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

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ClinicalTrials.gov Identifier: NCT02601014
Recruitment Status : Recruiting
First Posted : November 10, 2015
Last Update Posted : September 26, 2019
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Tracking Information
First Submitted Date  ICMJE August 21, 2015
First Posted Date  ICMJE November 10, 2015
Last Update Posted Date September 26, 2019
Actual Study Start Date  ICMJE March 15, 2016
Estimated Primary Completion Date September 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 6, 2015)
Change in PSA response (> 50% PSA decline) using PCWG2 guidelines [ Time Frame: 2 years ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02601014 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: November 6, 2015)
  • Durable PFS defined as lack of clinical/radiographic progression or death [ Time Frame: 2 years ]
    Reported along with the corresponding 95% binomial confidence intervals.
  • Incidence and severity of adverse events graded according to the National Cancer Institute (NIH) CTCAE version 4.0 [ Time Frame: 2 years ]
    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.
  • Incidence of serious adverse events graded according to NIH CTCAE version 4.0 [ Time Frame: 2 years ]
    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.
  • 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 ]
    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.
  • OS [ Time Frame: 3 years ]
    OS will be presented using Kaplan‐Meier estimates and corresponding 95% confidence intervals.
  • PFS based on Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 and PGWG2 [ Time Frame: 3 years ]
    PFS will be presented using Kaplan‐Meier estimates and corresponding 95% confidence intervals.
  • Proportion of patients converting from AR‐V7-positive to -negative (or changes in AR‐V7 expression) during treatment [ Time Frame: Up to 49 weeks ]
    The proportion of patients converting from AR-V7-positive to AR-V7-negative during treatment will be reported
  • PSA‐PFS defined as an increase in PSA that is >= 25% and >= 2 ng/mL, defined per the PCWG2 guidelines [ Time Frame: 3 years ]
    PSA-PFS will be presented using Kaplan‐Meier estimates and corresponding 95% confidence intervals.
  • Response duration in patients with objective response [ Time Frame: 12 months ]
  • Proportion of patients converting from AR‐V7-positive to -negative with the corresponding 95% binomial confidence interval [ Time Frame: Up to 49 weeks ]
    The proportion of patients with the corresponding 95% binomial confidence interval will be reported
  • Proportion of patients converting from AR‐V7-positive to -negative with changes in AR-V7 expression [ Time Frame: Up to 49 weeks ]
    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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Biomarker-Driven Therapy With Nivolumab and Ipilimumab in Treating Patients With Metastatic Hormone-Resistant Prostate Cancer Expressing AR-V7
Official Title  ICMJE Biomarker-Driven Phase-2 Study of Combined Immune Checkpoint Blockade for AR-V7-Expressing Metastatic Castration-Resistant Prostate Cancer (STARVE-PC)
Brief Summary 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Prostate Cancer
  • Recurrent Prostate Carcinoma
  • Stage IV Prostate Adenocarcinoma
Intervention  ICMJE
  • Biological: Ipilimumab
    Given IV
    Other Names:
    • Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
    • BMS-734016
    • MDX-010
    • MDX-CTLA4
    • Yervoy
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Biological: Nivolumab
    Given IV
    Other Names:
    • BMS-936558
    • MDX-1106
    • ONO-4538
    • Opdivo
Study Arms  ICMJE Experimental: Treatment (nivolumab and ipilimumab)
Patients 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.
Interventions:
  • Biological: Ipilimumab
  • Other: Laboratory Biomarker Analysis
  • Biological: Nivolumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 6, 2015)
15
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 2022
Estimated Primary Completion Date September 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Alice Jordan, MS 410-955-1239 ajorda30@jhmi.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02601014
Other Study ID Numbers  ICMJE J15119
NCI-2015-01325 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
J15119 ( Other Identifier: Johns Hopkins University/Sidney Kimmel Cancer Center )
IRB00070748 ( Other Identifier: JHM IRB )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study Sponsor  ICMJE Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Collaborators  ICMJE Bristol-Myers Squibb
Investigators  ICMJE
Principal Investigator: Emmanuel Antonarakis Johns Hopkins University/Sidney Kimmel Cancer Center
PRS Account Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP