Prostate Cancer Clinical Trial

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

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.

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Full 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 (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.

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.

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.

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

View Eligibility Criteria

Eligibility Criteria

Inclusion Criteria:

PHASE 1: Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
PHASE 2: ECOG performance status =< 2 (Karnofsky >= 60%)
Unless a patient has had orchiectomy by surgery, the patient is expected to be on antiandrogen therapy (ADT) for "medical castration". ADT needs to be maintained throughout the study. Testosterone level should be checked, and kept consistently lower than 50 ng/dL, similar to that obtained with bilateral orchiectomy
Progressive castration-resistant prostate cancer with two or more skeletal metastases identified by 99mTC bone scintigraphy. One or more lymph node metastases allowed, but not mandatory. Lymph node metastases in each individually must measure less than 3 cm in the longest dimension. Visible visceral organ metastases are not allowed. A diagnosis of prostate cancer must have been histologically confirmed at any time point
Baseline prostatic specific antigen (PSA) level of 1 ng/mL or higher with evidence of progressively increasing PSA values (two consecutive increases over the previous reference value)
Progression after at least one of the following: abiraterone, enzalutamide, apalutamide, darolutamide, or taxane chemotherapy (docetaxel, cabazitaxel). There is no maximum number of prior therapies. Prior immunotherapies (for example, Sipuleucel-T or pembrolizumab) do not exclude the patient from participation
Age >= 18 years. Castrate-resistant prostate cancer (CRPC) affects older adults and is rarely encountered in children and adolescents
Life expectancy >= 6 months
Albumin > 2.5 mg/dL
Hemoglobin > 9 mg/dL
Leukocytes >= 3,000/mcL
Absolute neutrophil count >= 1,500/mcL
Platelets >= 100,000/mcL
Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (with the exception of < 3 mg/dL for patients with Gilbert's disease)
Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN
Creatinine =< 1.5 x institutional ULN OR
Glomerular filtration rate (GFR) >= 40 mL/min/1.73 m^2
Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy (with no medications prohibited by this protocol [e.g. drug-drug interactions]) with undetectable viral load within 6 months are eligible for this trial
For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy (with no medications prohibited by this protocol [e.g. drug-drug interactions]), if indicated
Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load (with no medications prohibited by this protocol [e.g. drug-drug interactions])
Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional classification. To be eligible for this trial, patients should be class 2B or better
Concomitant use of physiologic corticosteroids is allowed
Concomitant use of bisphosphonates is allowed (use of bone health agents is mandatory - either denosumab [preferred] or bisphosphonates)
The effects of radium-223 dichloride, M3814, and avelumab on the developing human fetus are unknown. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 6 months after completion of Radium-223 dichloride, M3814, and avelumab administration
Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity (IDMC) who have a legally-authorized representative (LAR) and/or family member available will also be eligible
Patients must be able to swallow orally administered medication
Patients with asymptomatic, treated brain metastases are permitted if there is no evidence of progression for at least 4 weeks after central nervous system (CNS)-directed treatment, as ascertained by clinical examination and brain imaging (magnetic resonance imaging [MRI] or computed tomography [CT] scan) during the screening period

Exclusion Criteria:

Active autoimmune conditions or patients on chronic immunosuppression due to underlying autoimmune condition
Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study
Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia
Prior therapy with radionuclides (e.g., strontium, samarium, rhenium, radium)
Patients who are receiving any other investigational agents
Patients who have had previous hemibody external radiation
Patients who have had systemic radiotherapy with radioisotopes
Patients who have imminent/established spinal cord compression, pathological fracture in weight bearing bones or bone lesion with soft tissue component unless treated as appropriate with radiation and/or surgery before starting on trial
Patients who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to radium-223 dichloride, M3814, or avelumab

Patients unable to discontinue medications or substances that are potent inhibitors, inducers or sensitive substrates of CYP3A4/5 or CYP2C19 prior to study treatment are ineligible.

Medications or substances that are strong inhibitors of CYP3A4/5 or CYP2C19 must be discontinued at least 1 week prior to first M3814 dose.
Medications or substances that are strong inducers of CYP3A4/5 or CYP2C19 must be stopped at least 3 weeks prior to the first M3814 dose.
Drugs mainly metabolized by CYP3A with a narrow therapeutic index (as judged by the Investigator or authorized designee) must be discontinued at least 1 day prior to first M3814 dose.
Note: Because the lists of these agents are constantly changing, it is important to regularly consult a frequently- updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the- counter medicine or herbal product.
Patients with uncontrolled intercurrent illness
Patients with psychiatric illness/social situations that would limit compliance with study requirements
Patients must not have an active infection requiring systemic treatment

Patients must not use immunosuppressive medication =< 7 days of registration, EXCEPT for the following:

Intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection)
Systemic corticosteroids at physiologic doses =< 10 mg/day of prednisone or equivalent
Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
Patients who cannot discontinue concomitant H2 blockers or proton-pump inhibitors (PPIs). Patients may confer with the study doctor to determine if such medications can be discontinued. These must be discontinued >= 5 days prior to study treatment. Patients do not need to discontinue calcium carbonate
Patients receiving sorivudine or any chemically related analogues (such as brivudine) are excluded
Patients with a known history or present osteonecrosis of the jaw

