Clinical Trial - NCT03718091

M6620 (VX-970) in Selected Solid Tumors

Active, not recruiting

Sponsor: Massachusetts General Hospital

Collaborators: EMD Serono

Information provided by (Responsible party): Principal Investigator Massachusetts General Hospital Gregory Cote Principal Investigator

ClinicalTrials.gov Identifier: NCT03718091

Protocol Info

Short Description: Phase II M6620 in Selected Solid Tumors
Long Description: A Phase II Study of M6620 (VX-970) in Selected Solid Tumors
MGH Status: Closed
Sponsor: DF/HCC
Disease Program: Phase I

Next Steps


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Purpose

This research study is studying a drug called M6620 as a possible treatment for advanced solid tumor.
Condition Title Intervention Phase
Solid Tumor Leiomyosarcoma Osteosarcoma M6620 Phase 2
Study Type Interventional
Official Title A Phase II Study of M6620 (VX-970) in Selected Solid Tumors

Primary Outcome Measures

Changes in Phospho-Chk1 levels in biopsy specimens [Time Frame: Baseline, Day 15] [Designated as safety issue: ]

Change in yH2AX levels in biopsy specimens [Time Frame: Baseline, Day 15] [Designated as safety issue: ]

Disease Control Rate [Time Frame: 16 weeks] [Designated as safety issue: ]


Secondary Outcome Measures

Number of participants with treatment related Serious Adverse Events [Time Frame: From the start of treatment until 30 days after the end of treatment, up to approximately 5 years] [Designated as safety issue: ]

Estimated Enrollment: 223
Study Start Date: January 2019
Estimated Study Completion Date: April 2025
Estimated Primary Completion Date: April 2022
Arms Assigned Interventions

Experimental:Cohort T1: ATRX-mutant Leiomyosarcoma

M6620 will administered intravenously on days 1,4, 8, 11, 15, 18, 22, 25 on a 28-day cycle.

Experimental:Cohort T2: Truncating ATM Mutation

M6620 will administered intravenously on days 1,4, 8, 11, 15, 18, 22, 25 on a 28-day cycle.

Experimental:Cohort T3: Other HR Gene Mutations

M6620 will administered intravenously on days 1,4, 8, 11, 15, 18, 22, 25 on a 28-day cycle.

Experimental:Cohort 1A: Osteosarcoma

M6620 will administered intravenously on days 1,4, 8, 11, 15, 18, 22, 25 on a 28-day cycle.
Drug:M6620
M6620 is a drug designed to inhibit the ATR enzyme. Inhibiting ATR may block how cancers repair their naturally damaged DNA, handle cancer cell stress, and maintain cancer cell life and health.

Experimental:Cohort 1B: Leiomyosarcoma

M6620 will administered intravenously on days 1,4, 8, 11, 15, 18, 22, 25 on a 28-day cycle.

Experimental:Cohort 2: Truncating ATM mutation

M6620 will administered intravenously on days 1,4, 8, 11, 15, 18, 22, 25 on a 28-day cycle.

Experimental:Cohort 3A: Germline BRCA mutation

M6620 will administered intravenously on days 1,4, 8, 11, 15, 18, 22, 25 on a 28-day cycle.

Experimental:Cohort 3B: Other HR Alteration

M6620 will administered intravenously on days 1,4, 8, 11, 15, 18, 22, 25 on a 28-day cycle.

Experimental:Cohort 4A: MYC amplification, FBXW7 mutation

M6620 will administered intravenously on days 1,4, 8, 11, 15, 18, 22, 25 on a 28-day cycle.

Experimental:Cohort 4B: Cyclin E amplification

M6620 will administered intravenously on days 1,4, 8, 11, 15, 18, 22, 25 on a 28-day cycle.

Experimental:Cohort 5: ARID1A mutation

M6620 will administered intravenously on days 1,4, 8, 11, 15, 18, 22, 25 on a 28-day cycle.

Experimental:Cohort T4: SDH-Mutant GIST

M6620 will administered intravenously on days 1,4, 8, 11, 15, 18, 22, 25 on a 28-day cycle.

Eligibility

Ages Eligible for Study: N/A-N/A

Genders Eligible for Study: All

Accepts Healthly Volunteers: No

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).

Exclusion Criteria:

  • Participants who have had chemotherapy, immune therapy, other investigational therapy, major surgery, or radiotherapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study, or participants who have not recovered to = Grade 1 or baseline from therapies administered more than 3 weeks prior (with the exceptions of 1. Alopecia and peripheral neuropathies which may be = Grade 2 at study entry and 2. Laboratory abnormalities that are not listed in 3.1 and that are not considered clinically meaningful [e.g. decreased lymphocyte count, electrolyte abnormalities]
  • Participants who have received oral tyrosine kinase inhibitors (TKIs) within 5 half-lives of study entry.
  • Participants who have previously received treatment with an ATR inhibitor, including but not limited to M6620 (VX-970).
  • Participants with known untreated brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Participants with a history of brain metastases that have been treated, no longer require corticosteroids, and have been stable on imaging for at least one month following the end of treatment are permitted.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to M6620.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Pregnant women are excluded from this study because M6620 is an agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with M6620, breastfeeding should be discontinued if the mother is treated with M6620.
  • Known HIV-positive participants are ineligible because of the increased risk of lethal infections when treated with potentially marrow-suppressive therapy.
  • Patients with a history of another malignancy are excluded with the exception of 1. patients who remain disease-free for 3 years and 2. adequately treated cervical carcinoma in situ, non-melanoma skin cancer (e.g. basal cell, squamous cell carcinomas), low-risk thyroid cancer.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT03718091

Locations

  • United States, Massachusetts
    • Massachusetts General Hospital Cancer Center Boston, Massachusetts, United States, 02214
    • Beth Israel Deaconess Medical Center Boston, Massachusetts, United States, 02215
    • Boston Children Hospital Boston, Massachusetts, United States, 02215
    • Dana Farber Cancer Institute Boston, Massachusetts, United States, 02215

Sponsors and Collaborators

Massachusetts General Hospital

EMD Serono

More Information

No publications provided

Responsible Party: Principal Investigator Massachusetts General Hospital Gregory Cote Principal Investigator
ClinicalTrials.gov Identifier: NCT03718091
Other Study ID Numbers:
Study First Received:
Last Updated:
Health Authority:

Keywords provided by Massachusetts General Hospital:

Solid Tumor

leiomyosarcoma

Osteosarcoma

Additional relevant MeSH terms:

Osteosarcoma

Leiomyosarcoma

Next Steps


If you are interested in this protocol or in other treatment options at Massachusetts General Hospital, please Request a Consultation.







ClinicalTrials.gov processed this data on February 25, 2021