Avelumab and M6620 for the Treatment of DDR Deficient Metastatic or Unresectable Solid Tumors

NCT04266912 | Active Not Recruiting Phase 1 Results FDA Drug

• 2 other identifiers: 2018-1059NCI-2019-07598
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 1

Brief Summary

This phase I/II trial studies the side effects and best dose of avelumab with M6620 in treating patients with deoxyribonucleic acid (DNA) damage repair (DDR) deficient solid tumors that have spread to other places in the body (metastatic) or cannot be removed by surgery (unresectable). DDR deficiency refers to a decrease in the ability of cells to respond to damaged DNA and to repair the damage, which can be caused by genetic mutations. Immunotherapy with monoclonal antibodies, such as avelumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. M6620 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving avelumab together with M6620 may help to control DDR deficient metastatic or unresectable solid tumors.

Conditions

Metastatic Malignant Solid Neoplasm; Refractory Malignant Solid Neoplasm; Unresectable Malignant Solid Neoplasm

Outcome Measures

Primary Outcomes (1)

• Number of Patients With Dose Limiting Toxicities (DLT) as a Measure of Safety Profile to Determine the Recommended Phase 2 Dose (RP2D).

  A DLT was evaluated according to the NCI CTCAE 5.0 \& defined as: grade 4 neutropenia lasting greater than 7 days or febrile neutropenia, grade 3 thrombocytopenia with bleeding or grade 4 thrombocytopenia lasting greater than 7 days, any treatment related adverse event that in the opinion of the safety monitoring committee exposes participants to unacceptable risk, a delay of more than 4 weeks before receiving the next scheduled study drug due to persisting toxicities attributable to study drugs, grade 3 nausea, vomiting or diarrhea lasting greater than 72 hours with optimal care, grade 3 fatigue lasting greater or equal to 7 days, grade 3 pneumonitis of any duration, any grade 4 immune related toxicities, any other grade 3 or greater non-hematological AE, including infusion-related reactions of any duration, liver enzymes greater than 3 times above the upper limit of normal and concurrent total bilirubin elevation that is greater than 2 times above the upper limit of normal.

  The DLT monitoring time frame was the first 28-days of study participation (Cycle 1).

Study Arms (4)

Escalation Dose Level 1

EXPERIMENTAL

Berzosertib 240 mg/m2 once weekly + Avelumab 800 mg IV on days 1 and 15 of each 28-day cycle

Drug: Avelumab; Drug: Berzosertib

Escalation Dose Level 2

EXPERIMENTAL

Berzosertib 480 mg/m2 once weekly + Avelumab 800 mg IV on days 1 and 15 of each 28-day cycle

Drug: Avelumab; Drug: Berzosertib

Expansion Dose Level 1

EXPERIMENTAL

Berzosertib 240 mg/m2 once weekly + Avelumab 800 mg IV on days 1 and 15 of each 28-day cycle

Drug: Avelumab; Drug: Berzosertib

Expansion Dose Level 2

EXPERIMENTAL

Berzosertib 480 mg/m2 once weekly + Avelumab 800 mg IV on days 1 and 15 of each 28-day cycle

Drug: Avelumab; Drug: Berzosertib

Interventions

Avelumab DRUG

Given IV

Also known as: Bavencio, MSB-0010718C, MSB0010718C

Escalation Dose Level 1; Escalation Dose Level 2; Expansion Dose Level 1; Expansion Dose Level 2

Berzosertib DRUG

Given IV

Also known as: 2-Pyrazinamine, 3-(3-(4-((Methylamino)methyl)phenyl)-5-isoxazolyl)-5-(4-((1-methylethyl)sulfonyl)phenyl)-, M 6620, M6620, VX 970, VX-970, VX970

