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M6620 (VX-970) in Selected Solid Tumors

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ClinicalTrials.gov Identifier: NCT03718091
Recruitment Status : Recruiting
First Posted : October 24, 2018
Last Update Posted : January 14, 2019
Sponsor:
Collaborator:
EMD Serono
Information provided by (Responsible Party):
Gregory Cote, Massachusetts General Hospital

Brief Summary:
This research study is studying a drug called M6620 as a possible treatment for advanced solid tumor.

Condition or disease Intervention/treatment Phase
Solid Tumor Leiomyosarcoma Osteosarcoma Drug: M6620 Phase 2

Detailed Description:

This study is made up of two phases: a Translational Lead-In Phase and a Phase II. These two phases serve different functions. The translational lead-in phase is designed to test the drug on a small number of patients in efforts to gain information on two research questions:

  • If M6620 has an anti-cancer effect on participants
  • If M6620 research findings that were discovered in laboratory studies are also found in human research studies.

Phase II is a much larger study to determine if M6620 has an anti-cancer effect in different groups of patients.

The FDA (the U.S. Food and Drug Administration) has not approved M6620 as a treatment for any disease.

ATR is an enzyme in cells that is responsible for multiple functions including repairing damaged DNA, helping cells that are stressed during the DNA copying process, and working to maintain the ends of chromosomes. 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.

In this research study, the investigators are...

  • Gathering initial data on the anti-cancer activity of M6620 when given alone to participants within selected cancer populations
  • Determining if there are changes in the biological components in the participant's body that may be associated with damaged DNA repair

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 223 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of M6620 (VX-970) in Selected Solid Tumors
Actual Study Start Date : January 8, 2019
Estimated Primary Completion Date : April 30, 2022
Estimated Study Completion Date : April 30, 2025

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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.
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.
Other Name: VX-970

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.
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.
Other Name: VX-970

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.
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.
Other Name: VX-970

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.
Other Name: VX-970

Experimental: Cohort 1B: Leiomyosarcoma
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.
Other Name: VX-970

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.
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.
Other Name: VX-970

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.
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.
Other Name: VX-970

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.
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.
Other Name: VX-970

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.
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.
Other Name: VX-970

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.
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.
Other Name: VX-970

Experimental: Cohort 5: ARID1A mutation
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.
Other Name: VX-970




Primary Outcome Measures :
  1. Changes in Phospho-Chk1 levels in biopsy specimens [ Time Frame: Baseline, Day 15 ]
    Changes in the levels of Phospho-Chk1 in biopsy specimens of patients treated with M6620 monotherapy from baseline to cycle 1 day 15.

  2. Change in yH2AX levels in biopsy specimens [ Time Frame: Baseline, Day 15 ]
    Changes in the levels of yH2AX in biopsy specimens of patients treated with M6620 monotherapy from baseline to cycle 1 day 15.

  3. Disease Control Rate [ Time Frame: 16 weeks ]

    The number of participants that achieve either Stable Disease (SD), Partial Response (PR), or Complete Response (CR) as their best overall response.

    • Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.
    • Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
    • Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.


Secondary Outcome Measures :
  1. 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 ]
    Adverse events will be assessed using Common Terminology Criteria for Adverse Events (CTCAE 5.0)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   12 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03718091


Contacts
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Contact: Gregory M Cote, MD, PhD 617-724-4000 gcote@mgh.harvard.edu

Locations
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United States, Massachusetts
Massachusetts General Hospital Cancer Center Recruiting
Boston, Massachusetts, United States, 02214
Contact: Gregory M. Cote, MD, PhD    617-724-4000    gcote@mgh.harvard.edu   
Principal Investigator: Gregory M. Cote, MD, PhD         
Beth Israel Deaconess Medical Center Recruiting
Boston, Massachusetts, United States, 02215
Contact: Glen Weiss, MD       gweiss@bidmc.harvard.edu   
Principal Investigator: Glen Weiss, MD         
Boston Children Hospital Recruiting
Boston, Massachusetts, United States, 02215
Contact: Katherine Janeway, MD       KJANEWAY@PARTNERS.ORG   
Principal Investigator: Katherine Janeway         
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Geoffrey I. Shapiro, MD       GSHAPIRO@PARTNERS.ORG   
Principal Investigator: Geoffrey I. Shapiro, MD         
Sponsors and Collaborators
Massachusetts General Hospital
EMD Serono
Investigators
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Principal Investigator: Gregory M Cote, MD, PhD Massachusetts General Hospital

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Responsible Party: Gregory Cote, Principal Investigator, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT03718091     History of Changes
Other Study ID Numbers: 18-274
First Posted: October 24, 2018    Key Record Dates
Last Update Posted: January 14, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Gregory Cote, Massachusetts General Hospital:
Solid Tumor
leiomyosarcoma
Osteosarcoma
Additional relevant MeSH terms:
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Osteosarcoma
Leiomyosarcoma
Neoplasms
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Sarcoma
Neoplasms, Muscle Tissue