Clinical Trials /

Study of Nivolumab in Combination w Radium-223 in Men w Metastatic Castration Resistant Prostate Cancer



This is an open label, prospective, trial that begins with a phase Ib safety run-in followed by a phase II expansion cohort.

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:



Phase 1/Phase 2

Trial Eligibility



  • Brief Title: Study of Nivolumab in Combination w Radium-223 in Men w Metastatic Castration Resistant Prostate Cancer
  • Official Title: A Phase IB Study of Nivolumab in Combination With Radium-223 in Men With Metastatic Castration Resistant Prostate Cancer

Clinical Trial IDs

  • ORG STUDY ID: HCI126006
  • NCT ID: NCT04109729


  • Metastatic Castration-resistant Prostate Cancer


NivolumabRadium-223Treatment: all patients


This is an open label, prospective, trial that begins with a phase Ib safety run-in followed by a phase II expansion cohort.

Detailed Description

      Drug combination rationale Radium-223 is a calcium-mimetic radiopharmaceutical that has been
      approved for treatment of metastatic prostate cancer. Accumulating in areas of high bone
      turnover, such as bony metastases, radium-223 emits high energy alpha radiation within a
      narrow range thereby limiting toxicity (12). A pivotal phase III trial among patients with
      mCRPC and symptomatic bony metastases led to the approval of radium-223 (13). When compared
      to placebo, treatment with radium-223 resulted in an improved overall survival (OS) (3.6
      months, HR 0.70, 95% CI 0.58 to 0.83). This benefit was accompanied by no clinically
      significant difference in grade 3-4 adverse events between the two arms other than
      cytopenias. Patients also experienced a significant improvement in quality of life measures
      (14) with radium-223 compared to placebo.

      Immunotherapy is a promising area of research in many areas of oncology. However, only
      PROVENGE is currently approved in mCRPC, with ipilimumab, pembrolizumab, and nivolumab
      previously demonstrating limited clinical efficacy. Beer et al evaluated ipilimumab
      monotherapy versus placebo in asymptomatic or minimally symptomatic men with mCRPC (15).
      Patients could not have visceral metastatic disease or prior chemotherapy. There was no
      improvement in OS, the primary endpoint of this study, with ipilimumab over placebo. The
      median OS was 28.7 months (95% CI, 24.5 to 32.5 months) for ipilimumab versus 29.7 months
      (95% CI, 26.1 to 34.2 months) with placebo (HR 1.11; 95.87% CI, 0.88-1.39; P = .3667). There
      was suggestion of some clinical response with the ipilimumab arm demonstrating more PSA
      responses (23% vs 8%) and a longer median PFS (5.6 months vs 3.8 months). de Bono reported on
      the clinical efficacy of single agent pembrolizumab in mCRPC patients (16). They evaluated
      clinical activity based on the disease control rate (DCR), defined as no disease progression
      (i.e. CR + PR + SD). Eleven percent of patients had DCR of 6 months or greater, median follow
      up less than 12 months at the time of the study reporting. 19% of patients experienced any
      degree of PSA decline and 11% of patients had a 50% reduction or greater to PSA as the best
      response to therapy. Topalian et al evaluated the early safety and antitumor activity of
      monotherapy nivolumab in the basket trial CA209-003. Of the 296 patients treated, 17 were
      patients with CRPC. However, no objective responses (complete response or partial response)
      were seen in this patient population (17). Overall the response rate is modest, demonstrating
      some activity with immunotherapy but suggesting that combination therapy may be a more
      attractive approach.

      Recently the results of a prospective clinical trial of ipilimumab (CTLA-4 antagonist) and
      nivolumab (PD-1 antagonist) combination was reported in metastatic castration-resistant
      prostate cancer (18). 79 patients were treated and included patients who had previously
      progressed on docetaxel (cohort 2) and those who were docetaxel naïve (cohort 1). The
      objective response rate was 10% and 26% respectively. This therapy led to a significant
      number of significant adverse events, with a grade 3-4 AE rate of 51% and 39% respectively. A
      separate prospective pilot clinical trial in patients with high-risk disease as defined by
      presence of AR-V7 expression was also recently reported. The objective response rate was 25%
      in men with RECIST measurable disease and a 13% PSA response rate was observed overall (19).
      These studies demonstrate the significant improvement in clinical activity of combination
      immunotherapy over single-agent treatment in patients with metastatic castration-resistant
      prostate cancer. Overall the responses are still low even with the combination of multiple
      checkpoint inhibitors.

      Many intrinsic mechanisms of resistance may account for this relative lack of efficacy
      including minimal baseline immune infiltration within the tumor (20), presence of
      immunosuppressive cells such as myeloid derived suppressor cells within the tumor
      microenvironment (21), and low tumor mutation burden leading to a lack of significant
      antigenicity (22).

