Clinical Trials /

Phase IB Trial of Radium-223 and Niraparib in Patients With Castrate Resistant Prostate Cancer (NiraRad)

NCT03076203

Description:

This phase Ib trial studies the side effects and best dose of niraparib when given together with radium Ra223 dichloride in treating subjects with prostate cancer that keeps growing even when the amount of testosterone in the body is reduced to very low levels and has spread from the primary site to the bone. Radium Ra 223 dichloride, acts like calcium to target cancer in the bones and may deliver radiation directly to the bone tumors, limiting damage to the surrounding normal tissue. Niraparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving radium Ra 223 dichloride and niraparib may work better in treating subjects with hormone-resistant prostate cancer metastatic to the bone.

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Phase IB Trial of Radium-223 and Niraparib in Patients With Castrate Resistant Prostate Cancer (NiraRad)
  • Official Title: Phase IB Trial of Radium-223 and Niraparib in Patients With Castrate Resistant Prostate Cancer (NiraRad)

Clinical Trial IDs

  • ORG STUDY ID: 16G.085
  • NCT ID: NCT03076203

Conditions

  • Prostate Carcinoma Metastatic to the Bone
  • Stage IV Prostate Adenocarcinoma
  • Hormone-refractory Prostate Cancer

Interventions

DrugSynonymsArms
NiraparibMK4827, MK-4827Treatment (niraparib, radium Ra 223 dichloride)

Purpose

This phase Ib trial studies the side effects and best dose of niraparib when given together with radium Ra223 dichloride in treating subjects with prostate cancer that keeps growing even when the amount of testosterone in the body is reduced to very low levels and has spread from the primary site to the bone. Radium Ra 223 dichloride, acts like calcium to target cancer in the bones and may deliver radiation directly to the bone tumors, limiting damage to the surrounding normal tissue. Niraparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving radium Ra 223 dichloride and niraparib may work better in treating subjects with hormone-resistant prostate cancer metastatic to the bone.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine a safe dose of niraparib when combined with radium Ra 223 dichloride
      (radium-223) in patients with metastatic castrate-resistant prostate cancer (mCRPC) that have
      and have not received prior chemotherapy.

      SECONDARY OBJECTIVES:

      I. To determine the proportion of subjects with 50% prostate-specific antigen (PSA) reduction
      from baseline in men treated with niraparib and radium 223.

      II. To determine the radiographic PFS (rPFS) at 6 months in men treated with niraparib and
      radium 223.

      III. To determine the proportion of subjects that have circulating tumor cell (CTC)
      conversion (>= 5 to < 5/7.5ml) confirmed in a second assessment > 4 weeks later in men
      treated with niraparib and radium 223.

      IV. To determine the overall progression-free survival in men treated with niraparib and
      radium 223.

      V. To determine the time to total-ALP (alkaline phosphatase) progression defined in subjects
      with no total-ALP decline from baseline as >= 25% increase from the baseline value, at least
      12 weeks from baseline.

      VI. To determine the time to total-ALP (alkaline phosphatase) progression defined in patient
      with an initial total-ALP decline from baselines as >= 25% increase from the nadir value,
      which is confirmed by a second value obtained three or more weeks later.

      VII. To determine the total-ALP normalization, defined as the return of total-ALP value to
      within normal range at 12 weeks in 2 consecutive measurements (at least 2 weeks apart) after
      that of treatment in subjects who have their ALP above upper limit of normal (ULN) at
      baseline.

      VIII. To determine the long term safety-tolerability of the combination of niraparib and
      radium 223 in men treated with niraparib and radium 223.

      TERTIARY OBJECTIVES:

      I. Study of deoxyribonucleic acid (DNA) repair aberrations; whole exome and transcriptome in
      pre-therapy tumor biopsy samples.

      II. Compare changes in bone marrow micro-environment (hematopoietic stem cell [HSC] niche\
      C-X-C motif chemokine ligand 12 [CXCL12]/C-X-C motif chemokine receptor 4 [CXCR4] axis) pre
      and post therapy in up to 10 men treated with niraparib and radium 223.

      III. Evaluate the baseline plasma cell-free (cf)-DNA for aberrations in DNA repair genes such
      as breast cancer (BRCA)1, BRCA2, ataxia telangiectasia mutated (ATM), ataxia-telangiectasia
      and rad3-related (ATR), partner and localizer of brca2 gene (PALB2) as well as the androgen
      receptor (AR) gene via next generation sequencing.

