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Biomarker-Driven Therapy With Nivolumab and Ipilimumab in Treating Patients With Metastatic Hormone-Resistant Prostate Cancer Expressing AR-V7

NCT02601014

Description:

This phase II trial studies how well nivolumab and ipilimumab work in treating patients with hormone-resistant prostate cancer that has spread to other places in the body and express androgen receptor-variant-7 (AR-V7). Tumor cells expressing AR-V7 has been shown to be resistant to hormone therapy and some chemotherapy in patients with prostate cancer. Biomarker-driven therapy, such as nivolumab and ipilimumab, may work by blocking key biomarkers or proteins that help tumor cells to escape the immune system surveillance and this may help the immune system to kill tumor cells that express AR-V7.

Related Conditions:
  • Prostate Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Biomarker-Driven Therapy With Nivolumab and Ipilimumab in Treating Patients With Metastatic Hormone-Resistant Prostate Cancer Expressing AR-V7
  • Official Title: Biomarker-Driven Phase-2 Study of Combined Immune Checkpoint Blockade for AR-V7-Expressing Metastatic Castration-Resistant Prostate Cancer (STARVE-PC)

Clinical Trial IDs

  • ORG STUDY ID: J15119
  • SECONDARY ID: NCI-2015-01325
  • SECONDARY ID: J15119
  • SECONDARY ID: IRB00070748
  • NCT ID: NCT02601014

Conditions

  • Prostate Cancer
  • Recurrent Prostate Carcinoma
  • Stage IV Prostate Adenocarcinoma

Interventions

DrugSynonymsArms
IpilimumabAnti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, YervoyTreatment (nivolumab and ipilimumab)
NivolumabBMS-936558, MDX-1106, ONO-4538, OpdivoTreatment (nivolumab and ipilimumab)

Purpose

This phase II trial studies how well nivolumab and ipilimumab work in treating patients with hormone-resistant prostate cancer that has spread to other places in the body and express androgen receptor-variant-7 (AR-V7). Tumor cells expressing AR-V7 has been shown to be resistant to hormone therapy and some chemotherapy in patients with prostate cancer. Biomarker-driven therapy, such as nivolumab and ipilimumab, may work by blocking key biomarkers or proteins that help tumor cells to escape the immune system surveillance and this may help the immune system to kill tumor cells that express AR-V7.

Detailed Description

      PRIMARY OBJECTIVES:

      1. To evaluate the effect of administration of nivolumab and ipilimumab on the proportion of
      prostate-specific antigen (PSA) responses (> 50% PSA decline) in metastatic
      castration-resistant prostate cancer (mCRPC) patients with detectable AR‐V7 transcript in
      circulating tumor cells (CTCs).

      SECONDARY OBJECTIVES;

        1. To evaluate the safety and tolerability of ipilimumab + nivolumab in AR‐V7-positive
           patients.

        2. To determine the progression free survival (PFS).

        3. To determine the PSA‐PFS.

        4. To determine the proportion of "durable" responses.

        5. To determine the overall response rate (ORR).

        6. To determine the overall survival (OS).

        7. To evaluate changes in AR‐V7 detection (or expression levels) before and after treatment
           with ipilimumab + nivolumab and correlate with PSA responses.

        8. To explore potential biomarkers associated with clinical efficacy (ORR, PFS, and OS) of
           nivolumab and ipilimumab by analyzing absolute lymphocyte count in peripheral blood as
           well as programmed cell death 1 ligand 1 (PD‐L1) expression in CTCs and/or in tumor
           biopsies, and immune profiling of sera and tumor tissue.

      OUTLINE:

      Patients receive nivolumab intravenously (IV) over 60 minutes and ipilimumab IV over 90
      minutes every 3 weeks for 12 weeks. Patients then receive nivolumab IV over 60 minutes every
      2 weeks for 36 weeks in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up for 100 days and then every 3
      months.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (nivolumab and ipilimumab)ExperimentalPatients receive nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes every 3 weeks for 12 weeks. Patients then receive nivolumab IV over 60 minutes every 2 weeks for 36 weeks in the absence of disease progression or unacceptable toxicity.
  • Ipilimumab
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically or cytologically confirmed adenocarcinoma of the prostate

          -  Metastatic disease as defined by two or more bone metastases confirmed by bone
             scintigraphy or radiographic soft tissue metastasis

          -  Detectable circulating tumor cells (CTCs) with detectable AR‐V7 splice‐variant by
             reverse transcriptase (RT)‐polymerase chain reaction (PCR)

        For second cohort (amendment 1):

        The most recent therapy must be enzalutamide and enzalutamide will be continued for study
        duration despite progressive disease. The minimum required dose of Enzalutamide at
        enrolment should be no less than 80 mg once daily.

