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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

NCT04071236

Description:

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.

Related Conditions:
  • Prostate Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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
  • Official Title: A Phase I and Randomized Phase II Trial of Radium-223 Dichloride, M3814, &Amp; Avelumab in Advanced Metastatic Castrate-Resistant Prostate Cancer (mCRPC)

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-05620
  • SECONDARY ID: NCI-2019-05620
  • SECONDARY ID: 10301
  • SECONDARY ID: 10301
  • SECONDARY ID: UM1CA186689
  • SECONDARY ID: UM1CA186704
  • NCT ID: NCT04071236

Conditions

  • Castration-Resistant Prostate Carcinoma
  • Metastatic Prostate Carcinoma
  • Stage IV Prostate Cancer AJCC v8
  • Stage IVA Prostate Cancer AJCC v8
  • Stage IVB Prostate Cancer AJCC v8

Interventions

DrugSynonymsArms
AvelumabBavencio, MSB-0010718C, MSB0010718CArm C (radium-223 dichloride, nedisertib, avelumab)
Peposertib3-Pyridazinemethanol, alpha-(2-Chloro-4-fluoro-5-(7-(4-morpholinyl)-4-quinazolinyl)phenyl)-6-methoxy-, (alphaS)-, M 3814, M-3814, M3814, MSC 2490484A, MSC-2490484A, MSC2490484A, NedisertibArm B (radium-223 dichloride, nedisertib)

Purpose

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 nedisertib (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 nedisertib, 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 nedisertib 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 nedisertib 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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (radium-223 dichloride)Active ComparatorPatients receive radium-223 dichloride 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 (radium-223 dichloride, nedisertib)Active ComparatorPatients receive radium-223 dichloride as in Arm A and nedisertib PO or BID on days 3-26. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
    • Peposertib
    Arm C (radium-223 dichloride, nedisertib, avelumab)ExperimentalPatients receive radium-223 dichloride IV as in Arm A and nedisertib 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.
    • Avelumab
    • Peposertib

    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 20 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 abiraterone, enzalutamide, docetaxel, or other secondary hormonal
                 therapy. There is no maximum number of prior therapies
    
              -  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. Strong
                 inducers of CYP3A4/5 or CYP2C19 must be stopped at least 3 weeks prior to the first
                 dose. Drugs mainly metabolized by CYP3A with a narrow therapeutic index as judged by
                 the Investigator must stop at least 1 day prior to first M3814 dose. 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. The primary
                 elimination mechanism of avelumab is proteolytic degradation, thus there are no
                 contraindicated medications with respect to avelumab. Radium-223 dichloride should not
                 be given concurrently with abiraterone plus prednisone/prednisolone
    
              -  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
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:Male
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Dose-limiting toxicity (Phase 1)
    Time Frame:Up to 28 days
    Safety Issue:
    Description:Adverse events will be summarized as count and percentages, overall as well as by dose level/regimen, by severity, and by patient characteristics.

    Secondary Outcome Measures

    Measure: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
    Safety Issue:
    Description:Will be similarly analyzed using the KM method, log rank test and univariate and multivariate Cox model as described for rPFS.
    Measure:Overall survival (OS)
    Time Frame:From date of randomization to date of death due to any cause, assessed up to 2 years
    Safety Issue:
    Description:OS will be similarly analyzed using the KM method, log rank test and univariate and multivariate Cox model as described for rPFS.
    Measure:Symptomatic skeletal event (SSE)
    Time Frame:Up to 2 years post treatment
    Safety Issue:
    Description:Wiil be assessed per standardized case report form distinguishing between pathologic and non-pathologic fractures. SSE rate will be estimated using the KM estimates with 95% confidence interval.
    Measure:Incidence of toxicity and adverse events
    Time Frame:Up to 2 years post treatment
    Safety Issue:
    Description:Will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

    Details

    Phase:Phase 1/Phase 2
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:National Cancer Institute (NCI)

    Last Updated

    August 27, 2020