Testing the Combination of New Anti-cancer Drug Peposertib With Avelumab and Radiation Therapy for Advanced/Metastatic Solid Tumors and Hepatobiliary Malignancies
A Phase I/II Study of M3814 and Avelumab in Combination With Hypofractionated Radiation in Patients With Advanced/Metastatic Solid Tumors and Hepatobiliary Malignancies
5 other identifiers
interventional
103
1 country
46
Brief Summary
This phase I/II trial studies the best dose and side effects of peposertib and to see how well it works with avelumab and hypofractionated radiation therapy in treating patients with solid tumors and hepatobiliary malignancies that have spread to other places in the body (advanced/metastatic). Peposertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 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. Hypofractionated radiation therapy delivers higher doses of radiation therapy over a shorter period of time and may kill more tumor cells and have fewer side effects. Giving peposertib in combination with avelumab and hypofractionated radiation therapy may work better than other standard chemotherapy, hormonal, targeted, or immunotherapy medicines available in treating patients with solid tumors and hepatobiliary malignancies.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_1
Started Apr 2020
Longer than P75 for phase_1
46 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
August 15, 2019
CompletedFirst Posted
Study publicly available on registry
August 28, 2019
CompletedStudy Start
First participant enrolled
April 7, 2020
CompletedPrimary Completion
Last participant's last visit for primary outcome
July 1, 2027
ExpectedStudy Completion
Last participant's last visit for all outcomes
July 1, 2027
June 11, 2026
February 1, 2026
7.2 years
August 15, 2019
June 10, 2026
Conditions
Outcome Measures
Primary Outcomes (2)
Maximum tolerated doses and recommended phase 2 dose of peposertib (M3814) in combination with hypofractionated radiation and avelumab (Phase 1)
Will be determined by the occurrence of dose-limiting toxicities defined as the occurrence of one or more grade 3 adverse events that delays treatment for more than 7 days, or any grade 4-5 adverse events.
Up to 28 days
Objective response rate (Phase 2)
Defined as best overall response (compete response \[CR\] and partial response \[PR\] in non-irradiated lesions as opposed to stable disease \[SD\] or progressive disease) within 12 weeks following initiation of study treatment by Response Evaluation Criteria in Solid Tumors (RECIST 1.1).
Within 12 weeks following initiation of study treatment
Secondary Outcomes (10)
Pharmacokinetics of avelumab (Phase 1)
Day 7: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours; Day 21: predose, 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours
Pharmacokinetics of M3814 (Phase 1)
Day 21: predose
Disease control rate (Phase 2)
Up to 12 months
Progression free survival (PFS) (Phase 2)
From randomization until disease progression or death, assessed up to 12 months
PFS outside the irradiated field (Phase 2)
From randomization until disease progression outside the irradiated field or death, assessed up to 12 months
- +5 more secondary outcomes
Other Outcomes (11)
Tumor mutation burden
Baseline
Tumor mutation burden
Baseline
Tumor pattern
Baseline
- +8 more other outcomes
Study Arms (3)
Arm A (hypofractionated RT, avelumab)
ACTIVE COMPARATORPatients undergo 8 fractions of hypofractionated RT QD on days -17 to -7. Patients also receive avelumab IV over 60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo biopsy, CT, and collection of blood on the trial.
Arm B (hypofractionated RT, peposertib, avelumab)
EXPERIMENTALPatients undergo 8 fractions of hypofractionated RT QD on days -17 to -7. Patients also receive peposertib PO BID on days 1-28, and avelumab IV over 60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo biopsy, CT, and collection of blood on the trial.
Phase I (hypofractionated RT, peposertib, avelumab)
EXPERIMENTALPatients with advanced/metastatic malignant solid tumors undergo 8 fractions of hypofractionated RT QD on days -17 to -7. Patients also receive peposertib PO BID on days 1-28, and avelumab IV over 60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, biopsy, and collection of blood samples during screening and on study.
