COMbination of Bipolar Androgen Therapy and Nivolumab

NCT03554317 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: J1812IRB00164973
• Study Type: interventional
• Target: 45
• Locations: 1 country
• Sites: 3

Brief Summary

Single arm, multicenter, open-label Phase II study of the effects of parenteral testosterone in combination with nivolumab in men with metastatic castration-resistant prostate cancer who previously progressed on at least one novel androgen-receptor targeted therapy (i.e. Abiraterone acetate, Enzalutamide). Up to one taxane agent is permitted.

Conditions

Castration-resistant Prostate Cancer; Metastatic Prostate Cancer; Prostate Cancer

Keywords

Bipolar Androgen Therapy; Testosterone; Nivolumab

Outcome Measures

Primary Outcomes (1)

• Prostate Specific Antigen (PSA) Response to Bipolar Androgen Therapy + Nivolumab

  Number of participants with PSA response to Bipolar Androgen Therapy + Nivolumab. PSA response is counted for participants with ≥ 50% decline in PSA from baseline.

  2 years

Secondary Outcomes (6)

• Safety of Bipolar Androgen Therapy + Nivolumab As Determined by the Number of CTCAEs ≥ Grade 3

  2 years

• PSA Progression-Free Survival (PSA-PFS) to Bipolar Androgen Therapy + Nivolumab

  2 years

• Progression-Free Survival (PFS) to Bipolar Androgen Therapy + Nivolumab

  2 years

• Objective Response Rate (ORR) to Bipolar Androgen Therapy + Nivolumab

  2 years

• Durable Progression-Free Survival (Durable PFS) to Bipolar Androgen Therapy + Nivolumab

  2 years

Other Outcomes (7)

• PSA Response to Bipolar Androgen Therapy + Nivolumab in Patients With Gene Mutations

  2 years

• PSA Response to Bipolar Androgen Therapy + Nivolumab in Patients Without Gene Mutations

  2 years

• Clinical Response Association of Bipolar Androgen Therapy + Nivolumab to Mutation-associated Neoantigens (MANAs).

  3 years

Study Arms (1)

Bipolar Androgen Therapy + Nivolumab

EXPERIMENTAL

All participants must have a rising PSA and/or radiographic progression and prior treatment with at least one novel androgen receptor (AR) targeted therapy (i.e. abiraterone acetate, enzalutamide). Up to one taxane agent for metastatic castration-resistant prostate cancer is permitted. Patients will be treated with testosterone cypionate 400mg IM every 4 weeks for a lead-in period of 12 weeks. After the lead-in period, all patients will be treated with nivolumab 480mg IV every 4 weeks and maintained on testosterone cypionate 400mg IM every 4 weeks. Treatment \[with a minimum drug exposure of 12 weeks\] will be continued until PSA progression (PCGW3 criteria) or clinical/radiographic progression (whichever comes first), or until unmanageable toxicity requiring drug cessation.

Drug: Testosterone cypionate; Drug: Nivolumab

Interventions

Testosterone cypionate DRUG

Depot (DEPO)-Testosterone Injection, for intramuscular (IM) injection, contains testosterone cypionate which is the oil-soluble 17 (beta)-cyclopentylpropionate ester of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. Depot (DEPO)-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate.

Also known as: Depot (DEPO)-Testosterone Injection

Bipolar Androgen Therapy + Nivolumab

Nivolumab DRUG

Nivolumab Injection, 100 mg/10 mL (10 mg/mL) or 40 mg/4 mL (10 mg/mL), is a clear to opalescent, colorless to pale yellow liquid, which may contain light (few) particulates. The drug product is a sterile, non-pyrogenic, single-use, isotonic aqueous solution formulated at 10 mg/mL in sodium citrate, sodium chloride, mannitol, diethylenetriaminepentacetic acid (pentetic acid), and polysorbate 80 (Tween 80), at potential hydrogen (pH) 6.0 and includes an overfill to account for vial, needle, and syringe holdup. It is supplied in 10-cc Type I flint glass vials, stoppered with butyl rubber. The clinical study product is a sterile solution to be administered through parenteral intravenous infusion.

Also known as: BMS-936558, MDX1106, ONO-4538

Bipolar Androgen Therapy + Nivolumab

Eligibility Criteria

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

You may qualify if:

• Willing and able to provide signed informed consent.
• Males aged 18 years of age and above.
• Histological or cytologic proof of adenocarcinoma of the prostate.
• Known castration-resistant disease, defined according to Prostate Cancer Working Group 3 (PCWG3) 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 anti-androgen withdrawal prior to being eligible. The minimum time frame to document failure of anti-androgen withdrawal will be four weeks.
• Serum Prostate Specific Antigen (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.
• Documented bone lesions by the appearance of ≥ 2 new lesions by bone scintigraphy or dimensionally-measureable soft tissue metastatic lesion assessed by CT or MRI.
• Absolute PSA ≥ 2.0 ng/mL at screening.
• Must have PSA and/or radiographic progression on AT LEAST 1 novel AR targeted therapy (abiraterone acetate, enzalutamide). One prior chemotherapy agent for metastatic castration-resistant prostate cancer (mCRPC) will be allowed.
• Prior treatment with abiraterone, enzalutamide, bicalutamide, and/or ketoconazole is allowed. There is no limit on the maximum number or types of prior hormonal therapies received.
• Must be maintained on a GnRH analogue or have undergone orchiectomy.
• Radiographic evidence of metastatic disease by CT scan and bone scan, performed within the prior 4 weeks.
• Must have a soft tissue metastatic lesion available for biopsy collection to perform tumor tissue analysis.
• Karnofsky Performance Status (KPS): ≥ 70% within 14 days before start of study treatment (ECOG ≤ 2).

You may not qualify if:

• Has received external-beam radiotherapy within the last 2 weeks prior to start of study treatment.
• Prior oral anti-androgen (e.g. bicalutamide, nilutamide, enzalutamide, apalutamide), or androgen synthesis inhibitor (e.g. abiraterone, orteronel) within the past 2 weeks is not permitted. 5-alpha reductase inhibitor therapy (e.g. finasteride, dutasteride) is allowed, as long as subject has been stable on medication for past 6 months.
• Prior treatment with chemotherapy for the treatment of metastatic hormone sensitive prostate cancer is allowed if the last dose of chemotherapy was greater than 6 months prior to enrollment. In addition, one chemotherapy agent for mCRPC will be allowed.
• Patients who have received prior treatment with bipolar androgen therapy (e.g. testosterone, BAT) are excluded.
• Pain due to metastatic prostate cancer requiring opioid therapy.
• Patients with an intact prostate AND urinary obstructive symptoms are excluded (which includes patients with urinary symptoms from benign prostatic hyperplasia (BPH)).
• Patients receiving anticoagulation therapy with Coumadin are not eligible for study. (Patients on non-coumadin anticoagulants (Lovenox, Xarelto, etc.) are eligible for study. Patients on Coumadin who can be transitioned to Lovenox or Xarelto prior to starting study treatments will be eligible).
• Patients with prior history of an arteriovenous thromboembolic event within the last 12 months are excluded.
• Patients allergic to sesame seed oil or cottonseed oil are excluded.
• Involvement in the planning and/or conduct of the study (applies to both BMS staff and/or staff at the study site).
• Participation in another clinical study with an investigational product during the last 4 weeks/28 days.
• Patients should be excluded if they have had prior systemic treatment with an anti-Programmed Cell Death Protein (PD)-1, anti-PD-L1, anti-PD-L2, anti-Cytotoxic T-lymphocyte-Associated Protein (CTLA)-4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways (e.g. immune checkpoint antagonists).
• Evidence of disease in sites or extent that, in the opinion of the investigator, would put the patient at risk from therapy with testosterone (e.g. femoral metastases with concern over fracture risk, severe and extensive spinal metastases with concern over spinal cord compression, extensive liver metastases).
• Concurrent use of other anticancer agents or treatments, with the following exceptions:
• Ongoing treatment with leutinizing hormone-releasing hormone (LHRH) agonists or antagonists, denosumab (Prolia) or bisphosphonate (e.g. 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.

Sponsors & Collaborators

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

Study Sites (3)

UCSF Helen Diller Family Comprehensive Cancer Center

San Francisco, California, 94115, United States

Location

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, 21287, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Related Publications (1)

• Markowski MC, Taplin ME, Aggarwal R, Sena LA, Wang H, Qi H, Lalji A, Sinibaldi V, Carducci MA, Paller CJ, Marshall CH, Eisenberger MA, Sanin DE, Yegnasubramanian S, Gomes-Alexandre C, Ozbek B, Jones T, De Marzo AM, Denmeade SR, Antonarakis ES. Bipolar androgen therapy plus nivolumab for patients with metastatic castration-resistant prostate cancer: the COMBAT phase II trial. Nat Commun. 2024 Jan 2;15(1):14. doi: 10.1038/s41467-023-44514-2.

  PMID: 38167882 DERIVED

MeSH Terms

Conditions

Prostatic Neoplasms

Interventions

testosterone 17 beta-cypionate; Testosterone Propionate; Nivolumab

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)

Testosterone; Androstenols; Androstenes; Androstanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Testosterone Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Dr. Mark Markowski
• Organization: Johns Hopkins Sidney Kimmel Comprehensive Cancer Center

mmarko12@jhmi.edu

410-614-0567

Study Officials

• Mark Markowski, MD, Ph.D

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

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

Study Record Dates

• First Submitted: May 23, 2018
• First Posted: June 13, 2018
• Study Start: September 5, 2018
• Primary Completion: October 27, 2022
• Study Completion: January 6, 2023
• Last Updated: February 20, 2024
• Results First Posted: October 3, 2023

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)