Study is for people with:

Prostate Cancer

Phase:

Phase 1

Estimated Enrollment:

90

Study ID:

NCT04071236

Recruitment Status:

Recruiting

Sponsor:

National Cancer Institute (NCI)

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There are 25 Locations for this study

See Locations Near You

Los Angeles County-USC Medical Center
Los Angeles California, 90033, United States More Info
Site Public Contact
Contact
323-865-0451
Anishka D'Souza
Principal Investigator
USC / Norris Comprehensive Cancer Center
Los Angeles California, 90033, United States More Info
Site Public Contact
Contact
323-865-0451
Anishka D'Souza
Principal Investigator
UC Irvine Health/Chao Family Comprehensive Cancer Center
Orange California, 92868, United States More Info
Site Public Contact
Contact
877-827-8839
[email protected]
Nataliya Mar
Principal Investigator
University of California Davis Comprehensive Cancer Center
Sacramento California, 95817, United States
UM Sylvester Comprehensive Cancer Center at Coral Gables
Coral Gables Florida, 33146, United States More Info
Site Public Contact
Contact
305-243-2647
Russ A. Kuker
Principal Investigator
UM Sylvester Comprehensive Cancer Center at Deerfield Beach
Deerfield Beach Florida, 33442, United States More Info
Site Public Contact
Contact
305-243-2647
Russ A. Kuker
Principal Investigator
University of Miami Miller School of Medicine-Sylvester Cancer Center
Miami Florida, 33136, United States More Info
Site Public Contact
Contact
305-243-2647
Russ A. Kuker
Principal Investigator
UM Sylvester Comprehensive Cancer Center at Kendall
Miami Florida, 33176, United States More Info
Site Public Contact
Contact
305-243-2647
Russ A. Kuker
Principal Investigator
Emory University Hospital Midtown
Atlanta Georgia, 30308, United States More Info
Site Public Contact
Contact
888-946-7447
Mehmet A. Bilen
Principal Investigator
Emory University Hospital/Winship Cancer Institute
Atlanta Georgia, 30322, United States More Info
Site Public Contact
Contact
404-778-1868
Mehmet A. Bilen
Principal Investigator
Emory Saint Joseph's Hospital
Atlanta Georgia, 30342, United States More Info
Site Public Contact
Contact
404-851-7115
Mehmet A. Bilen
Principal Investigator
University of Kansas Clinical Research Center
Fairway Kansas, 66205, United States More Info
Site Public Contact
Contact
913-588-3671
[email protected]
Rahul A. Parikh
Principal Investigator
University of Kansas Cancer Center
Kansas City Kansas, 66160, United States More Info
Site Public Contact
Contact
913-588-3671
[email protected]
Rahul A. Parikh
Principal Investigator
University of Kansas Cancer Center-Overland Park
Overland Park Kansas, 66210, United States
University of Kansas Hospital-Westwood Cancer Center
Westwood Kansas, 66205, United States More Info
Site Public Contact
Contact
913-588-3671
[email protected]
Rahul A. Parikh
Principal Investigator
University of Kentucky/Markey Cancer Center
Lexington Kentucky, 40536, United States More Info
Site Public Contact
Contact
859-257-3379
Zin W. Myint
Principal Investigator
Wayne State University/Karmanos Cancer Institute
Detroit Michigan, 48201, United States More Info
Site Public Contact
Contact
313-576-9790
[email protected]
Elisabeth I. Heath
Principal Investigator
Siteman Cancer Center at West County Hospital
Creve Coeur Missouri, 63141, United States
University of Kansas Cancer Center at North Kansas City Hospital
North Kansas City Missouri, 64116, United States More Info
Site Public Contact
Contact
913-588-3671
[email protected]
Rahul A. Parikh
Principal Investigator
Washington University School of Medicine
Saint Louis Missouri, 63110, United States
Siteman Cancer Center-South County
Saint Louis Missouri, 63129, United States
Siteman Cancer Center at Saint Peters Hospital
Saint Peters Missouri, 63376, United States
Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center
Lebanon New Hampshire, 03756, United States More Info
Site Public Contact
Contact
800-639-6918
[email protected]
Rodwell Mabaera
Principal Investigator
Laura and Isaac Perlmutter Cancer Center at NYU Langone
New York New York, 10016, United States
Ohio State University Comprehensive Cancer Center
Columbus Ohio, 43210, United States More Info
Site Public Contact
Contact
800-293-5066
[email protected]
Edmund Folefac
Principal Investigator
Thomas Jefferson University Hospital
Philadelphia Pennsylvania, 19107, United States
UT Southwestern/Simmons Cancer Center-Dallas
Dallas Texas, 75390, United States More Info
Site Public Contact
Contact
214-648-7097
[email protected]
Kevin D. Courtney
Principal Investigator

How clear is this clinincal trial information?

Study is for people with:

Prostate Cancer

Phase:

Phase 1

Estimated Enrollment:

90

Study ID:

NCT04071236

Recruitment Status:

Recruiting

Sponsor:


National Cancer Institute (NCI)

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