Interventions
Undergo collection of blood samples
Given PO
Undergo hypofractionated RT
Given IV
Undergo biopsy of tumor
Undergo CT scan
Eligibility Criteria
You may qualify if:
- PHASE 1: Patients must have a histologically confirmed metastatic or locally advanced unresectable solid tumor that has progressed on or after available standard of care therapy or for which no acceptable standard of care therapy exists, or in which the patient declines standard of care therapy (each patient that declines standard of care therapy will be documented in the case report form)
- PHASE 2: Patients must have a histologically confirmed metastatic or locally advanced unresectable cholangiocarcinoma/gallbladder carcinoma that has progressed on gemcitabine, cisplatin, and durvalumab/pembrolizumab
- Age \>= 18 years
- Because no dosing or adverse event data are currently available on the use of peposertib (M3814) in combination with avelumab in patients \< 18 years of age
- Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%)
- Patients with at least 1 index lesion to irradiate for whom palliative radiation treatment is indicated (including but not limited to pain and/or symptom control, prevention of disease -related complications, and preservation of organ function). Lung and liver lesions are preferred, though alternate lesions may be considered after discussion with trial principal investigator (PI). Up to 2 lesions may be considered for irradiation provided at least 1 lesion will receive the study treatment of total of 60 Gy and all prescribed irradiation will be completed within the radiation window
- Patients with at least 1 Response Evaluation Criteria in Solid Tumors (RECIST) measurable lesion (to be unirradiated) (defined as those accurately measured in at least one dimension, with the longest diameter to be recorded for non-nodal lesions and the shortest diameter for nodal lesions). Measurable is defined as at least 10 mm in longest diameter for solid tumors, at least 15 mm in shortest diameter for lymph nodes
- Patients must be willing to undergo fresh biopsies at baseline (as opposed to using archival tissue), in the event their baseline tissue was obtained \> 12 months prior to study consent and/or they are randomized to the gamma H2AX, pNBS1 and pKAP1 IFA with beta CATN segmentation assay
- Absolute neutrophil count (ANC) \>= 1,500/mcL
- Platelet count \>= 100,000/mcL
- Hemoglobin \>= 9.0 g/dL
- Serum creatinine =\< 1.5 x upper limit of normal (ULN) OR calculated serum creatinine clearance (glomerular filtration rate \[GFR\] can be used in place of creatinine or creatinine clearance) \>= 60 mL/min for participants with creatinine levels \> 1.5 x institutional ULN
- Calculate serum creatinine clearance using the standard Cockcroft-Gault formula
- Serum total bilirubin =\< 1.5 x ULN or direct bilirubin =\< ULN for participants with total bilirubin \> 1.5 x ULN
- Patients with known Gilbert disease with serum bilirubin level =\< 3 x ULN are eligible
- +7 more criteria
You may not qualify if:
- PHASE I: Patients who have received prior anti-CTLA-4, anti-PD-1, anti-PD-L1 or other immune checkpoint inhibitor therapeutic antibodies or pathway-targeting agents
- PHASE II: Patients who have received prior anti-CTLA-4, anti-PD-1, anti-PD-L1 or other immune checkpoint inhibitor therapeutic antibodies or pathway-targeting agents with the following exceptions:
- Patients who have only received previous durvalumab (anti-PD-L1) in combination with gemcitabine +/- cisplatin as part of first line therapy (TOPAZ-1 regimen) are eligible
- Patients who have only received previous pembrolizumab (anti-PD-1) in combination with gemcitabine +/- cisplatin as part of first line therapy (KEYNOTE-966 regimen) are eligible
- Patients who have had chemotherapy, definitive radiation, biological cancer therapy, or investigational agent/device within 21 days of first planned dose of study therapy (within 14 days for palliative radiation). Previously irradiated lesions may be re-irradiated provided there is disease progression in the irradiated lesion and the prescribed radiation dosage can safely be re- administered
- Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities \> Common Terminology Criteria for Adverse Events \[CTCAE\] grade 1) with the exception of alopecia
- Patients with untreated/uncontrolled central nervous system (CNS)/leptomeningeal disease. Patients with asymptomatic, treated CNS disease are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy and the following criteria are met:
- Radiographic demonstration of clinical stability upon the completion of CNS-directed therapy and no evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study done \>= 4 weeks from completion of radiotherapy and \>= 2 weeks from discontinuation of corticosteroids
- No stereotactic radiation or whole-brain radiation within 28 days prior to randomization
- Patients with active autoimmune disease requiring systemic corticosteroids greater than the equivalent of prednisone 10 mg daily including but not limited to: systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, colitis, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis, with the following exceptions:
- Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone are eligible
- Patients with controlled type 1 diabetes mellitus on a stable insulin regimen are eligible
- Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic manifestations only who require only low potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%) are eligible
- Patients receiving treatment with systemic immunosuppressive medications (including, but not limited to, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor \[TNF\] agents) within 6 weeks must discontinue these medications prior to starting peposertib (M3814) and avelumab, with the exception of:
- Patients with active autoimmune disease managed with systemic corticosteroids less than the equivalent of prednisone 10 mg daily
- +20 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (46)
City of Hope Comprehensive Cancer Center
Duarte, California, 91010, United States
UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
Irvine, California, 92612, United States
UC San Diego Moores Cancer Center
La Jolla, California, 92093, United States
UC Irvine Health/Chao Family Comprehensive Cancer Center
Orange, California, 92868, United States
University of California Davis Comprehensive Cancer Center
Sacramento, California, 95817, United States
UCHealth University of Colorado Hospital
Aurora, Colorado, 80045, United States
Smilow Cancer Hospital-Derby Care Center
Derby, Connecticut, 06418, United States
Smilow Cancer Hospital Care Center-Fairfield
Fairfield, Connecticut, 06824, United States
Smilow Cancer Hospital Care Center at Glastonbury
Glastonbury, Connecticut, 06033, United States
Smilow Cancer Hospital Care Center at Greenwich
Greenwich, Connecticut, 06830, United States
Smilow Cancer Hospital Care Center - Guilford
Guilford, Connecticut, 06437, United States
Smilow Cancer Hospital Care Center at Saint Francis
Hartford, Connecticut, 06105, United States
Smilow Cancer Center/Yale-New Haven Hospital
New Haven, Connecticut, 06510, United States
Yale University
New Haven, Connecticut, 06520, United States
Yale-New Haven Hospital North Haven Medical Center
North Haven, Connecticut, 06473, United States
Smilow Cancer Hospital Care Center at Long Ridge
Stamford, Connecticut, 06902, United States
Smilow Cancer Hospital-Torrington Care Center
Torrington, Connecticut, 06790, United States
Smilow Cancer Hospital Care Center-Trumbull
Trumbull, Connecticut, 06611, United States
Smilow Cancer Hospital-Waterbury Care Center
Waterbury, Connecticut, 06708, United States
Smilow Cancer Hospital Care Center - Waterford
Waterford, Connecticut, 06385, United States
MedStar Georgetown University Hospital
Washington D.C., District of Columbia, 20007, United States
Sibley Memorial Hospital
Washington D.C., District of Columbia, 20016, United States
UM Sylvester Comprehensive Cancer Center at Aventura
Aventura, Florida, 33180, United States
UM Sylvester Comprehensive Cancer Center at Coral Gables
Coral Gables, Florida, 33146, United States
UM Sylvester Comprehensive Cancer Center at Deerfield Beach
Deerfield Beach, Florida, 33442, United States
University of Miami Miller School of Medicine-Sylvester Cancer Center
Miami, Florida, 33136, United States
UM Sylvester Comprehensive Cancer Center at Kendall
Miami, Florida, 33176, United States
UM Sylvester Comprehensive Cancer Center at Plantation
Plantation, Florida, 33324, United States
Emory University Hospital Midtown
Atlanta, Georgia, 30308, United States
Emory University Hospital/Winship Cancer Institute
Atlanta, Georgia, 30322, United States
Emory Saint Joseph's Hospital
Atlanta, Georgia, 30342, United States
Northwestern University
Chicago, Illinois, 60611, United States
Wayne State University/Karmanos Cancer Institute
Detroit, Michigan, 48201, United States
Weisberg Cancer Treatment Center
Farmington Hills, Michigan, 48334, United States
Rutgers Cancer Institute of New Jersey
New Brunswick, New Jersey, 08903, United States
Bellevue Hospital Center
New York, New York, 10016, United States
Laura and Isaac Perlmutter Cancer Center at NYU Langone
New York, New York, 10016, United States
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
New York, New York, 10032, United States
NYP/Weill Cornell Medical Center
New York, New York, 10065, United States
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania, 15232, United States
Smilow Cancer Hospital Care Center - Westerly
Westerly, Rhode Island, 02891, United States
Vanderbilt University/Ingram Cancer Center
Nashville, Tennessee, 37232, United States
Huntsman Cancer Institute/University of Utah
Salt Lake City, Utah, 84112, United States
VCU Massey Comprehensive Cancer Center
Richmond, Virginia, 23298, United States
University of Wisconsin Carbone Cancer Center - Eastpark Medical Center
Madison, Wisconsin, 53718, United States
University of Wisconsin Carbone Cancer Center - University Hospital
Madison, Wisconsin, 53792, United States
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Kristen R Spencer
Laura and Isaac Perlmutter Cancer Center at NYU
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- NIH
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
August 15, 2019
First Posted
August 28, 2019
Study Start
April 7, 2020
Primary Completion (Estimated)
July 1, 2027
Study Completion (Estimated)
July 1, 2027
Last Updated
June 11, 2026
Record last verified: 2026-02
Data Sharing
- IPD Sharing
- Will share
NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.