Phase II Trial of Enzalutamide for Castrate-resistant Prostate Cancer (CRPC) With Correlative Assessment of Androgen Receptor (AR) Signaling and Whole-exome and Transcriptome Sequencing
Overview
- Phase
- Phase 2
- Intervention
- Enzalutamide
- Conditions
- Metastatic Castration-resistant Prostate Cancer
- Sponsor
- Dana-Farber Cancer Institute
- Enrollment
- 67
- Locations
- 5
- Primary Endpoint
- Number of Patients With Gene Alterations
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief Summary
This research study is evaluating a drug called enzalutamide in metastatic castration resistant prostate cancer. Enzalutamide is already FDA approved for metastatic castration resistant prostate cancer after treatment with chemotherapy.
The purpose of this study is to analyze features of tumor specimens sampled prior to therapy and at disease progression to determine why patients respond or stop responding to treatment with Enzalutamide.
Prior chemotherapy is not a requirement of this trial.
Detailed Description
After the screening procedures confirm that the patient is able to participate in the study, * The patient will have the first of two required prostate biopsies prior to starting study treatment. * The patient will be given a prescription for study drug and a study drug-dosing diary for each treatment cycle. Each treatment cycle lasts 28 days (4 weeks), during which time the patient will be taking the study drug once daily. The diary will also include special instructions for taking the study drug. The study drug (enzalutamide) should be taken orally (by mouth) at home. On Day 1 of each cycle (+/- 4 days), the following procedures will be performed in clinic: * A medical history. * A Physical examination * Performance status * Blood tests (2-3 tablespoons). * The patient will be asked about medications they are currently taking, including over-the counter medications, herbal remedies, vitamins, and supplements. * The patient will be asked about any disease-related symptoms they are experiencing. * The patient will receive a new supply and the medication diary will be reviewed. Every 12 weeks (+/-1 week) the following procedures will be performed in clinic: * Blood tests. A small sample of the patient's blood (about 1-2 tablespoons) will be collected. This blood will be collected for specialized laboratory tests. * A (CT) scan of the patient's chest and a CT or MRI scan of abdomen, and pelvis and a bone scan will be performed every 12 weeks (+/- 1 week) while the patient is on active treatment. If your baseline CT of the patient's chest does not show disease, the investigator may not asked for this to be repeated. End of Study Visit in clinic: * A medical history. * A physical examination * Performance status * Blood tests (2-3 tablespoons) * The patient will be asked about any disease-related symptoms If the patient completed at least 4 cycles of enzalutamide, the patient will undergo a second of two required biopsies.
Investigators
Mary-Ellen Taplin, MD
Principal Investigator
Dana-Farber Cancer Institute
Eligibility Criteria
Inclusion Criteria
- •Participants must meet the following criteria on screening examination to be eligible to participate in the study:
- •Be a male ≥ 18 years of age.
- •Participants must have histologically or cytologically confirmed adenocarcinoma of the prostate without ≥50% neuroendocrine differentiation or small cell histology.
- •Participants must have progressive disease as defined by either:
- •Castrate resistant disease as defined by PCWG. Participants must have a rise in PSA on two successive determinations at least one week apart and PSA levels ≥ 2 ng/ml (only the screening PSA needs to be ≥ 2 ng/ml) and testosterone levels \< 50 ng/dL, OR
- •Soft tissue progression defined by RECIST 1.1, OR
- •Bone disease progression defined by PCWG2 with two or more new lesions on bone scan.
- •CRPC with metastatic disease with at least one site of metastatic disease must be amenable to needle biopsy. Soft tissue biopsy sites include: lymph node or visceral metastases. Bone sites include lumbar vertebrae, pelvic bones and long bones. Excluded sites are thoracic, cervical vertebrae, skull and rib lesions. Biopsy site will be selected with guidance of interventional radiologist determining best site to optimize balance of obtaining useful tissue for analysis and minimizing risk.
- •Participants without orchiectomy must be maintained on LHRH agonist/antagonist therapy.
- •Participants may have had any number of previous hormonal therapies (antiandrogens, steroids, estrogens, finasteride, dutasteride, ketoconazole, abiraterone) provided these were discontinued ≥ 4 weeks before enrollment.
Exclusion Criteria
- •Participants who exhibit any of the following conditions at screening will not be eligible for admission into the study.
- •Uncontrolled illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements within 6 months of enrollment.
- •Clinically significant heart disease as evidenced by:
- •Myocardial infarction within 6 months of enrollment.
- •Uncontrolled angina within 6 months of enrollment.
- •Congestive heart failure NYHA Class III or IV, or a history of congestive heart failure NYHA Class III or IV in the past, unless a screening ECHO or MUGA within 3 months results in a left ventricular ejection fraction ≥ 45%.
- •Clinically significant ventricular arrhythmias.
- •History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place.
- •Bradycardia as indicated by a heart rate \< 50 beats per minute at screening visit.
- •Hypotension as indicated by SBP ≤ 85 on 2 consecutive measurements.
Arms & Interventions
Enzalutamide
Administration: 160 mg orally once daily with a 28-day cycle. Treatment will be continued until evidence of symptomatic or radiographic progression or the participant is taken off the study for another reason. Dosing: 160 mg orally taken once daily as four 40 mg capsules.
Intervention: Enzalutamide
Outcomes
Primary Outcomes
Number of Patients With Gene Alterations
Time Frame: Tumor biopsies were performed at pre-study and progression. Progression occurred up to 41 months after initiation of enzalutamide.
Serial biopsies was performed at pre-study and progression to analyze mechanisms of resistance to enzalutamide, such as alterations in AR (mutations, amplifications), tumor suppression genes, DNA repair genes, and SPOP. Whole exome sequencing was performed on tumor tissue biopsies.
Secondary Outcomes
- Changes in Serum Androgen Concentrations Between Baseline and Subsequent Assessment Visits(Not collected.)
- Number of Participants With a PSA Response(PSA was measured at pre-treatment, each C1D1 (1 cycle=28 days), end of treatment, and follow-up visits (every 6 months). PSA were measured up to 52 months.)
- Toxicity Measurements(Toxicity was reported at pre-study, every cycle, and end of treatment visit. Patients reported toxicities up to 39 months.)
- Number of Participants With PSA Response Stratified by Gene Alterations in Serial Tumor Biopsies(Tumor biopsies will be performed at pre-treatment and end of treatment visit. Treatment cycle is 28 days. PSA was collected up to 52 months.)
- Subsequent Lines of Therapy(Subsequent treatments were followed up to 31 months after discontinuation of study drug.)
- Response of Measurable Disease at Baseline(Imaging was performed at pre-study and every 12 weeks on treatment. Treatment cycles is 28 days. Patients were assessed up to 41 months.)
- Duration of Response of Measurable Disease(Imaging was performed at pre-study and every 12 weeks on treatment. Treatment cycles is 28 days. Patients were assessed up to 41 months.)
- Duration of PSA Response(PSA was measured at pre-treatment, each C1D1 (1 cycle=28 days), end of treatment, and follow-up visits (every 6 months). PSA were measured up to 52 months.)