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A Study of M6620 in Treating Patients with Solid Tumors

Trial Status: Active

This phase II trial studies how well M6620 works in treating patients with solid tumors. ATR is an enzyme in cells that is responsible for multiple functions including repairing damaged DNA. In cancer cells, active ATR enzymes protect the cancer by helping the cells repair damage, stay alive, and maintain health. 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. Administration of M6620 may therefore assist in the slowing of growth or destruction of some cancers.

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. Other ATM mutations with sufficient evidence of gene inactivation may be considered eligible after review. Testing may be completed via the Dana-Farber Cancer Institute (DFCI)/Brigham and Women's Hospital (BWH) OncoPanel, Massachusetts General Hospital (MGH) SNaPshot, or any other Clinical Laboratory Improvement Act (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, missense or other inactivating mutation designated as deleterious. Other deleterious mutations may be considered after discussion with the overall principal investigator (PI). * 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 for T1, T2, and T3; age >= 12 years for T4.
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky [KPS] >= 60%; KPS of 50 is not permitted).
  • For T1, T2, and T3, 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. If the biopsy is deemed unsafe, the patient may enroll with the permission of the overall PI (though the patient will not count towards accrual numbers).
  • 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. Other ATM mutations with sufficient evidence of gene inactivation may be considered eligible. 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 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 measurable disease.
  • 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): Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/ALT(serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN; OR =< 5 x institutional ULN if liver metastases are present.
  • Adult participants (age >= 18 years): Serum or plasma creatinine =< 1.5 x institutional ULN, OR
  • Adult participants (age >= 18 years): Creatinine clearance >= 60 mL/min by Cockcroft-Gault equation for participants with creatinine levels above 1.5 x institutional ULN.
  • Pediatric participants (age < 18 years): ALT (SGPT) =< 3 x institutional (ULN) * Note: for the purposes of this study, the ULN for SGPT will be defined as 45 U/L.
  • Pediatric participants (age < 18 years): 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
  • Pediatric participants (age < 18 years): Creatinine clearance >= 60 mL/min/1.73 m^2 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, or major surgery within 3 weeks (2 weeks for radiotherapy); (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 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 human immunodeficiency virus (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.
  • Patients with Li Fraumeni syndrome or ataxia telangiectasia syndrome.

Massachusetts

Boston
Beth Israel Deaconess Medical Center
Status: ACTIVE
Contact: Andrea Julie Bullock
Brigham and Women's Hospital
Status: ACTIVE
Contact: Geoffrey Ira Shapiro
Dana-Farber Cancer Institute
Status: ACTIVE
Contact: Geoffrey Ira Shapiro
Massachusetts General Hospital Cancer Center
Status: ACTIVE
Contact: Gregory Michael Cote

PRIMARY OBJECTIVES:

I. To determine the preliminary anti-cancer activity of ATR kinase inhibitor M6620 (M6620) monotherapy in selected cancer populations including ATRX-mutated leiomyosarcoma (LMS), ATM-mutated solid tumors, BRCA1/2 and other homologous repair (HR)-mutated cancers, malignancies with replicative stress, ARID1A-mutated cancers, and SDH-deficient gastrointestinal stromal tumors (GIST). (Translational lead-in)

II. To determine changes in the pharmacodynamic endpoints of phosphorylated (phospho)-Chk1 and gamma H2AX in biopsy specimens of patients treated with M6620 monotherapy. (Translational lead-in)

III. To determine the anti-cancer activity of M6620 monotherapy in selected cancer populations including osteosarcoma, LMS, ATM-mutated solid tumors, BRCA1/2 and other HR-mutated cancers, malignancies with replicative stress, and ARID1A-mutated cancers. (Phase II)

SECONDARY OBJECTIVES:

I. To determine correlations between selected biomarkers and M6620 monotherapy anti-cancer activity, including mutations detected in targeted next generation (NextGen) sequencing (NGS), alanine aminotransferase (ALT) status (telomeric repeat-containing ribonucleic acid [RNA] [TERRA] in situ hybridization [ISH], C-circle assay), ATM, RAD51, MYC, cyclin E and ARID1A immunohistochemistry (IHC).

II. To confirm the safety and overall tolerability of M6620 in these patient populations.

OUTLINE:

Patients receive ATR kinase inhibitor M6620 intravenously (IV) over 60 minutes on days 1, 4, 8, 11, 15, 18, 22, and 25. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After 16 weeks (4 cycles), patients may receive ATR kinase inhibitor M6620 weekly on days 1, 8, 15, and 22 after discussion with the site principal investigator.

After completion of study treatment, patients are followed for 30 days.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Gregory Michael Cote

  • Primary ID 18-274
  • Secondary IDs NCI-2019-01731
  • Clinicaltrials.gov ID NCT03718091