          -  Known castration‐resistant disease, defined according to Prostate Cancer Working Group
             2 (PCWG2) criteria as:

               -  Castrate serum testosterone level: =< 50 ng/dL (=< 1.7 nmol/L)

               -  Subjects who have failed initial hormonal therapy, either by orchiectomy or by
                  using a gonadotropin-releasing hormone (GnRH) agonist in combination with an
                  anti‐androgen, must first progress through antiandrogen withdrawal prior to being
                  eligible; the minimum timeframe to document failure of anti‐androgen withdrawal
                  will be four weeks

               -  Serum PSA progression defined as two consecutive increases in PSA over a previous
                  reference value within 6 months of first study treatment, each measurement at
                  least one week apart; serum PSA at screening >= 2 ng/mL OR

                    -  Documented bone lesions by the appearance of two or more new lesions by bone
                       scintigraphy OR

                    -  Bidimensionally‐measureable soft tissue metastatic lesion assessed by
                       computed tomography (CT) or magnetic resonance imaging (MRI)

          -  Karnofsky performance status (KPS): >= 70% within 14 days before start of study
             treatment (Eastern Cooperative Oncology Group [ECOG] =< 1)

          -  Life expectancy: at least 6 months

          -  White blood count (WBC) >= 2000/uL

          -  Neutrophils >= 1500/uL

          -  Platelets >= 100 x10^3/uL

          -  Hemoglobin > 9.0 g/dL

          -  Serum creatinine =< 1.5 x upper limit of normal (ULN) or creatinine clearance (CrCl)
             >= 40 mL/min (if using the Cockcroft‐Gault formula)

          -  Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x ULN

          -  Total bilirubin =< 1.5 x ULN (except subjects with Gilbert syndrome, who can have
             total bilirubin < 3.0 mg/dL)

          -  Men who are sexually active with women of childbearing potential (WOCBP) must use any
             contraceptive method with a failure rate of less than 1% per year; men receiving
             nivolumab and who are sexually active with WOCBP will be instructed to adhere to
             contraception for a period of 31 weeks after the last dose of investigational product

          -  WOCBP is defined as any female who has experienced menarche and has not undergone
             surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not
             postmenopausal; menopause is defined clinically as 12 months of amenorrhea in a woman
             over 45 in the absence of other biological or physiological causes; in addition, women
             under the age of 55 must have a documented serum follicle stimulating hormone (FSH)
             level less than 40 mIU/mL

          -  No evidence (within 5 years) of prior malignancies (except successfully treated basal
             cell or squamous cell carcinoma of the skin)

          -  The subject is willing and able to comply with the protocol, and agrees to return to
             the hospital for follow‐up visits and examination

          -  The subject has been fully informed about the study and has signed the informed
             consent form and, where appropriate, Health Insurance Portability and Accountability
             Act (HIPAA) authorization for release of personal health information

               -  NOTE: HIPAA authorization may be included in the informed consent or obtained
                  separately

        Exclusion Criteria:

          -  Has received an investigational therapeutic drug within the last 4 weeks prior to
             start of study treatment, or is scheduled to receive one during the treatment period

          -  Has received external radiotherapy within the last 4 weeks prior to start of study
             treatment

          -  Previous therapy with antiandrogens within 4 weeks

          -  Patients should be excluded if they have had prior systemic treatment with an
             anti‐programmed cell death protein 1 (PD‐1), anti‐PD‐L1, anti‐programmed cell death 1
             ligand 2 (PD‐L2), anti‐cytotoxic T-lymphocyte-associated protein 4 (CTLA‐4) antibody,
             or any other antibody or drug specifically targeting T‐cell costimulation or immune
             checkpoint pathways

          -  Symptomatic metastatic disease with signs of rapid progression per investigator's
             clinical judgment

          -  Concurrent use of other anticancer agents or treatments, with the following
             exceptions:

               -  Ongoing treatment with luteinizing hormone-releasing hormone (LHRH) agonists or
                  antagonists, denosumab (Prolia) or bisphosphonate (eg, zoledronic acid) is
                  allowed; ongoing treatment should be kept at a stable schedule; however, if
                  medically required, a change of dose, compound, or both is allowed

          -  Any treatment modalities involving major surgery within 4 weeks prior to the start of
             study treatment

          -  Symptomatic nodal disease, i.e. scrotal, penile or leg edema (>= Common Terminology
             Criteria for Adverse Events [CTCAE] grade 3)

          -  Patients are excluded if they have active brain metastases or leptomeningeal
             metastases; subjects with brain metastases are eligible if metastases have been
             treated and there is no magnetic resonance imaging (MRI) evidence of progression for
             at least 4 weeks after treatment is complete and within 28 days prior to the first
             dose of nivolumab administration; there must also be no requirement for
             immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone
             equivalents) for at least 2 weeks prior to study drug administration

          -  Patients should be excluded if they have an active, known or suspected autoimmune
             disease (e.g. inflammatory bowel disease, rheumatoid arthritis, autoimmune hepatitis,
             lupus, celiac disease); subjects are permitted to enroll if they have vitiligo, type I
             diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring
             hormone replacement, psoriasis not requiring systemic treatment, or conditions not
             expected to recur in the absence of an external trigger

          -  Patients should be excluded if they have a condition requiring systemic treatment with
             either corticosteroids (> 10 mg daily prednisone equivalents) or other
             immunosuppressive medications within 14 days of study drug administration; inhaled or
             topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents
             are permitted in the absence of active autoimmune disease

