Testosterone Therapy in Castration Resistant Prostate Cancer

Square Wave Testosterone Therapy in Castration Resistant Prostate Cancer

This is an open-labeled, single-arm, interventional pilot study. It is being done to determine the feasibility of the administration of transdermal testosterone alternating with enzalutamide, as well as the safety and efficacy.

Study Overview

• Status: Completed
• Conditions: Prostate Cancer; Castration-Resistant Prostate Cancer
• Intervention / Treatment: Drug: Transdermal Testosterone; Drug: Standard of Care, Enzalutamide

Detailed Description

The primary endpoint of this trial is to determine the feasibility of the administration of transdermal testosterone alternating with enzalutamide. High dose testosterone has shown activity in phase II studies of patients with castration resistant metastatic prostate cancer; however, these studies have generally employed the intramuscular formulation. It has been hypothesized that the transdermal formulation will show activity but will have less potential for toxicity due to extremely high levels of circulating testosterone (i.e. thrombotic events). In addition, this will allow for a steady state of elevated testosterone, rather than the peaks and troughs seen with the IM approach.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Provision to sign and date the consent form
2. Male and age > or = 18 years old
3. Stated willingness to comply with all study procedures and be available for the duration of the study
4. Histologically or cytologically proven adenocarcinoma of the prostate
5. Ongoing ADT for prostate cancer with a GnRH analogue/antagonist or bilateral orchiectomy for at least 6 months prior to day 1
6. Patients on a first generation anti-androgen (e.g. bicalutamide, flutamide, nilutamide) must have at least a 6-week washout prior to randomization and must show continued PSA progression
7. Serum testosterone level <50ng/dL at the screening visit

8. Progressive disease at screening as defined by one or more of the following criteria:

   • PSA progression: minimum of 2 rising values within an interval of >1 week between values. And a value at screening of >1ng/mL
   • Soft tissue progression on CT or MRI based on RECIST 1.1 criteria or progression of bone disease according to PCWG3 criteria
9. Patients worst pain in the last 24 hours must rank less than 4 on a 0-10 scale and patients cannot be on daily narcotic medications to treat cancer-related pain. This assessment must occur within the screening window and be documented in the patient's medical record.

10. Acceptable Clinical laboratory values at Screening Visit which include:

    • Absolute neutrophil count ≥ 1000/uL; platelet count ≥ 100,000/uL, hemoglobin ≥ 8g/dL
    • Total bilirubin ≤ 1.5xULN (unless documented Gilbert's); alanine aminotransferase or aspartate aminotransferase ≤ 2.5xULN
    • Creatinine ≤ 2mg/dL
    • Hemoglobin ≤ 17.5 g/dL
11. Evidence of metastatic disease at any time point on axial imaging or bone scan, or previous biopsy. Stage IV pelvic lymph node involvement is acceptable
12. Must use a condom if having sex with a pregnant woman
13. A male patient and his female partner who is of childbearing potential must use 2 acceptable methods of birth control (one of which must include a condom as a barrier method of contraception) starting at screening and continuing throughout the study period and for 3 months after final study drug administration
14. Patients may have received any number of lines of therapy for castration resistant disease

Exclusion Criteria:

1. Requires urinary catheterization for voiding due to obstruction secondary to prostatic enlargement that is well documented to be due to prostate cancer or benign prostatic hyperplasia
2. Evidence of disease in sites or extent that, in the opinion of the investigator, would put the patient at risk from therapy with testosterone due to a potential tumor flare (e.g. high-risk bone lesions which may result in fracture or spinal cord compression

3. Clinically significant cardiovascular disease as evidenced by any of the following:

   • Myocardial infarction with 6 months of screening
   • uncontrolled angina within 3 months of screening
   • NYHA class 3 or 4 congestive heart failure
   • clinically significant ventricular arrhythmia
   • Mobitz II/Second degree/or 3rd degree heart block without a pacemaker in place; uncontrolled HTN (systolic >180mmHg or diastolic >105mmHg at screening
4. Previous exposure to a second-generation anti-androgen i.e enzalutamide or apalutamide
5. Received investigational agent within 2 weeks of screening
6. Therapy with antineoplastic systemic chemotherapy or biological therapy within 2 weeks of screening
7. Radiation therapy within 2 weeks of screening
8. History of a prior malignancy (excluding an adequately treated basal or squamous cell skin cancer, superficial bladder cancer, or a cancer in situ) within 5 years prior to study enrollment
9. History of gastrointestinal disorders (medical disorders or extensive surgery) that may interfere with the absorption of the study agent
10. Known or suspected brain metastasis or active leptomeningeal disease
11. History of seizure at any time in the past. Also, history of loss of consciousness or transient ischemic attack within 12 months of Day 1 visit
12. Have any condition that, in the opinion of the investigator, would compromise the well-being of the subject or the study or prevent the subject from meeting or performing study requirements

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Square Wave Testosterone Therapy + SOC; All patients will receive transdermal testosterone. All patients will also receive standard of care enzalutamide. Patients will alternate between the two therapies.	Drug: Transdermal Testosterone; Patients will be prescribed 2 packets of testosterone gel 1% containing 50mg per packet to apply transdermally daily.; Drug: Standard of Care, Enzalutamide; Patients will take four 40mg capsules of enzalutamide for a total daily dose of 160mg.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility of the Administration of Transdermal Testosterone Alternating with Enzalutamide	This study will be considered feasible if at least 50% of patients approached for participation enroll and if at least 50% of patients that initiate therapy do not withdraw consent for participation.	Study start date to study end date, up to 12 months, or until patient death