Escalation Dose Level 1; Escalation Dose Level 2; Expansion Dose Level 1; Expansion Dose Level 2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective
• Subjects will be eligible for this study based on the presence of actionable aberrations in one or more of the following DNA damage response (DDR) genes: ARID1A, ATM, ATR, ATRX, BAP1, BARD1, BRCA1/2, BRIP1, CDK12, CHEK2, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCM, MRE11A, MSH2, NBN (NBS1), PALB2, RAD51, RAD51C, RAD51D, SMARCB1, and VHL, or other related genes at the discretion of the principal investigator in consultation with the MD Anderson Cancer Center Institute for Personalized Cancer Therapy Precision Oncology Decision Support (PODS) group. Variant interpretation for actionability will be performed by PODS
• Subjects with germline defects in DDR genes are eligible for this trial
• The collection of archival tumor tissue (within 1 year prior to study enrollment) will be mandatory. Tumor biopsies on cycle 1 day 15 will be mandatory. Subjects will not be put at undue risk to obtain the biopsy at cycle 1 day 15 (C1D15). A biopsy at C1D15 will not be required if it poses a serious/severe complication risk greater than 2%. All other biopsy time points are not mandatory but will be strongly encouraged where feasible. These include at baseline and at disease progression. Archival and fresh tissue requests can be waived in exceptional circumstances with principal investigator (PI) approval and only where rationale is documented
• Subjects must have received at least 1 line of systemic therapy in the advanced/metastatic setting. Subjects with diseases without known effective options, and subjects who had declined standard of care therapy prior to study introduction are also eligible
• Subjects enrolling in the dose escalation should have progressed on or be intolerant to all therapies known to confer a clinical benefit. Subjects must not have refused all available therapies
• Subjects who have received prior therapy with immune checkpoint inhibitors (ICIs) are eligible for this trial. Subjects with a standard-of-care option for an immune checkpoint inhibitor are eligible
• Subjects must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1, or patients may have bone metastatic disease evaluable by Prostate Cancer Working Group 3 (PCWG3) for subjects with metastatic castration-resistant prostate cancer (CRPC), or according to tumor evaluation criteria best suited and accepted for the tumor type to be evaluated
• Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Subjects must have a life expectancy \>= 12 weeks
• Absolute neutrophil count \>= 1.5 x 10\^9/L
• Platelets \>= 100 x 10\^9/L
• Hemoglobin \>= 9 g/dL or \>= 5.6 mmol/L
• Total bilirubin =\< 1.5 X the institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT)/ alanine aminotransferase (ALT) serum glutamic-pyruvic transaminase (SGPT) =\< 2.5 X institutional ULN or =\< 5 X institutional ULN in the presence of liver metastases

You may not qualify if:

• Anticancer systemic therapy or radiotherapy within 4 weeks or 5 half-lives, whichever is shorter prior to starting the study agents. Prior palliative radiotherapy to metastatic lesion(s) is permitted, provided it has been completed 2 weeks prior to study enrollment, and no clinically significant toxicities are expected (e.g., mucositis, esophagitis)
• Known symptomatic brain metastases requiring steroids. Patients with previously treated diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to study enrollment, have discontinued corticosteroid treatment for these metastases for at least 4 weeks and are neurologically stable
• Current use of immunosuppressive medication at the time of study enrollment, EXCEPT for the following permitted steroids:
• Intranasal, inhaled, topical steroids, eye drops, or local steroid injection (e.g., intra-articular injection)
• Systemic corticosteroids at physiologic doses =\< 10 mg/day of prednisone or equivalent
• Steroids as premedication for hypersensitivity reactions (e.g. computed tomography \[CT\] scan premedication)
• Subjects who had major surgery within 4 weeks prior to study enrollment
• Known prior severe hypersensitivity to investigational products or any component in their formulations, including known severe hypersensitivity reactions to monoclonal antibodies (National Cancer Institute \[NCI\] Common Terminology Criteria for Adverse Events \[CTCAE\] version \[v\] 5 grade \>= 3)
• Active infection requiring systemic therapy
• Known history of immune-mediated colitis, inflammatory bowel disease, pneumonitis, and pulmonary fibrosis
• Active or prior autoimmune disease that may deteriorate when receiving an immunostimulatory agent. Patients with type I diabetes, vitiligo, psoriasis, or hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible
• Prior organ transplantation including allogenic stem cell transplantation
• Diagnosis of myelodysplastic syndrome (MDS)
• Vaccination within 4 weeks of study enrollment and while on trial is prohibited except for the administration of inactivated vaccines
• Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (\< 6 month prior to enrollment), myocardial infarction (\< 6 months prior to enrollment), unstable angina, congestive heart failure (\>= New York Heart Association Classification class II) or a serious cardiac arrhythmia requiring medication

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead

Study Sites (1)

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Links

• M D Anderson Cancer Center website

MeSH Terms

Conditions

Neoplasm Metastasis

Interventions

avelumab; berzosertib

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Timothy A. Yap
• Organization: M.D. Anderson Cancer Center

tyap@mdanderson.org

713-563-1930

Study Officials

• Timothy A Yap

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 26, 2019
• First Posted: February 12, 2020
• Study Start: March 17, 2020
• Primary Completion: November 13, 2024
• Study Completion: December 31, 2025
• Last Updated: November 25, 2025
• Results First Posted: October 20, 2025

Record last verified: 2025-11

Locations

US (1)