      External beam radiation therapy (EBRT) has been shown in preclinical models to alter the
      tumor microenvironment and may work synergistically with PD-1 inhibition. EBRT plus PD-1
      inhibition resulted in improved tumor control compared to either agent alone in murine models
      (23). Alteration to PD-1 expression has also been observed with radium-223, suggesting
      potential synergy of these two strategies (24). Promotion of antigen presentation and antigen
      spreading may account for some of the beneficial effects of this combination in addition to
      the observed immunomodulatory effects on T-lymphocyte populations (25). The combination of
      EBRT plus checkpoint inhibitors has demonstrated promising efficacy in some early phase
      clinical trials (26,27).

      Kwon et al evaluated men with mCRPC who had progressed on docetaxel to receive radiation
      therapy to a bone metastasis followed by randomization to ipilimumab or placebo (28). The
      median OS was prolonged with ipilimumab (11.2 months vs 10.0 months). However, given high
      toxicity early with ipilimumab, the primary endpoint was not statistically significant (HR
      0.85; 95% CI 0.72-1.00; p=0.053). This benefit was even more evident in patients with good
      risk disease (median OS 22.7 mo vs 15.8 mo; HR 0.62, 95% CI 0.45-0.86; p=0.0038). This
      suggests that radiation therapy may provide added benefit to immunotherapy compared to
      ipilimumab monotherapy, especially in patients with a more favorable biology such as in
      patients lacking visceral metastasis (29) as will be tested in this clinical trial of
      nivolumab plus radium-223.

      T-regulatory cells (defined as CD4+/FOXP3+ T-cells) are immune suppressive. A higher
      concentration in PBMCs and tumor infiltrating lymphocytes has been shown to correlate with an
      increased risk of disease relapse in localized renal cell carcinoma (30). Additionally, it
      also is associated with a worse prognosis in patients with metastatic melanoma (31). CD8+
      T-cells are cytotoxic to tumor cells. A high level of CD8+ T-cells has recently been
      associated with an increased response to immunotherapy in patients with metastatic renal cell
      carcinoma (32). CD8+ and CD4+/FOXP3+ T-cell concentrations are associated with overall
      prognosis in patients with metastatic melanoma (33). The concentration of CD8+ lymphocytes is
      low in patients with prostate cancer (34). Animal models suggest that the combination of
      radiation therapy and checkpoint inhibitors provides synergistic activity through the
      alteration of the tumor microenvironment with increased CD8+ T-lymphocytes (35).

      Radium-223 may overcome some of these mechanisms of resistance to single-agent checkpoint
      inhibitor therapy though immunomodulatory effects of radiation therapy to the
      microenvironment in addition to direct cytotoxicity of tumor cells leading to increased
      antigen presentation. We hypothesize that radium-223 plus nivolumab will result in
      significant, favorable tumor microenvironment alterations leading to significant clinical
      activity in mCRPC.

Trial Arms

Treatment: all patientsExperimental
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Male subject aged ≥ 18 years.

          -  Histologically confirmed adenocarcinoma of the prostate.

          -  Diagnosis of metastatic, castration-resistant prostate cancer without evidence of
             visceral metastasis.

          -  Symptomatic bone metastasis as determined by the treating physician.

          -  Castrate levels of testosterone as defined as < 50 ng/dL.

          -  ECOG Performance Status ≤ 2.

          -  Adequate organ function as defined as:

               -  Hematologic:

                    -  White blood cell count (WBC) ≥ 2000/mm3

                    -  Absolute neutrophil count (ANC) ≥ 1500/mm3

                    -  Platelet count ≥ 100,000/mm3

                    -  Hemoglobin ≥ 10g/dL

               -  Hepatic:

                    -  Total Bilirubin ≤ 1.5x institutional upper limit of normal (ULN) unless
                       there is a known history of Gilbert's syndrome.

                    -  AST(SGOT)/ALT(SGPT) ≤ 5 × institutional ULN

               -  Renal:

                    -  Estimated creatinine clearance ≥ 30 mL/min by Cockcroft-Gault formula:

                    -  Males: ((140-age)×weight[kg])/(serum creatinine [mg/dL]×72)

          -  Highly effective contraception throughout the study and for at least 7 months after
             last study treatment administration if the risk of conception exists.

          -  Recovery to baseline or ≤ Grade 1 CTCAE v 5.0 from toxicities related to any prior
             treatments, unless AE(s) are clinically non-significant and/or stable on supportive
             therapy as determined by the treating physician.

          -  Able to provide informed consent and willing to sign an approved consent form that
             conforms to federal and institutional guidelines.

