Testing the Addition of a New Anti-cancer Drug, M3814 (Peposertib), to the Usual Radiotherapy in Patients With Locally Advanced Pancreatic Cancer

Brief summary public domain (ClinicalTrials.gov)

This phase I/II trial studies the safety, side effects and best dose of M3814 and to see how well it works when given together with radiation therapy in treating patients with pancreatic cancer that has spread to nearby tissue or lymph nodes (locally advanced). M3814 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 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 M3814 and hypofractionated radiation therapy together may be safe, tolerable and/or more effective than radiation therapy alone in treating patients with locally advanced pancreatic cancer.

Detailed description public domain (ClinicalTrials.gov)

PRIMARY OBJECTIVES: I. To evaluate the safety and tolerability of M3814 (peposertib) in combination with hypofractionated radiotherapy in patients receiving treatment for locally advanced pancreatic adenocarcinoma (LAPC). (Phase I) II. To determine the difference in progression free survival (PFS) between patients with LAPC treated with hypofractionated radiotherapy in combination with M3814 (peposertib) as compared to patients treated with hypofractionated radiotherapy alone. (Phase II) SECONDARY OBJECTIVES: I. To observe and record anti-tumor activity. (Phase I) II. To evaluate plasma pharmacokinetic (PK) profiles of M3814 (peposertib) in patients receiving hypofractionated radiotherapy. (Phase I) III. To compare the 2-year overall survival (OS) rate of patients treated with hypofractionated radiotherapy plus M3814 (peposertib) to that of those treated with hypofractionated radiotherapy alone. (Phase II) IV. To compare the objective response rate (ORR) by imaging of patients treated with hypofractionated radiotherapy plus M3814 (peposertib) to that of those treated with hypofractionated radiotherapy alone. (Phase II) V. To compare the disease control rate in patients treated with hypofractionated radiotherapy plus M3814 (peposertib) as compared to those patients treated with hypofractionated radiotherapy alone. (Phase II) VI. To explore gene signature patterns in baseline patient tumor tissues that may suggest response to the combination of M3814 (peposertib) and radiotherapy, as identified on whole exome sequencing and ribonucleic acid (RNA) sequencing (seq). (Phase II) EXPLORATORY OBJECTIVE: I. To explore changes in gene signature induced by M3814 (peposertib) and hypofractionated radiotherapy treatment as identified in analysis of cell-free deoxyribonucleic acid (DNA) from the peripheral blood. (Phase II) OUTLINE: This is a phase I, dose-escalation study of M3814 followed by a phase II study. PHASE I: Patients undergo hypofractionated radiation therapy for 5 fractions every other day (QOD) over 2 weeks and receive M3814 orally (PO) once daily (QD) for 14 days in the absence of disease progression or unacceptable toxicity. PHASE II: Patients are randomized to 1 of 2 groups. GROUP I: Patients undergo hypofractionated radiation therapy for 5 fractions QOD over 2 weeks and receive M3814 PO QD for 14 days in the absence of disease progression or unacceptable toxicity. GROUP II: Patients undergo hypofractionated radiation therapy for 5 fractions QOD over 2 weeks and receive placebo PO QD for 14 days in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection and tissue biopsy on study. Patients also undergo computed tomography (CT) and magnetic resonance imaging (MRI) during screening and on study. After completion of study treatment, patients are followed up at 30, 60, and 90 days, and then every 3 months for up to 2 years.

Intervention public domain (ClinicalTrials.gov)

Procedure: Biopsy Procedure. Undergo tissue collection

Intervention public domain (ClinicalTrials.gov)

Procedure: Biospecimen Collection. Undergo blood sample collection

Intervention public domain (ClinicalTrials.gov)

Procedure: Computed Tomography. Undergo CT

Intervention public domain (ClinicalTrials.gov)

Radiation: Hypofractionated Radiation Therapy. Undergo hypofractionated radiation therapy

Intervention public domain (ClinicalTrials.gov)

Procedure: Magnetic Resonance Imaging. Undergo MRI

Intervention public domain (ClinicalTrials.gov)

Drug: Peposertib. Given PO

Intervention public domain (ClinicalTrials.gov)

Other: Placebo Administration. Given PO

Arm public domain (ClinicalTrials.gov)

Phase I (hypofractionated radiation therapy, M3814) (experimental): Patients in Phase I undergo hypofractionated radiation therapy for 5 fractions QOD over 2 weeks and receive M3814 PO QD for 14 days in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection and tissue biopsy on study. Patients also undergo CT and MRI during screening and on study.