          -  Permitted therapies include topical, ocular, intra‐articular, intranasal, and
             inhalational corticosteroids (with minimal systemic absorption); physiologic
             replacement doses of systemic corticosteroids are permitted, even if > 10 mg/day
             prednisone equivalents; a brief course of corticosteroids for prophylaxis (eg,
             contrast dye allergy) or for treatment of nonautoimmune conditions (e.g. delayed‐type
             hypersensitivity reaction caused by contact allergen) is permitted

          -  Drugs with a predisposition to hepatoxicity should be used with caution in patients
             treated with nivolumab-containing regimen

          -  Patients should be excluded if they have a positive test for hepatitis B virus surface
             antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating
             acute or chronic infection

          -  Patients should be excluded if they have known history of testing positive for human
             immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)

          -  Allergies and adverse drug reaction

          -  History of allergy to study drug components

          -  History of severe hypersensitivity reaction to any monoclonal antibody

          -  Other primary tumor (other than castration-resistant prostate cancer [CRPC]) including
             hematological malignancy present within the last 5 years (except non‐melanoma skin
             cancer or low‐grade superficial bladder cancer)

          -  Has imminent or established spinal cord compression based on clinical findings and/or
             MRI

          -  Any other serious illness or medical condition that would, in the opinion of the
             investigator, make this protocol unreasonably hazardous, including, but not limited
             to:

               -  Any uncontrolled infection

               -  Cardiac failure NYHA (New York Heart Association) III or IV

               -  Crohn's disease or ulcerative colitis

               -  Bone marrow dysplasia

               -  Known allergy to any of the compounds under investigation

               -  Unmanageable fecal incontinence
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Change in PSA response (> 50% PSA decline) using PCWG2 guidelines
Time Frame:2 years
Safety Issue:
Description:The maximum decline in PSA will be reported for each patient using a waterfall plot. The proportion of PSA responses (> 50% PSA decline) and the corresponding 95% binomial confidence intervals will be reported.

Secondary Outcome Measures

Measure:Durable PFS defined as lack of clinical/radiographic progression or death
Time Frame:2 years
Safety Issue:
Description:Reported along with the corresponding 95% binomial confidence intervals.
Measure:Incidence and severity of adverse events graded according to the National Cancer Institute (NIH) CTCAE version 4.0
Time Frame:2 years
Safety Issue:
Description:Standard safety summaries will be provided for treatment exposure, patient disposition, adverse events leading to discontinuation, serious adverse events, and all events resulting in death, including those up to 30 days after treatment discontinuation. The incidence of adverse events will be tabulated and reviewed for potential significance and clinical importance.
Measure:Incidence of serious adverse events graded according to NIH CTCAE version 4.0
Time Frame:2 years
Safety Issue:
Description:Standard safety summaries will be provided for treatment exposure, patient disposition, adverse events leading to discontinuation, serious adverse events, and all events resulting in death, including those up to 30 days after treatment discontinuation. The incidence of adverse events will be tabulated and reviewed for potential significance and clinical importance.
Measure:ORR defined as proportion of patients with complete response (CR) or partial response (PR) in measurable soft-tissue lesions as defined by RECIST version 1.1
Time Frame:3 years
Safety Issue:
Description:ORR will be estimated as the proportion of subjects whose best overall response is either a CR or PR with corresponding 95% binomial confidence interval.
Measure:OS
Time Frame:3 years
Safety Issue:
Description:OS will be presented using Kaplan‐Meier estimates and corresponding 95% confidence intervals.
Measure:PFS based on Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 and PGWG2
Time Frame:3 years
Safety Issue:
Description:PFS will be presented using Kaplan‐Meier estimates and corresponding 95% confidence intervals.
Measure:Proportion of patients converting from AR‐V7-positive to -negative (or changes in AR‐V7 expression) during treatment
Time Frame:Up to 49 weeks
Safety Issue:
Description:The proportion of patients converting from AR-V7-positive to AR-V7-negative during treatment will be reported
Measure:PSA‐PFS defined as an increase in PSA that is >= 25% and >= 2 ng/mL, defined per the PCWG2 guidelines
Time Frame:3 years
Safety Issue:
Description:PSA-PFS will be presented using Kaplan‐Meier estimates and corresponding 95% confidence intervals.
Measure:Response duration in patients with objective response
Time Frame:12 months
Safety Issue:
Description:
Measure:Proportion of patients converting from AR‐V7-positive to -negative with the corresponding 95% binomial confidence interval
Time Frame:Up to 49 weeks
Safety Issue:
Description:The proportion of patients with the corresponding 95% binomial confidence interval will be reported
Measure:Proportion of patients converting from AR‐V7-positive to -negative with changes in AR-V7 expression
Time Frame:Up to 49 weeks
Safety Issue:
Description:The changes in AR‐V7 expression, expressed as a ratio of AR‐V7 to full‐length AR (AR‐FL) will be analyzed over time using linear mixed effects models.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Trial Keywords

  • Hormone-Resistant Prostate Cancer
  • Prostate Carcinoma Metastatic in the Bone

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