        Exclusion Criteria:

          -  Active or prior autoimmune disease that might deteriorate when receiving an
             immunostimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, hypo-or
             hyperthyroid disease or other autoimmune diseases in the opinion of the treating
             physician that is clinically insignificant or not requiring systemic immunosuppressive
             treatment are eligible.

          -  Current use of immunosuppressive medication at the time of study enrollment, EXCEPT
             for the following permitted steroids:

               -  Intranasal, inhaled, topical steroids, eye drops or local steroid injection (eg,
                  intra-articular injection);

               -  Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or

               -  Steroids as premedication for hypersensitivity reactions (eg, computed tomography
                  (CT) scan premedication).

          -  Prior or concurrent malignancy (other than adenocarcinoma of the prostate).

             --Note: Patients with 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 as approved by
             the Principle Investigator.

          -  The subject has uncontrolled, significant intercurrent or recent illness that would
             preclude safe study participation.

          -  Clinically significant cardiovascular disease: myocardial infarction (<6 months prior
             to enrollment), unstable angina, congestive heart failure (> New York Heart
             Association Classification Class IIB) or a serious cardiac arrhythmia requiring

          -  Known HIV infection with a detectable viral load at the time of screening.

             --Note: Patients on effective antiretroviral therapy with an undetectable viral load
             at the time of screening are eligible for this trial.

          -  Known chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection with a
             detectable viral load.

             --Note: Patients with an undetectable HBV viral load are eligible. Patients with an
             undetectable HCV viral load are eligible.

          -  Live attenuated vaccinations within 4 weeks of the first dose of radium-223 and while
             on trial is prohibited.

          -  Known prior severe hypersensitivity to investigational product or any component in its
             formulations, including known severe hypersensitivity reactions to monoclonal
             antibodies (NCI CTCAE v5.0 Grade ≥ 3).

          -  Subjects taking prohibited medications as described in Section 6.4.1. A washout period
             of prohibited medications for a period of at least 5 half-lives or as clinically
             indicated should occur prior to the start of treatment.
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase Ib:To assess the safety of nivolumab in combination w Radium-223 in patients w metastatic castrate resistant prostate cancer.
Time Frame:Safety lead-in evaluation consisting of 6 subjects. The observation period is defined as the time from cycle one day one until the first cycle of nivolumab is completed (from cycle one day one to cycle three day 28).
Safety Issue:
Description:Hypothesis:Treatment w Nivolumab in combo w Radium-223 is safe in patients w metastatic castrate resistant prostate cancer An overall proportion of subjects w gr3 or higher non-heme adverse events 20% higher than reported in Checkmate-214 trial would be evidence of unacceptable toxicity. In that study the sum of the proportion of subjects w gr3+ non-heme adverse events, attributed to study therapy, was 46%. The null that the rate of gr3+ non-heme toxicity is 46% or less will be tested after every 10 pts and at the end of the trial at the nominal one sided 0.10 significance level. With 36 evaluable subjects there will be at least 87% power to reject the null if the true proportion is 66%. Checkmate-214 is a comparison since the ipilimumab-nivolumab combo represents the immunotherapy combo with the highest frequency of irAEs that is currently FDA approved based on nivolumab 3mg/kg dosing, the dose used in this trial. A toxicity rate higher is not acceptable for further development.

Secondary Outcome Measures

Measure:To assess PSA progression free survival defined by the Prostate Cancer Working Group 3 (PCWG3).
Time Frame:up to 24 months
Safety Issue:
Description:Measurement of clinical activity of nivolumab in combination with Radium-223 in study population.
Measure:To assess correlation of bone metabolism markers with clinical response.
Time Frame:between baseline and C4D15 (about 5 months)
Safety Issue:
Description:Measurement of clinical activity of nivolumab in combination with Radium-223 in study population.
Measure:To assess response rates by serum PSA (defined by proportion of patients obtaining a 50% PSA reduction and the proportion of patients obtaining a 90% PSA reduction).
Time Frame:up to 24 months
Safety Issue:
Description:Measurement of clinical activity of nivolumab in combination with Radium-223 in study population.
Measure:To assess time to first symptomatic skeletal related event (defined as symptomatic fracture, surgery or radiation to bone, or spinal cord compression).
Time Frame:up to 24 months
Safety Issue:
Description:Measurement of clinical activity of nivolumab in combination with Radium-223 in study population.
Measure:To assess radiographic progression-free survival as defined by the PCWG3 criteria.
Time Frame:up to 24 months
Safety Issue:
Description:Measurement of clinical activity of nivolumab in combination with Radium-223 in study population.


Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Utah

Last Updated

October 19, 2020