Trials / Active Not Recruiting

Active Not RecruitingNCT04068194

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

Status: Active Not Recruiting
Phase: Phase 1 / Phase 2
Study type: Interventional
Enrollment: 103 (estimated)

Sponsor: National Cancer Institute (NCI) · NIH
Sex: All
Age: 18 Years
Healthy volunteers: Not accepted

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.

Detailed description

PRIMARY OBJECTIVES: I. To determine the safety and tolerability and recommended phase 2 dose (RP2D) of peposertib (M3814) in combination with hypofractionated radiation and avelumab in patients with advanced/metastatic solid tumors. (Phase I) II. To determine the efficacy of the combination of hypofractionated radiation, peposertib (M3814), and avelumab as compared to the combination of hypofractionated radiation and avelumab in patients with advanced/metastatic hepatobiliary tumors by objective response rate (ORR) in non-irradiated lesions within 12 weeks following initiation of study treatment. (Phase II) SECONDARY OBJECTIVES: I. To observe and record anti-tumor activity. (Phase I) II. To characterize the pharmacokinetic (PK) profile of peposertib (M3814) in combination with avelumab. (Phase I) III. To determine the efficacy and safety of the combination of hypofractionated radiation, peposertib (M3814), and avelumab as compared to hypofractionated radiation and avelumab by measurement of disease control rate (DCR), duration of response (DOR), progression free survival (PFS), PFS outside the irradiated field, and overall survival (OS) in patients with advanced/metastatic hepatobiliary tumors. (Phase II) IV. To determine if baseline deoxyribonucleic acid (DNA) repair defects inherent to some cholangiocarcinomas correlate with a more dramatic response to radiation compared to those without as measured by gamma H2AX, phosphorylated (p)NBS1 and pKAP1 immunofluorescence (IFA) with beta CATN segmentation assay. (Phase II) V. To characterize the pharmacokinetic (PK) profiles of peposertib (M3814) and avelumab. (Phase II) EXPLORATORY OBJECTIVES: I. To perform molecular profiling assays on malignant and normal tissues, including, but not limited to, whole exome sequencing (WES), ribonucleic acid (RNA) sequencing (RNAseq), mass cytometry (CyTOF), multiplexed ion beam imaging (MIBI), and T cell receptor sequencing in order to: Ia. To determine if baseline tumor mutation burden and pattern, and neoantigen burden correlate with response; Ib. To determine if combination therapy results in changes in the immune landscape in both the tumor and the host that correlate with response; Ic. To determine if baseline defects in deoxyribonucleic acid (DNA) damage repair in some cholangiocarcinomas correlate with an increased response. OUTLINE: This is a phase I, dose-escalation study of peposertib followed by a phase II study. PHASE I: Patients with advanced/metastatic malignant solid tumors undergo 8 fractions of hypofractionated radiation therapy (RT) every day (QD) on days -17 to -7. Patients also receive peposertib orally (PO) twice daily (BID) on days 1-28, and avelumab intravenously (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 computed tomography (CT), biopsy, and collection of blood samples during screening and on study. PHASE II: Patients with advanced/metastatic cholangiocarcinoma/gallbladder cancer are randomized to 1 of 2 arms. ARM A: Patients 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 CT, biopsy, and collection of blood samples during screening and on study. ARM B: Patients 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 After completion of study treatment, patients are followed up at 30 days, every 3 months for 1 year, every 6 months for year 2, then annually thereafter.

Conditions

Interventions

Type	Name	Description
DRUG	Avelumab	Given IV
PROCEDURE	Biopsy Procedure	Undergo biopsy of tumor
PROCEDURE	Biospecimen Collection	Undergo collection of blood samples
PROCEDURE	Computed Tomography	Undergo CT scan
RADIATION	Hypofractionated Radiation Therapy	Undergo hypofractionated RT
DRUG	Peposertib	Given PO

Timeline

Start date: 2020-04-07
Primary completion: 2027-07-01
Completion: 2027-07-01
First posted: 2019-08-28
Last updated: 2026-04-13

Locations

46 sites across 1 country: United States

Regulatory

FDA-regulated drug study

Source: ClinicalTrials.gov record NCT04068194. Inclusion in this directory is not an endorsement.