A Phase I and Randomized Phase II Trial of Radium-223 Dichloride, M3814, &Amp; Avelumab in Advanced Metastatic Castrate-Resistant Prostate Cancer (mCRPC)
Summary
This phase I/II trial studies the best dose of M3814 when given together with radium-223 dichloride or with radium-223 dichloride and avelumab and to see how well they work in treating patients with castrate-resistant prostate cancer that had spread to other places in the body (metastatic). M3814 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radioactive drugs, such as radium-223 dichloride, may carry radiation directly to tumor cells and not harm normal cells. 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. This study is being done to find out the better treatment between radium-223 dichloride alone, radium-223 dichloride in combination with M3814, or radium-223 dichloride in combination with both M3814 and avelumab, to lower the chance of prostate cancer growing or spreading in the bone, and if this approach is better or worse than the usual approach for advanced prostate cancer not responsive to hormonal therapy.
Detailed 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.
Arms & interventions
- DrugAvelumab
Given IV
- ProcedureBiospecimen Collection
Undergo blood sample collection
- ProcedureBone Scan
Undergo bone scan
- ProcedureComputed Tomography
Undergo CT
- ProcedureMagnetic Resonance Imaging
Undergo MRI
- DrugPeposertib
Given PO
- OtherQuestionnaire Administration
Ancillary studies
- RadiationRadium Ra 223 Dichloride
Given IV
Outcome measures
Primary
Dose-limiting toxicity (Phase 1)
Adverse events will be summarized as count and percentages, overall as well as by dose level/regimen, by severity, and by patient characteristics.
Time frame: Up to 28 days
Radiographic progression free survival (rPFS) (Phase 2)
Empirical survival probabilities will be estimated by the Kaplan-Meier (KM) product limit method by arms and the survival difference between arms will be compared by 1-sided log rank test.
Time frame: Date of randomization to date of scan showing either skeletal or extraskeletal progression following Prostate Cancer Clinical Trials Working Group 3 methodology or death, assessed up to 2 years
Secondary
PFS
Time frame: From date of randomization to the event of disease recurrence/progression or death due to any cause, assessed up to 2 years
Overall survival (OS)
Time frame: From date of randomization to date of death due to any cause, assessed up to 2 years
Symptomatic skeletal event (SSE)
Time frame: Up to 2 years post treatment
Incidence of toxicity and adverse events
Time frame: Up to 2 years post treatment
Eligibility criteria
Study locations (32)
City of Hope Comprehensive Cancer Center
Duarte, California, 91010
Los Angeles General Medical Center
Los Angeles, California, 90033
USC / Norris Comprehensive Cancer Center
Los Angeles, California, 90033
UC Irvine Health/Chao Family Comprehensive Cancer Center
Orange, California, 92868
University of California Davis Comprehensive Cancer Center
Sacramento, California, 95817
UM Sylvester Comprehensive Cancer Center at Aventura
Aventura, Florida, 33180
UM Sylvester Comprehensive Cancer Center at Coral Gables
Coral Gables, Florida, 33146
UM Sylvester Comprehensive Cancer Center at Deerfield Beach
Deerfield Beach, Florida, 33442
University of Miami Miller School of Medicine-Sylvester Cancer Center
Miami, Florida, 33136
UM Sylvester Comprehensive Cancer Center at Kendall
Miami, Florida, 33176
UM Sylvester Comprehensive Cancer Center at Plantation
Plantation, Florida, 33324
Emory University Hospital Midtown
Atlanta, Georgia, 30308
Emory University Hospital/Winship Cancer Institute
Atlanta, Georgia, 30322
Emory Saint Joseph's Hospital
Atlanta, Georgia, 30342
University of Kansas Clinical Research Center
Fairway, Kansas, 66205
University of Kansas Cancer Center
Kansas City, Kansas, 66160
University of Kansas Cancer Center-Overland Park
Overland Park, Kansas, 66210
University of Kansas Hospital-Westwood Cancer Center
Westwood, Kansas, 66205
University of Kentucky/Markey Cancer Center
Lexington, Kentucky, 40536
Wayne State University/Karmanos Cancer Institute
Detroit, Michigan, 48201
Siteman Cancer Center at Saint Peters Hospital
City of Saint Peters, Missouri, 63376
Siteman Cancer Center at West County Hospital
Creve Coeur, Missouri, 63141
University of Kansas Cancer Center at North Kansas City Hospital
North Kansas City, Missouri, 64116
Washington University School of Medicine
St Louis, Missouri, 63110
Siteman Cancer Center-South County
St Louis, Missouri, 63129
Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center
Lebanon, New Hampshire, 03756
Laura and Isaac Perlmutter Cancer Center at NYU Langone
New York, New York, 10016
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, 43210
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, 73104
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania, 19107
UT Southwestern/Simmons Cancer Center-Dallas
Dallas, Texas, 75390
Huntsman Cancer Institute/University of Utah
Salt Lake City, Utah, 84112