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

NCT02601014 | Completed Phase 2 Results DMC

• 3 other identifiers: J15119NCI-2015-01325IRB00070748
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

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.

Conditions

Prostate Cancer; Recurrent Prostate Carcinoma; Stage IV Prostate Adenocarcinoma

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Change in PSA Response

  Number of participants with greater than 50% decline in PSA from start of treatment, sustained for \>= 4 weeks, as defined by Prostate Cancer Working Group 2 (PCWG2) criteria.

  up to 3 years

Secondary Outcomes (9)

• Durable Progression Free Survival (PFS)

  up to 3 years

• Number of Participants Experiencing Adverse Events

  up to 3 years

• Objective Response Rate (ORR)

  up to 3 years

• Overall Survival

  up to 3 years

• Progression Free Survival (PFS)

  up to 3 years

Study Arms (2)

Nivolumab and ipilimumab

EXPERIMENTAL

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.

Biological: Ipilimumab; Biological: Nivolumab

Enzalutamide plus Nivolumab and Ipilimumab

EXPERIMENTAL

Patients will continue on standard of care enzalutamide, with the addition of 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.

Biological: Ipilimumab; Biological: Nivolumab; Drug: Enzalutamide

Interventions

Ipilimumab BIOLOGICAL

Given 1 mg/kg IV

Also known as: Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, Yervoy

Enzalutamide plus Nivolumab and Ipilimumab; Nivolumab and ipilimumab

Nivolumab BIOLOGICAL

Given 3 mg/kg IV

Also known as: BMS-936558, MDX-1106, ONO-4538, Opdivo

Enzalutamide plus Nivolumab and Ipilimumab; Nivolumab and ipilimumab

Enzalutamide DRUG

given orally per standard of care

Also known as: Xtandi

Enzalutamide plus Nivolumab and Ipilimumab

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: lead
• Bristol-Myers Squibb: collaborator

Study Sites (1)

Johns Hopkins University/Sidney Kimmel Cancer Center

Baltimore, Maryland, 21287, United States

Location

Related Publications (2)

• Boudadi K, Suzman DL, Anagnostou V, Fu W, Luber B, Wang H, Niknafs N, White JR, Silberstein JL, Sullivan R, Dowling D, Harb R, Nirschl TR, Veeneman BA, Tomlins SA, Wang Y, Jendrisak A, Graf RP, Dittamore R, Carducci MA, Eisenberger MA, Haffner MC, Meeker AK, Eshleman JR, Luo J, Velculescu VE, Drake CG, Antonarakis ES. Ipilimumab plus nivolumab and DNA-repair defects in AR-V7-expressing metastatic prostate cancer. Oncotarget. 2018 Jun 19;9(47):28561-28571. doi: 10.18632/oncotarget.25564. eCollection 2018 Jun 19.

  PMID: 29983880 RESULT

• Shenderov E, Boudadi K, Fu W, Wang H, Sullivan R, Jordan A, Dowling D, Harb R, Schonhoft J, Jendrisak A, Carducci MA, Eisenberger MA, Eshleman JR, Luo J, Drake CG, Pardoll DM, Antonarakis ES. Nivolumab plus ipilimumab, with or without enzalutamide, in AR-V7-expressing metastatic castration-resistant prostate cancer: A phase-2 nonrandomized clinical trial. Prostate. 2021 May;81(6):326-338. doi: 10.1002/pros.24110. Epub 2021 Feb 26.

  PMID: 33636027 RESULT

MeSH Terms

Conditions

Prostatic Neoplasms

Interventions

Ipilimumab; CTLA-4 Antigen; Nivolumab; enzalutamide

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Immune Checkpoint Proteins; Costimulatory and Inhibitory T-Cell Receptors; Receptors, Immunologic; Receptors, Cell Surface; Membrane Proteins; Antigens, Differentiation, T-Lymphocyte; Antigens, Differentiation; Antigens, Surface; Antigens; Biological Factors; Biomarkers

Results Point of Contact

• Title: Emmanuel Antonarakis, MD
• Organization: University of Minnesota Division of Hematology, Oncology and Transplantation

anton401@umn.edu

612-301-2180

Study Officials

• Emmanuel Antonarakis

  Johns Hopkins University/Sidney Kimmel Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 21, 2015
• First Posted: November 10, 2015
• Study Start: March 15, 2016
• Primary Completion: December 3, 2020
• Study Completion: October 6, 2021
• Last Updated: February 3, 2022
• Results First Posted: February 3, 2022

Record last verified: 2022-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)