      IV. Compare gene expression changes in baseline and serial (at end of cycle 1 and 3) whole
      blood ribonucleic acid (RNA) (collect blood in edetic acid [EDTA] tubes and RNA-later) using
      Nanostring PanCancer and immunology panel.

      V. Evaluate the baseline CTCs for nuclear androgen receptor (AR), phosphorylated (p) nuclear
      factor kappa-beta (NF-kB), and gamma-H2A histone family member X (H2AX) foci via
      immunostaining.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (niraparib, radium Ra 223 dichloride)ExperimentalPatients receive niraparib orally daily and radium Ra 223 dichloride IV over 1 minute every 4 weeks. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
  • Niraparib

Eligibility Criteria

        Inclusion Criteria:

          -  Histologic or cytologic diagnosis of adenocarcinoma of the prostate without
             neuroendocrine differentiation or small cell features

          -  Bone metastases

          -  Documented progressive metastatic CRPC based on at least one of the following
             criteria:

               -  PSA progression defined as a miminum of 2 rising PSA levels with a minimum of a 1
                  week interval and a minimum PSA of 2 ng/mL

                  -1.0 ng/mL is the minimal starting PSA value if confirmed rise is the only
                  indication of progression

               -  Soft-tissue progression defined as an increase >= 20% in the sum of the longest
                  diameter (LD) of all target lesions based on the smallest sum LD since treatment
                  started or the appearance of one or more new lesions or the appearance of new
                  lesions

               -  Documented appearance of new lesions by bone scan

          -  Agree to undergo a tumor/bone marrow biopsy or submit archival tissue. Note: Tissue
             sample collected from primary or metastatic site is acceptable on study. Once each
             stratum begins enrollment at the 300mg dose level, 5 subjects from each stratum will
             complete a bone marrow biopsy. Due to the dose assignment method used in this study,
             the 10 subjects requiring a bone marrow biopsy on study will be determined on a case
             by case basis after consent

          -  Age ≥ 18 years.

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

          -  Must have received at least 1 line of AR-targeted therapy or androgen bio-synthesis
             inhibitor (e.g., abiraterone acetate, enzalutamide, apalutamide) for prostate cancer

          -  Testosterone =< 50 ng/dL; subjects must continue primary androgen deprivation with an
             luteinizing hormone-releasing hormone (LHRH) analogue (agonist or antagonist) if they
             have not undergone orchiectomy

          -  Subjects on long term (>= 6 months) first generation anti-androgen therapy (e.g.
             flutamide, bicalutamide, nilutamide) will need to discontinue anti-androgen therapy
             for 4 weeks (wash out period) and show evidence of disease progression off the
             anti-androgen; subjects that have been on a first generation anti-androgen 6 months or
             less will need to discontinue therapy prior to registration (no wash out period
             required)

          -  Subjects on second generation anti-androgen therapy (enzalutamide) or androgen
             bio-synthesis inhibitor (abiraterone acetate) will need to discontinue therapy 2 weeks
             prior to registration (wash out period)

          -  Subjects on treatment with chemotherapy or any investigational therapeutic agent will
             need to discontinue therapy 4 weeks prior to registration (wash out period)

          -  Absolute neutrophil count (ANC) >= 1,500/uL

          -  Hemoglobin >= 10 g/dL

          -  Platelet count >= 150,000/uL

          -  Creatinine =< 1.5 x the institutional ULN

          -  Potassium > 3.5 mmol/L (within institutional normal range)

          -  Total Bilirubin =< 1.5 ULN (unless documented Gilbert's disease)

          -  Serum glutamic oxaloacetic transaminase (SGOT) aspartate aminotransferase (AST) =< 2.5
             x ULN

          -  Serum glutamate pyruvate transaminase (SGPT) alanine aminotransferase (ALT) =< 2.5 x
             ULN

          -  Men must agree to use adequate contraception prior to study entry, for the duration of
             study participation and for at least 6 months after last radium 223 dose

          -  Must be able to take oral medication without crushing, dissolving or chewing capsules

          -  May have received prior radiation therapy or surgery; however, at least 21 days must
             have elapsed since completion of radiation therapy or surgery and patient must have
             recovered from all side effects at the time of registration

          -  Ability to understand and the willingness to sign a written informed consent document
             that is approved by the local institutional review board

        Exclusion Criteria:

