have metastatic or progressive osteosarcoma treated with at least one prior systemic therapy.
• •For enrollment to cohort 1B: participants must have metastatic or progressive leiomyosarcoma treated with at least one prior systemic therapy.
• •For enrollment to cohorts 2 - 5: participants must have a histologically or cytologically confirmed advanced solid tumor for which no standard curative therapy is available.
• •For enrollment to cohort 2: participants must have a truncating ATM mutation. Testing may be completed via the DFCI/BWH OncoPanel, MGH SNaPshot, or any other CLIA-certified method.
• •For enrollment to cohort 3A: participants must have a germline mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function). Testing may be completed via the DFCI/BWH OncoPanel, MGH SNaPshot, or any CLIA-certified laboratory.
• •For enrollment to cohort 3B: participants must have a somatic mutation in BRCA1 or BRCA2, or another mutation within a known HR gene including BARD1, BRIP1, CDK12, CHEK2, FANCA, FANCC, FANCE, FANCF, FANCM, MRE11A, NBN, PALB2, RAD51B, RAD51C, or RAD51D. Other (unlisted) mutations within known HR genes may be considered with approval from the site principal investigator.
• •For enrollment to cohort 4A: participants must have a MYC amplification of greater than 6-fold or an FBXW7 truncating or missense mutation designated as deleterious, as determined by the DFCI/BWH OncoPanel, MGH SNaPshot, or any other CLIA-certified method.
• •For enrollment to cohort 4B: participants must have a CCNE1 amplification of greater than 8-fold as determined by the DFCI/BWH OncoPanel, MGH SNaPshot, or any other CLIA-certified method.
• •For enrollment to cohort 5: participants must have an ARID1A mutation as determined by the DFCI/BWH OncoPanel, MGH SNaPshot, or any other CLIA-certified method.
• •For enrollment to cohort 1A: Age \> 12
• •For enrollment to cohorts 1B - 5: Age ≥ 18
• •ECOG performance status ≤ 2 (Karnofsky ≥ 60%; KPS of 50 is not permitted) for participants ≥ 16 years of age, Lansky ≥ 50% for participants \< 16 years of age
• •Participants must have archival tissue available for analysis
• •All Participants:
• •If any participant could enroll to more than one cohort based on mutational status, the cohort enrollment decision will be discussed with the overall principal investigator. For example, if a participant has both an ATM mutation and an FBXW7 mutation and thus could enroll to either Cohort 2 or Cohort 4A, the decision of which cohort to enroll to will be made in conjunction with the overall principal investigator. The decision as to which cohort the participant should be enrolled on must be made prior to the initiation of study treatment.
• •Participants must have RECIST 1.1 measurable disease.
• •Participants must have normal organ and marrow function as defined below:
• •All Participants:
• •Absolute neutrophil count ≥ 1,500/mcL
• •Platelets ≥ 100,000/mcL
• •Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN) for age
• •Adult Participants (Age ≥ 18 years):
• •AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional ULN; OR
• •* 5 × institutional ULN if liver metastases are present
• •Serum or plasma creatinine ≤ 1.5 × institutional ULN, OR
• •Creatinine clearance ≥ 60 mL/min by Cockcroft-Gault equation for participants with creatinine levels above 1.5 × institutional ULN
• •Pediatric Participants (Age \< 18 years):
• •ALT (SGPT) ≤ 3 × institutional (ULN)
• •-for the purposes of this study, the ULN for SGPT will be defined as 45 U/L.
• •Serum or plasma creatinine Participants 13 - 15 years: males ≤ 1.5 mg/dL, females
• •≤ 1.4 mg/dL, participants 16 - 17 years: males ≤ 1.7 mg/dL, females ≤ 1.4 mg/dL; OR
• •Creatinine clearance ≥ 60 mL/min/1.73 m2 by Schwartz formula for participants with creatinine levels above the limits described above
• •* The effects of M6620 on the developing human fetus are unknown. For this reason and because anti-cancer agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 6 months after completion of M6620 administration.
• •* Ability to understand and the willingness to sign a written informed consent document (or parent or legally authorized representative, if minor).