Testosterone Therapy in Castration Resistant Prostate Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Square Wave Testosterone Therapy in Castration Resistant Prostate Cancer

Conditions
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Prostate Cancer, Castration-Resistant Prostate Cancer

Intervention / Treatment
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* Drug: Transdermal Testosterone
* Drug: Standard of Care, Enzalutamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision to sign and date the consent form Male and age > or = 18 years old Stated willingness to comply with all study procedures and be available for the duration of the study Histologically or cytologically proven adenocarcinoma of the prostate Ongoing ADT for prostate cancer with a GnRH analogue/antagonist or bilateral orchiectomy for at least 6 months prior to day 1 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 Serum testosterone level <50ng/dL at the screening visit 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 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. 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 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 Must use a condom if having sex with a pregnant woman 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 Patients may have received any number of lines of therapy for castration resistant disease Exclusion Criteria: 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 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 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 Previous exposure to a second-generation anti-androgen i.e enzalutamide or apalutamide Received investigational agent within 2 weeks of screening Therapy with antineoplastic systemic chemotherapy or biological therapy within 2 weeks of screening Radiation therapy within 2 weeks of screening 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 History of gastrointestinal disorders (medical disorders or extensive surgery) that may interfere with the absorption of the study agent Known or suspected brain metastasis or active leptomeningeal disease 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 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: This is a longitudinal pilot, single arm, interventional study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Square Wave Testosterone Therapy + SOC<br>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<br>* Patients will be prescribed 2 packets of testosterone gel 1% containing 50mg per packet to apply transdermally daily.<br>Drug: Standard of Care, Enzalutamide<br>* Patients will take four 40mg capsules of enzalutamide for a total daily dose of 160mg.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Square Wave Testosterone Therapy, Androgen Deprivation Therapy, Transdermal Testosterone, Feasibility Study