          -  Concurrent treatment with any other investigational therapeutic agents

          -  More than one prior line of chemotherapy

          -  More than one prior line of therapy with a second generation anti-androgen
             (enzalutamide, ARN-509, etc.) or androgen bio-synthesis inhibitor (abiraterone
             acetate, TAK 700, etc.); patient may have had one second generation anti-androgen or
             androgen bio-synthesis inhibitor but not both sequentially; subjects that have
             received combination therapy with second generation anti-androgen plus an androgen
             bio-synthesis inhibitor would be eligible (e.g., enzalutamide plus abiraterone acetate
             as one line of therapy on a clinical trial). Note, subjects who have had one line of
             therapy in a hormone-sensitive setting or one line of therapy in castrate resistant
             setting are eligible for study.

          -  Prior isotope therapy with strontium-89, samarium or RAD223

          -  Subjects with known symptomatic brain metastases

          -  All herbal, alternative and food supplements (i.e. PC-Spes, saw palmetto, St. John's
             wort, etc.) must be discontinued before registration; Subjects may continue on a daily
             multi-vitamin, calcium and vitamin D

          -  Pre-planned concurrent cytotoxic chemotherapy, surgery, or radiation therapy during
             protocol treatment; radiation therapy is not permitted while on study

          -  All hormonal-acting agents (including diethylstilbestrol/DES, aldosterone, and
             spironolactone) must be discontinued before registration; no washout period will be
             required for any of these agents

          -  Initiation of bisphosphonate/denosumab therapy during the study; subjects on stable
             doses of bisphosphonates or the tumor necrosis factor receptor superfamily member 11a,
             subfamily L (RANK-L) inhibitor, denosumab, which have been started no less than 4
             weeks prior to registration, may continue on this medication

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure (New York Heart Association class III
             and IV heart failure), unstable angina pectoris, cardiac arrhythmia, or psychiatric
             illness/social situations that would limit compliance with study requirements or
             concurrent medications that alter cardiac conduction

          -  Subjects with a "currently active" second malignancy other than non-melanoma skin or
             superficial urothelial cancers are not eligible; Subjects are not considered to have a
             "currently active" malignancy if they have completed therapy and are now considered
             without evidence of disease for 2 years

          -  Subjects with any known history of myelodysplastic syndrome (MDS) or acute myeloid
             leukemia (AML)

          -  Subjects with known persistent (> 4 weeks) >= grade 2 toxicity from prior cancer
             therapy

          -  Subjects with known >= grade 3 hematological toxicity lasting greater than 7 days with
             the last chemotherapy regimen

          -  Subjects with chronic conditions associated with non-malignant abnormal bone growth
             (e.g., Paget's disease of bone)

          -  Subjects who have used any of the following within 4 weeks prior to registration:
             blood or platelet transfusions, erythropoietin, and biologic response modifiers such
             as granulocyte macrophage colony-stimulating factor (GM-CSF) or granulocyte
             colony-stimulating factor (G-CSF)

          -  Subjects with baseline QT prolongation > 470 msec

          -  Subjects receiving concomitant medications that prolong corrected QT interval (QTc)

          -  Subjects with bulky visceral disease defined as > 4 cm

          -  Known disorder affecting gastrointestinal absorption

          -  Subjects with known allergies, hypersensitivity, or intolerance to niraparib or its
             excipients

          -  Subjects requiring escalating doses of prednisone or steroids for control of disease
             at the time of screening. Note: If subjects are receiving prednisone or steroids, they
             must continue on the same dose they were receiving at the time of screening while
             being treated on study

          -  HIV positive subjects with 1 or more of the following:

               -  Not receiving highly active antiretroviral therapy

               -  A change in antiretroviral therapy within 6 months of the start of screening
                  (except if, after consultation with the sponsor on exclusion criterion 26c. a
                  change is made to avoid a potential drug-drug interaction with the study drug)

               -  receiving antiretroviral therapy that may interfere with the study drug (consult
                  the sponsor for review of medication prior to enrollment)

               -  CD4 cont <350 at screening

               -  An acquired autoimmunodeficiency syndrome-defining opportunistic infection within
                  6 months of the start of screening
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose of niraparib to combine with radium Ra 223 dichloride based on dose limiting toxicities graded by National Cancer Institute, Common Toxicity Criteria, version 4.0
Time Frame:12 weeks
Safety Issue:
Description:There will be three dose levels of niraparib combined with standard doses of Radium 223 to be evaluated for safety

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Sidney Kimmel Cancer Center at Thomas Jefferson University

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