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Castration-resistant Prostate CancerPhase 2COMBAT-CRPCNCT03554317

COMbination of Bipolar Androgen Therapy and Nivolumab

A Phase 2 study testing Testosterone cypionate and Nivolumab in people with Castration-resistant Prostate Cancer and Metastatic Prostate Cancer, run by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins at 3 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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). Read more about this study

Who is it for?
Ages 18 years and older, men only
What is being tested?
Testosterone cypionate and Nivolumab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
45 participants
Where
3 sitesUnited States
Study dates
5 Sep 2018to 6 Jan 2023
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • Men only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • 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.
  • Or
  • 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).
  • Participants must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below:
  • Hemoglobin ≥ 9.0 g/dL with no blood transfusion in the past 28 days.
  • Absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L
  • Platelet count ≥ 100 x 10^9/L
  • Total bilirubin within institutional upper limit of normal (ULN) (In patients with Gilbert's syndrome, total bilirubin < 1.5x institutional ULN will be acceptable).
  • Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) within institutional upper limit of normal.
  • Participants must have creatinine clearance estimated ≥ 40 mL/min.
  • Participants must have a life expectancy ≥ 6 months.
  • Male participants and their partners, who are sexually active and of childbearing potential, must agree to the use of two highly effective forms of contraception in combination, throughout the period of taking study treatment and for 7 months after the last dose of nivolumab to prevent pregnancy in a partner.
  • No evidence (within 5 years) of prior malignancies (except successfully treated basal cell or squamous cell carcinoma of the skin).

Who cannot join

  • 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)).
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  • 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.
  • 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 (≥ CTCAE Grade 3).
  • Patients are excluded if they have active known 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 testosterone 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 (e.g. contrast dye allergy) or for treatment of non-autoimmune conditions (e.g. delayed-type hypersensitivity reaction caused by contact allergen) is permitted.
  • As there is potential for hepatic toxicity with nivolumab, drugs with a predisposition to hepatotoxicity 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).
  • History of allergy to study drug components.
  • History of severe hypersensitivity reaction to any monoclonal antibody.
  • Other primary tumor (other than 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 major infection.
  • Cardiac failure New York Heart Association (NYHA) Class III or IV.
  • Crohn's disease or ulcerative colitis.
  • Bone marrow dysplasia.
  • Known allergy to any of the compounds under investigation.
  • Unmanageable fecal incontinence.
  • Persistent toxicities (> CTCAE Grade 2) caused by previous cancer therapy, excluding alopecia.
  • Poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 6 months) myocardial infarction, uncontrolled major seizure disorder, extensive interstitial bilateral lung disease, or any psychiatric disorder that prohibits obtaining informed consent.

Trial locations and contacts

3 sites in 1 country.

United States3 sites

  • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

    Baltimore, Maryland, 21287

  • Dana-Farber Cancer Institute

    Boston, Massachusetts, 02215

  • UCSF Helen Diller Family Comprehensive Cancer Center

    San Francisco, California, 94115

Other trials in United States

About this study

Official title: COMbination of Bipolar Androgen Therapy and Nivolumab in Patients With Metastatic Castration-Resistant Prostate Cancer

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.

Read the detailed description

The trial will enroll up to 44 participants (45 were enrolled because the last two patients consented at two sites simultaneously). Eligible participants will continue on androgen ablative therapy with a GnRH analogue (i.e. Zoladex, Trelstar, Eligard, or Lupron) if they have not undergone orchiectomy. Following enrollment, participants will receive an intramuscular injection of testosterone cypionate 400mg every 4 weeks for a lead-in period of 12 weeks. After the lead-in period, all participants will be treated with nivolumab 480mg IV every 4 weeks and maintained on testosterone cypionate 400mg IM every 4 weeks. Assessments for response to testosterone + nivolumab will be performed approximately every 3 months. Treatment [with a minimum drug exposure of 12 weeks] will be continued until PSA progression (Prostate Cancer Working Group 3 [PCWG3] criteria) or clinical/radiographic progression (whichever comes first), or until unmanageable toxicity requiring drug cessation.

Being tested
Testosterone cypionate, Nivolumab
Keywords
Bipolar Androgen Therapy, Testosterone, Nivolumab
Medical subject headings
Prostatic Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Testosterone cypionateDrug

    Also called Depot (DEPO)-Testosterone Injection

    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.

  • NivolumabDrug

    Also called BMS-936558, MDX1106, ONO-4538

    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.

Study groups in NCT03554317
Study groupRoleWhat they receive
Bipolar Androgen Therapy + NivolumabExperimentalAll 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.
Receives: Drug: Testosterone cypionate; Drug: Nivolumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: 2 years

Secondary outcomes (6)

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

    Number of participants that experience adverse events grade ≥ 3, as defined by Common Terminology Criteria for Adverse Events (CTCAE).

    Measured: 2 years

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

    Number of months from the time of initiation on Bipolar Androgen Therapy + Nivolumab therapy until PSA increase of 25% over a nadir value, confirmed by a follow-up PSA at least 4 weeks apart.

    Measured: 2 years

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

    Median number of months from the time of the first dose to objective radiographic tumor progression or death, whichever comes first, as defined by RECIST 1.1 Criteria for progressive disease or death.

    Measured: 2 years

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

    Percentage of patients achieving a complete or partial response in target lesions as defined by RECIST 1.1 Criteria.

    Measured: 2 years

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

    Number of participants without clinical/radiographic progression for > 6 months from the start of treatment.

    Measured: 2 years

  6. Median Overall Survival (OS) to Bipolar Androgen Therapy + Nivolumab

    Median number of months from study enrollment to death from any cause up to 2 years after the last dose of study treatment received.

    Measured: 3 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted13 Jun 2018
  2. Study start5 Sep 2018
  3. Primary completion27 Oct 2022
  4. Study completion6 Jan 2023

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
45 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03554317
Sponsor's protocol ID
J1812
Other IDs
IRB00164973
Acronym
COMBAT-CRPC
Status last verified
Feb 2024
First submitted
23 May 2018
Last updated
20 Feb 2024
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 38167882

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Testosterone cypionate and Nivolumab in people with Castration-resistant Prostate Cancer and Metastatic Prostate Cancer, run by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins at 3 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 26 inclusion and 37 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 20 Feb 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 3 Oct 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Prostate Specific Antigen (PSA) Response to Bipolar Androgen Therapy + Nivolumab (time frame: 2 years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03554317, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Feb 2024.

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