Testosterone Revival Abolishes Negative Symptoms, Fosters Objective Response and Modulates Enzalutamide Resistance

NCT02286921 | Completed Phase 2 Results DMC

• 3 other identifiers: J14146IRB00046414W81XWH-14-2-0189
• Study Type: interventional
• Target: 222
• Locations: 1 country
• Sites: 17

Brief Summary

Asymptomatic men with progressive metastatic Castration-resistant prostate cancer (CRPC) post- treatment with abiraterone acetate (pre-chemotherapy for metastatic disease) will be treated on a randomized, multi-Institutional open label study to determine if treatment with intramuscular T given on a dose/schedule designed to result in rapid cycling from the polar extremes of supraphysiologic to near castrate levels \[i.e. Bipolar Androgen Therapy (BAT)\] will improve primary and secondary objectives vs. enzalutamide as standard therapy.

Conditions

Castration Resistant Metastatic Prostate Cancer

Keywords

Testosterone; Enzalutamide; Abiraterone; Androgen Ablative Therapies; Bipolar Androgen Therapy

Outcome Measures

Primary Outcomes (1)

• Progression Free Survival as Measured by Number of Months Until Clinical or Radiographic Progression

  Time to clinical progression will be defined as months from randomization to any of the following (whichever occurs earlier): * Cancer pain requiring initiation of chronic administration of opiate analgesia (oral opiate use for ≥3 weeks; parenteral opiate use for ≥7 days. Patients with cancer pain requiring opiate analgesia for relief should also be assessed by the investigator for the need for initiating systemic chemotherapy or palliative radiation. * Development of a skeletal-related event (SRE): pathologic fracture, spinal cord compression, or need for surgical intervention or radiation therapy to the bone. * Development of clinically significant symptoms due to loco-regional tumor progression (e.g. urinary obstruction) requiring surgical intervention or radiation therapy.

  up to 2 years

Secondary Outcomes (13)

• Radiographic Progression

  up to 2 years

• Prostate-Specific Antigen Response Rate

  Up to 2 years

• Objective Response Rate as Determined by RECIST

  Up to 2 years

• Time to Prostate-Specific Antigen Progression

  Up to 2 years

• Quality of Life as Assessed by the Positive Affect Score of the Positive and Negative Affect Schedule (PANAS)

  up to 1 year

Study Arms (2)

Arm A: Testosterone cypionate or testosterone enanthate

EXPERIMENTAL

Patients on BAT will receive testosterone cypionate or testosterone enanthate administered as an intramuscular injection. A dose of 400 mg of either agent will be injected intramuscularly (IM) every 28 days.

Drug: Testosterone cypionate; Drug: Testosterone Enanthate

Arm B: Enzalutamide

EXPERIMENTAL

Patients randomized to enzalutamide will be prescribed enzalutamide 40 mg tablets and instructed to take 4 tablets per day orally for 28 days/cycle.

Drug: Enzalutamide

Interventions

Testosterone cypionate DRUG

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

Also known as: Depo-Testosterone Injection

Arm A: Testosterone cypionate or testosterone enanthate

Enzalutamide DRUG

Enzalutamide is a white crystalline non-hygroscopic solid. It is practically insoluble in water. Enzalutamide is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides. The inactive ingredients are caprylocaproyl polyoxylglycerides, butylated hydroxyanisole, butylated hydroxytoluene, gelatin, sorbitol sorbitan solution, glycerin, purified water, titanium dioxide, and black iron oxide.

Also known as: Xtandi

Arm B: Enzalutamide

Testosterone Enanthate DRUG

Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative.

Also known as: Delatestryl

Arm A: Testosterone cypionate or testosterone enanthate

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Eastern Cooperative Oncology Group Performance status ≤2
• Age ≥18 years
• Histologically-confirmed adenocarcinoma of the prostate
• Treated with continuous androgen ablative therapy (either surgical castration or luteinizing hormone-releasing hormone agonist/antagonist)
• Documented castrate level of serum testosterone (\<50 ng/dl)
• Metastatic disease radiographically documented by CT/MRI or bone scan.
• Must have had disease progression while on abiraterone acetate alone or abiraterone acetate in combination with other investigational agents based on:
• Prostate-specific antigen progression defined as an increase in Prostate-specific antigen, as determined by 2 separate measurements taken at least 1 week apart
• And/Or
• Radiographic disease progression, based on RECIST 1.1 in patients with measurable soft tissue lesions, or PCWG2 for patients with bone disease
• Screening Prostate-specific antigen must be ≥ 1.0 ng/mL.
• Prior treatment with additional second line hormone therapies is allowed.
• No prior treatment with enzalutamide, Apalutamide (ARN-509), Darolutamide (ODM-201), galeterone or other investigational androgen receptor targeted treatment is allowed.
• Prior docetaxel for hormone-sensitive prostate cancer is permitted if ≤ 6 doses were given in conjunction with first-line androgen deprivation therapy and \>12 months since last dose of docetaxel.
• Prior treatment with Provenge vaccine and 223Radium (Xofigo) is allowed if \>4 weeks from last dose.

You may not qualify if:

• Pain due to metastatic prostate cancer requiring treatment intervention.
• Eastern Cooperative Oncology Group Performance status ≥3
• Prior treatment with enzalutamide is prohibited
• Prior treatment with docetaxel or cabazitaxel for metastatic castration-resistant prostate cancer is prohibited.
• Requires urinary catheterization for voiding due to obstruction secondary to prostatic enlargement well documented to be due to prostate cancer or benign prostatic hyperplasia (BPH).
• 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)
• Evidence of serious and/or unstable pre-existing medical, psychiatric or other condition (including laboratory abnormalities) that could interfere with patient safety or provision of informed consent to participate in this study
• Active uncontrolled infection, including known history of HIV/AIDS or hepatitis B or C.
• Any psychological, familial, sociological, or geographical condition that could potentially interfere with compliance with the study protocol and follow-up schedule.
• Patients receiving anticoagulation therapy with Coumadin are not eligible for study. \[Patients on non-coumadin anticoagulants (Lovenox, Xarelto, etc.) are eligible for study. Patients on Coumadin who can be transitioned to lovenox prior to starting study treatments will be eligible\].
• Patients with prior history of a thromboembolic event within the last 12 months that is not being treated with systemic anticoagulation are excluded.
• Patients allergic to sesame seed oil or cottonseed oil are excluded.
• Major surgery (eg, requiring general anesthesia) within 3 weeks before screening, or has not fully recovered from prior surgery (ie, unhealed wound). Note: subjects with planned surgical procedures to be conducted under local anesthesia may participate.

Sponsors & Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: lead
• United States Department of Defense: collaborator

Study Sites (17)

Unversity of Alabama

Birmingham, Alabama, 35294, United States

Location

City of Hope

Duarte, California, 91010, United States

Location

University of Colorado Cancer Center

Aurora, Colorado, 80045, United States

Location

Sibley Memorial Hospital

Washington D.C., District of Columbia, 20016, United States

Location

Piedmont Cancer Institute

Atlanta, Georgia, 30318, United States

Location

University of Chicago

Chicago, Illinois, 60637, United States

Location

University of Kansas Cancer Center

Kansas City, Kansas, 66160, United States

Location

Tulane University Medical Center

New Orleans, Louisiana, 70112, United States

Location

University of Maryland

Baltimore, Maryland, 21201, United States

Location

SKCCC at Johns Hopkins

Baltimore, Maryland, 21205, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Neraska Cancer Specialists

Omaha, Nebraska, 68130, United States

Location

Rutgers Cancer Institute of New Jersey

New Brunswick, New Jersey, 08901, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

Allegheny Health Network

Pittsburgh, Pennsylvania, 15212, United States

Location

Huntsman Cancer Institute

Salt Lake City, Utah, 84112, United States

Location

University of Washing

Seattle, Washington, 98109, United States

Location

Related Publications (1)

• Denmeade SR, Wang H, Agarwal N, Smith DC, Schweizer MT, Stein MN, Assikis V, Twardowski PW, Flaig TW, Szmulewitz RZ, Holzbeierlein JM, Hauke RJ, Sonpavde G, Garcia JA, Hussain A, Sartor O, Mao S, Cao H, Fu W, Wang T, Abdallah R, Lim SJ, Bolejack V, Paller CJ, Carducci MA, Markowski MC, Eisenberger MA, Antonarakis ES. TRANSFORMER: A Randomized Phase II Study Comparing Bipolar Androgen Therapy Versus Enzalutamide in Asymptomatic Men With Castration-Resistant Metastatic Prostate Cancer. J Clin Oncol. 2021 Apr 20;39(12):1371-1382. doi: 10.1200/JCO.20.02759. Epub 2021 Feb 22.

  PMID: 33617303 DERIVED

MeSH Terms

Interventions

testosterone 17 beta-cypionate; enzalutamide; testosterone enanthate

Results Point of Contact

• Title: Dr. Samual Denmeade
• Organization: SKCCC at JHU

denmesa@jhmi.edu

410-955-8875

Study Officials

• Samuel Denmeade, MD

  Johns Hopkins School of Medicine - Sidney Kimmel Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

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

Study Record Dates

• First Submitted: October 22, 2014
• First Posted: November 10, 2014
• Study Start: January 1, 2015
• Primary Completion: October 26, 2018
• Study Completion: February 21, 2020
• Last Updated: November 6, 2020
• Results First Posted: May 1, 2019

Record last verified: 2020-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (17)