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-fo