This phase II trial studies how well giving testosterone at levels higher than normally found in the body (supraphysiological) works to enhance chemotherapy treatment, and Lutetium 177Lu-prostate specific-membrane antigen (PSMA)-617 (LuPSMA) in patients with prostate cancer that has progressed despite being previously treated with androgen therapies and has spread from where it first started (prostate) to other places in the body (metastatic castration-resistant prostate cancer). In patients that have developed progressive cancer in spite of standard hormonal treatment, administering supraphysiological testosterone may result in regression of tumors by causing deoxyribonucleic acid (DNA) damage in tumor cells that have adapted to low testosterone conditions. Carboplatin is in a class of medications known as platinum-containing compounds. Carboplatin works by killing, stopping or slowing the growth of tumor cells. Etoposide is in a class of medications known as podophyllotoxin derivatives. It blocks a certain enzyme needed for cell division and DNA repair and may kill tumor cells. Radioactive drugs, such as LuPSMA, may carry radiation directly to tumor cells and not harm normal cells. Giving supraphysiological levels of testosterone and carboplatin or etoposide or LuPSMA together may be an effective treatment for metastatic castration-resistant prostate cancer.
OUTLINE: Patients are assigned based on personal preference to 1 of 3 cohorts. COHORT I: Patients are then assigned to 1 of 3 sub-cohorts within cohort I. COHORT Ia: Patients continue to receive ADT and receive testosterone cypionate intramuscularly (IM) on day 1 of cycle 1. Patients then receive testosterone cypionate IM and carboplatin intravenously (IV) on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. COHORT Ib: Patients continue to receive ADT and receive carboplatin IV on day 1 of cycle 1. Patients then receive testosterone cypionate IM and carboplatin IV on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. COHORT Ic: Patients continue to receive ADT and receive testosterone cypionate IM and carboplatin IV on day 1 of cycle 1. Patients then receive testosterone cypionate IM and carboplatin IV on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. COHORT II: Patients are then assigned to 1 of 3 sub-cohorts within cohort II. COHORT IIa: Patients continue to receive ADT and receive testosterone cypionate IM on day 1 of cycle 1. Patients then receive testosterone cypionate IM on day 1 and etoposide orally (PO) once daily (QD) on days 1-14 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. COHORT IIb: Patients continue to receive ADT and receive etoposide PO QD on days 1-14 of cycle 1. Patients then receive testosterone cypionate IM on day 1 and etoposide PO QD on days 1-14 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. COHORT IIc: Patients continue to receive ADT and receive testosterone cypionate IM on day 1 and etoposide PO QD on days 1-14 of cycle 1. Patients then receive testosterone cypionate IM on day 1 and etoposide PO QD on days 1-14 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. COHORT III: Patients are assigned to 1 of 3 sub-cohorts within cohort III. COHORT IIIa: Patients continue to receive ADT and receive testosterone cypionate intramuscularly (IM) on day 1 of cycles 1-6. Patients receive LuPSMA IV on day 1 of cycles 2-6. Cycles repeat every 6 weeks for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive testosterone cypionate intramuscularly (IM) on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo 68Ga-PSMA positron emission tomography (PET) at screening and single photon emission computed tomography (SPECT)/CT throughout the study. COHORT IIIb: Patients continue to receive ADT and LuPSMA IV on day 1 of cycles 1-6. Patients also receive receive testosterone cypionate IM on day 1 of cycles 2-6 . Cycles repeat every 6 weeks for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients receive testosterone cypionate IM on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo 68Ga-PSMA PET at screening and single SPECT/CT throughout the study. COHORT IIIc: Patients continue to receive ADT and receive testosterone cypionate IM on day 1 and LuPSMA IV on day 1 of cycles 1-6. Cycles repeat every 6 weeks for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive testosterone cypionate IM on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo 68Ga-PSMA PET at screening and single SPECT/CT throughout the study. All patients undergo a biopsy on study and blood sample collection on study, and bone scans, dual x-ray absorptiometry (DEXA) and computed tomography (CT) scans throughout the trial. Patients may also undergo an optional second biopsy at the end of study treatment. After completion of study treatment, patients are followed up at 30 days, and then every 6 months for 2 years.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
69
Undergo a biopsy
Undergo blood sample collection
Undergo bone scan
Given IV
Undergo CT
Given PO
Ancillary studies
Ancillary studies
Given IM
Given LuPSMA IV
Undergo DEXA
Given gallium 68Ga-PSMA-617
Undergo 68Ga-PSMA PET
Undergo SPECT/CT
Fred Hutch/University of Washington Cancer Consortium
Seattle, Washington, United States
RECRUITINGGreater than or equal to 50% decline in prostate-specific antigen from baseline (PSA50) response rate
Will assess \>= 50% decline in PSA following treatment with combination bipolar androgen therapy (BAT) and genotoxic chemotherapy (at least 12 weeks of total therapy). Will be calculated as the percentage with 95% confidence interval (CI) of the total number of subjects that achieved a PSA50 response.
Time frame: From baseline up to 3 years
Radiographic response
Will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Best radiographic response for each patient will be presented in a waterfall plot.
Time frame: Up to 3 years
Radiographic progression-free survival (PFS)
Will be assessed using RECIST 1.1 and Prostate Cancer Working Group 3 (PCWG3) criteria. Will be presented with Kaplan-Meier curves, and the median survival with 95% CI will be calculated. Rates will be reported as percentages with 95% CI.
Time frame: The start of treatment until disease progression (per modified RECIST criteria or PCWG3 criteria for bone lesions), clinical progression (as determined by the treating physician), or death, whichever occurs first, assessed up to 3 years
PSA PFS
Will be assessed using PCWG3 criteria. Will be presented with Kaplan-Meier curves, and the median survival with 95% CI will be calculated. Rates will be reported as percentages with 95% CI. Best on study PSA for each patient will be presented in a waterfall plot.
Time frame: Time from the start of treatment until PSA progression (as defined by PCWG3 criteria), assessed up to 3 years
Overall survival
Will be presented with Kaplan-Meier curves, and the median survival with 95% CI will be calculated. Rates will be reported as percentages with 95% CI.
Time frame: The start of treatment until death from any cause, assessed up to 3 years
Patient-reported outcome measure (PROMS) questionnaires
Will be assessed by average change in quality of life (QOL) scores (total and for each domain) for each survey will be calculated at each timepoint. A paired t-test will used to assess for statistically significant changes in QOL from baseline to subsequent timepoints, and linear mixed effects models will be used to evaluate trends over all timepoints.
Time frame: Up to 3 years
Incidence of adverse events
Will be assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Time frame: Up to 30 days after completion of study treatment
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