Radiation Medication (Radium-223 Dichloride) Versus Radium-223 Dichloride Plus Radiation Enhancing Medication (M3814) Versus Radium-223 Dichloride Plus M3814 Plus Avelumab (a Type of Immunotherapy) for Advanced Prostate Cancer Not Responsive to Hormonal Therapy

Description

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of peposertib (M3814) in combination with radium-223 dichloride or in combination with radium-223 dichloride and avelumab in patients with advanced metastatic castrate-resistant prostate cancer (mCRPC) based on dose limiting toxicities (DLTs) in the doublet or triplet combinations. (Phase 1) II. Radiographic progression free survival (rPFS) will be evaluated based on both skeletal and extraskeletal progression following Prostate Cancer Working Group 3 (PCWG3) methodology. (Phase 2)

SECONDARY OBJECTIVES:

I. To determine the time to the first symptomatic skeletal event [SSE]. II. To determine the safety of radium-223 dichloride, M3814, and avelumab combination treatment.

III. To observe and record anti-tumor activity. IV. To evaluate progression free survival (PFS) and overall survival (OS). V. To evaluate symptomatic skeletal events (SSE) per standardized case report form (CRF) distinguishing between pathologic and non-pathogenic fractures.

VI. To explore patient-reported symptomatic adverse events (AE) for tolerability of each treatment arm.

VII. To examine the radium-223 dichloride bio-distribution and absorbed dose in each bone metastatic lesions as well as elsewhere in the body including critical organs using dosimetry.

EXPLORATORY OBJECTIVES:

I. To perform molecular profiling assays on malignant and normal tissues, including, but not limited to, whole exome sequencing (WES), and messenger ribonucleic acid (RNA) sequencing (RNAseq), in order to:

Ia. Identify potential predictive and prognostic biomarkers beyond any genomic alteration by which treatment may be assigned, and Ib. Identify resistance mechanisms using genomic deoxyribonucleic acid (DNA)- and RNA-based assessment platforms.

II. To contribute genetic analysis data from de-identified biospecimens to Genomic Data Commons (GDC), a well annotated cancer molecular and clinical data repository, for current and future research; specimens will be annotated with key clinical data, including presentation, diagnosis, staging, summary treatment, and if possible, outcome.

III. To bank plasma and peripheral immune cells from patients to assess predictive biomarkers of response at the Experimental Therapeutics Clinical Trials Network (ETCTN) biorepository at Nationwide Children’s Hospital.

IV. To correlate change in level of total alkaline phosphatase, bone-specific alkaline phosphatase, and serum osteocalcin to rPFS and OS.

OUTLINE: This is a phase I, dose-escalation study of peposertib, followed by a phase II study. Patients are randomized to 1 of 3 arms.

ARM A: Patients receive radium-223 dichloride intravenously (IV) over 1 minute on day 1. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, bone scan, and computed tomography (CT) or magnetic resonance imaging (MRI) throughout the study.

ARM B: Patients receive radium-223 dichloride as in Arm A and peposertib orally (PO) once daily (QD) or twice daily (BID) on days 3-26. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, bone scan, and CT or MRI throughout the study.

ARM C: Patients receive radium-223 dichloride IV as in Arm A and peposertib PO QD or BID as in Arm B. Patients also receive avelumab IV over 60 minutes on days 1 and 15 of cycles 2-6. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, bone scan, and CT or MRI throughout the study.

After completion of study treatment, patients are followed up at 30 days and then every 3 months for up to 2 years.