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Official Title

A Phase I and Randomized Phase II Trial of Radium-223 Dichloride, M3814, & Avelumab in Advanced Metastatic Castrate-Resistant Prostate Cancer (mCRPC)

Phase
Phase 1/Phase 2
Sponsor
National Cancer Institute (NCI)
Enrollment
90
Timeline
Oct 2020 → Apr 2026
About This Study

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.

Eligibility Criteria

Inclusion Criteria

  • 1PHASE 1: Eastern Cooperative Oncology Group (ECOG) performance status =\< 1 (Karnofsky \>= 70%)
  • 2PHASE 2: ECOG performance status =\< 2 (Karnofsky \>= 60%)
  • 3Unless 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
  • 4Progressive 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
  • 5Baseline 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)
  • 6Progression 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
  • 7Age \>= 18 years. Castrate-resistant prostate cancer (CRPC) affects older adults and is rarely encountered in children and adolescents
  • 8Life expectancy \>= 6 months
  • 9Albumin \> 2.5 mg/dL
  • 10Hemoglobin \> 9 g/dL
  • 11Leukocytes \>= 3,000/mcL
  • 12Absolute neutrophil count \>= 1,500/mcL
  • 13Platelets \>= 100,000/mcL
  • 14Total bilirubin =\< 1.5 x institutional upper limit of normal (ULN) (with the exception of \< 3 mg/dL for patients with Gilbert's disease)
  • 15Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase \[SGPT\]) =\< 3 x institutional ULN
  • 16Creatinine =\< 1.5 x institutional ULN OR
  • 17Glomerular filtration rate (GFR) \>= 40 mL/min/1.73 m\^2
  • 18Human 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
  • 19For 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
  • 20Patients 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 \[e.g. drug-drug interactions\])
  • 21Patients 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
  • 22Patients 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
  • 23Concomitant use of physiologic corticosteroids is allowed
  • 24Concomitant use of bisphosphonates is allowed (use of bone health agents is mandatory - either denosumab \[preferred\] or bisphosphonates)
  • 25The 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
  • 26Ability 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
  • 27Patients must be able to swallow orally administered medication
  • 28Patients 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 CT scan) during the screening period

Exclusion Criteria

  • 1Active autoimmune conditions or patients on chronic immunosuppression due to underlying autoimmune condition
  • 2Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study
  • 3Patients 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
  • 4Patients who are receiving any other investigational agents
  • 5Patients who have had previous hemibody external radiation
  • 6Patients 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
  • 7Patients who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to radium-223 dichloride, M3814, or avelumab
  • 8Patients 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.
  • 9Medications or substances that are strong inhibitors of CYP3A4/5 or CYP2C19 must be discontinued at least 1 week prior to first M3814 dose.
  • 10Medications or substances that are strong inducers of CYP3A4/5 or CYP2C19 must be stopped at least 3 weeks prior to the first M3814 dose.
  • 11Drugs 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.
  • 12Note: 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.
  • 13Radium-223 dichloride should not be given concurrently with abiraterone plus prednisone/prednisolone
  • 14Patients with uncontrolled intercurrent illness
  • 15Patients with psychiatric illness/social situations that would limit compliance with study requirements
  • 16Patients must not have an active infection requiring systemic treatment
  • 17Patients must not use immunosuppressive medication =\< 7 days of registration, EXCEPT for the following:
  • 18Intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection)
  • 19Systemic corticosteroids at physiologic doses =\< 10 mg/day of prednisone or equivalent
  • 20Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
  • 21Patients 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
  • 22Patients receiving sorivudine or any chemically related analogues (such as brivudine) are excluded
  • 23Patients with a known history or present osteonecrosis of the jaw

Locations

32 sites participating in this study

Emory University Hospital Midtown

Atlanta, Georgia 30308

Active, Not Recruiting

Emory University Hospital/Winship Cancer Institute

Atlanta, Georgia 30322

Active, Not Recruiting

Emory Saint Joseph's Hospital

Atlanta, Georgia 30342

Active, Not Recruiting
Data sourced from ClinicalTrials.govView on ClinicalTrials.gov →