Arm public domain (ClinicalTrials.gov)

Phase II Group I (hypofractionated radiation therapy M3814) (experimental): Patients in Phase II undergo hypofractionated radiation therapy for 5 fractions QOD over 2 weeks and receive M3814 PO QD for 14 days in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection and tissue biopsy on study. Patients also undergo CT and MRI during screening and on study.

Arm public domain (ClinicalTrials.gov)

Phase II Group II(hypofractionated radiation therapy, placebo) (placebo comparator): Patients in Phase II undergo hypofractionated radiation therapy for 5 fractions QOD over 2 weeks and receive placebo PO QD for 14 days in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection and tissue biopsy on study. Patients also undergo CT and MRI during screening and on study.

Primary outcome public domain (ClinicalTrials.gov)

Maximum tolerated dose (Phase I). Time frame: Up to 14 days.

Primary outcome public domain (ClinicalTrials.gov)

Recommended phase 2 dose (Phase I). Time frame: Up to 14 days.

Primary outcome public domain (ClinicalTrials.gov)

Progression-free survival rate (Phase II). The 95% confidence intervals will be provided. Time frame: Time from randomization to progression or death whichever occurs first, assessed up to 2 years.

Secondary outcome public domain (ClinicalTrials.gov)

Overall survival (OS). Time frame: Time between the date of randomization and the date of patient death, assessed up to 2 years.

Secondary outcome public domain (ClinicalTrials.gov)

Two-year OS. Time frame: At 2 years.

Secondary outcome public domain (ClinicalTrials.gov)

Overall response rate. Time frame: Up to 2 years.

Secondary outcome public domain (ClinicalTrials.gov)

Disease control rate. Time frame: Up to 2 years.

Secondary outcome public domain (ClinicalTrials.gov)

Pharmacokinetic markers of M3814. Time frame: Up to 2 years.

Secondary outcome public domain (ClinicalTrials.gov)

Gene signature of tumor. Time frame: Up to 2 years.

Eligibility public domain (ClinicalTrials.gov)

Inclusion Criteria: * Patients must have pathologically confirmed pancreatic adenocarcinoma. Patients with alternative or mixed histologies (i.e., squamous, neuroendocrine, acinar, colloid) are not eligible * Received 4-6 months of induction chemotherapy with fluorouracil, irinotecan, leucovorin and oxaliplatin (FOLFIRINOX), fluorouracil, liposomal irinotecan, leucovorin, oxaliplatin (NALIRIFOX), or gemcitabine/Abraxane, as per standard of care * Patients must have locally advanced pancreatic cancer according to National Comprehensive Cancer Network (NCCN) Guidelines (version 1.2020) on pancreas protocol CT scan performed within 21 days of registration. Locally advanced disease is defined as any of the following: * For head or uncinate process tumors: * Solid tumor contact with superior mesenteric artery \> 180 degrees * Solid tumor contact with the celiac axis \> 180 degrees * Solid tumor contact with the common or proper hepatic arteries \> 180 degrees or * For pancreatic body or tail tumors: * Solid tumor contact of \> 180 degrees with the superior mesenteric artery or celiac axis * Solid tumor contact with the celiac axis and aortic involvement or * Unreconstructible superior mesenteric vein or portal vein due to tumor involvement or occlusion (can be due to tumor or bland thrombus) * The determination of locally advanced pancreatic cancer and plan for non-operative treatment on this clinical trial must be confirmed through local multi-disciplinary review * Measurable disease per response evaluation criteria in solid tumors (RECIST) version (v)1.1 * Age \>= 18 years. Because no dosing or adverse event data are currently available on the use of M3814 (peposertib) in combination with hypofractionated radiation in patients \< 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials * Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%) * Leukocytes \>= 4,000/mcL * Absolute neutrophil count \>= 1.5 x 10\^9/L. * Hemoglobin \>= 9 g/dL * Platelets \>= 100 x 10\^9/L * Total bilirubin =\< 2.0 x institutional upper limit of normal (ULN) * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) =\< 3 x institutional ULN * Creatinine =\< 1.5 x institutional ULN * Glomerular filtration rate (GFR) \>= 51 mL/min/1.73 m\^2 * Human immunodeficiency virus (HIV)-infected patients on …

Enrollment public domain (ClinicalTrials.gov)

Enrollment: 92 participants (estimated).