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety of the Administration of Transdermal Testosterone Alternating with Enzalutamide	Safety will be assessed based on the Common Terminology Criteria of Adverse Events (CTCAE) v5.0 criteria, in which rates of Grade 1-5 AE will be assessed, with a prticular attention to grade 3-5 events	Study start date to study end date, up to 12 months, or until patient death
Prostate Specific Antigen (PSA) Response Rate	PSA response rates as measured by serum PSA at designated study visits. Response will be defined as a decline in the serum PSA of 50% from baseline value at start of study.	Study start date to study end date, up to 12 months, or until patient death
Time to Radiographic Progression	Time to radiographic progression as measured by Response Evaluation Criteria in Solid Tumors (RECIST).	Study start date to study end date, up to 12 months, or until patient death
Time to Radiographic Progression	Time to radiographic progression as measured by Prostate Cancer Clinical Trials Working Group 3 (PCWG3) imaging criteria.	Study start date to study end date, up to 12 months, or until patient death
Time to PSA Progression	This will be defined by the PCWG3.	Study start date to study end date, every four weeks, up to 12 months, or until patient death
Maximum Decrease in PSA	PSA will be assessed at baseline and every four weeks. Maximum decrease assessed through these measurements.	Study start date to study end date, up to 12 months, or until patient death
Physical Function Change	Assessed through handgrip exercises.	Study start date to study end date, up to 12 months, or until patient death
Physical Function Change	Assessed through chair rise exercises.	Study start date to study end date, up to 12 months, or until patient death
Patient Activation	Assessed using the Self-Efficacy for Physical Activity Scale (SEPA), which uses a 5 point Likert scale.	Study start date to study end date, up to 12 months, or until patient death
Reported Fatigue	Measured by the Functional Assessment of Cancer Therapy-Fatigue (FACT-Fatigue 13).	Study start date to study end date, up to 12 months, or until patient death
Patient Mood and Depression Evaluation	Measured through the Center for Epidemiologic Studies-Depression Scale (CES-D), which uses a point system based on responses ranging from "not at all" to "all the time."	Study start date to study end date, up to 12 months, or until patient death
Bone Health	Standard bone densometry assessment will be used to calculate T and Z score to determine normal, osteopenic, or osteoporotic bone mineral density.	Study start date to study end date, up to 12 months, or until patient death
Body Composition	Measured by a DXA scanner. Free fat mass and lean body mass will be assessed to determine sarcopenic obesity.	Study start date to study end date, up to 12 months, or until patient death
Quality of Life Assessment	Measured by the Functional Assessment of Cancer Therapy-Prostate (FACT-P).	Study start date to study end date, up to 12 months, or until patient death
Change in Hormones	Change in testosterone, estrogen, and sex hormone binding globulin.	Study start date to study end date, up to 12 months, or until patient death
Self-Reported Physical Function	Measured by the PROMIS-PA.	Study start date to study end date, up to 12 months, or until patient death
Energy Expenditure	Measured by hood assessment.	Study start date to study end date, up to 12 months, or until patient death
Change in Max Repetition	Measured by subject's maximal leg press over time in the energy-balance laboratory.	Study start date to study end date, up to 12 months, or until patient death
Change in Spontaneous Physical Activity and Sedentary Time	Measured through accelerometry. Patients will wear an accelerometer for one week at initiation and again one month later.	Study start date to study end date, up to 12 months, or until patient death
PSA Response in this Cohort of Patients vs Historical Cohorts	Assessed through IM testosterone historical data.	Study start date to study end date, up to 12 months, or until patient death

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Collaborators: Cancer League of Colorado
• Investigators: Principal Investigator: Laura Graham, MD, University of Colorado, Denver

Study record dates

Study Major Dates

• Study Start (Actual): January 18, 2019
• Primary Completion (Actual): August 14, 2024
• Study Completion (Actual): September 30, 2025

Study Registration Dates

• First Submitted: November 6, 2018
• First Submitted That Met QC Criteria: November 6, 2018
• First Posted (Actual): November 8, 2018

Study Record Updates

• Last Update Posted (Estimated): November 6, 2025
• Last Update Submitted That Met QC Criteria: November 4, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: Androgen Deprivation Therapy; Feasibility Study; Square Wave Testosterone Therapy; Transdermal Testosterone
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Prostatic Diseases; Male Urogenital Diseases; Prostatic Neoplasms; Health Services Administration; Health Care Quality, Access, and Evaluation; Quality of Health Care; Quality Indicators, Health Care; Standard of Care; enzalutamide
• Other Study ID Numbers: 18-0821.cc

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The deidentified participant data will be shared after any study publication (between 6 and 36 months post publication). Study protocol also available.
• IPD Sharing Time Frame: Between 6 and 36 months post publication
• IPD Sharing Access Criteria: Sound proposal with IRB approval. Analyses can be be in keeping with the submitted protocol. This will be reviewed internally for use.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes