This partially randomized phase I/II trial studies the side effects and how well sirolimus works when given together with docetaxel and carboplatin in treating patients with castration-resistant prostate cancer that has spread to other places in the body (metastatic). Biological therapies, such as sirolimus, use substances made from living organisms that may stimulate or suppress the immune system in different ways and stop tumor cells from growing. Drugs used in chemotherapy, such as docetaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving sirolimus together with docetaxel and carboplatin may kill more tumor cells.
PRIMARY OBJECTIVES: I. To define the recommended phase 2 dose (RP2D) of sirolimus combined with docetaxel and carboplatin in the treatment of metastatic castration resistant prostate cancer (CRPC). (Phase I) II. To assess the effectiveness of sirolimus in suppressing the induction of the deoxyribonucleic acid (DNA) damage secretory component WNT16B in tumor stroma following docetaxel and carboplatin. (Phase II) EXPLORATORY OBJECTIVES: I. To assess maximal prostate-specific antigen (PSA) response to sirolimus combined with docetaxel and carboplatin. (Phase I) II. To assess PSA response duration to sirolimus combined with docetaxel and carboplatin. (Phase I) III. To assess response of measurable disease. (Phase I) IV. To assess time to progression of bone lesions or measurable disease (Response Evaluation Criteria in Solid Tumors \[RECIST\] 1.1). (Phase I) V. To assess effect of sirolimus with docetaxel and carboplatin on DNA damage surrogates in cancer associated stroma compared to untreated and docetaxel and carboplatin treated stroma. (Phase I) VI. To assess maximal PSA response to sirolimus combined with docetaxel and carboplatin. (Phase II) VII. To assess PSA response duration to sirolimus combined with docetaxel and carboplatin. (Phase II) VIII. To assess response of measurable disease (RECIST 1.1). (Phase II) IX. To assess time to progression of bone lesions or measurable disease (RECIST 1.1). (Phase II) X. To assess toxicity of the RP2D dose of sirolimus with docetaxel and carboplatin. (Phase II) XI. To determine the effect of docetaxel and carboplatin therapy on the DNA damage secretory program (DDSP) in serum. (Phase II) XII. To determine response to sirolimus, docetaxel and carboplatin in tumors with mutation of DNA repair pathway genes (breast cancer gene 2 \[BRCA2\], ataxia telangiectasia mutated \[ATM\] and other Fanconi anemia complementation groups \[FANC\] pathway members). (Phase II) XIII. To correlate the presence of DNA repair pathway mutations in circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) with tumor biopsy and correlate changes in CTC number and ctDNA mutation levels with clinical responses. (Phase II) OUTLINE: This is a phase I, dose de-escalation study of sirolimus followed by a phase II study. PHASE I: Patients receive sirolimus orally (PO) on day -2\*. Patients also receive docetaxel intravenously (IV) over 30-60 minutes and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days for 10 cycles in the absence of disease progression or unacceptable toxicity. PHASE II: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive docetaxel IV over 30-60 minutes and carboplatin IV over 30 minutes on day 1. Beginning in cycle 2 and continuing in subsequent cycles, patients also receive sirolimus PO on day -2. Treatment repeats every 21 days for 10 cycles in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive sirolimus PO on day -2. Patients also receive docetaxel IV over 30-60 minutes and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days for 10 cycles in the absence of disease progression or unacceptable toxicity. \* NOTE: Patients receive sirolimus 2 days prior to chemotherapy day 1 (there is no day 0).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
28
Fred Hutch/University of Washington Cancer Consortium
Seattle, Washington, United States
Percentage Change in Deoxyribonucleic Acid (DNA) Damage Secretory Program Induction (DDSP) (Phase II)
Will be determined by the level of genetic expression of WNT16, IL6, or SFRP2 in tissue after chemotherapy (carboplatin/docetaxel) compared to background/baseline measurement. The primary metric of DDSP induction will be quantitative reverse transcription-polymerase chain reaction, which is quantitative, but in the event of ribonucleic acid degradation in sample processing, the alternative measure will be immunohistochemistry (0-2 scale of expression).
Time frame: Baseline up to day 21 after starting treatment
Incidence of Adverse Events Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (Phases I and II)
Safety will be assessed through summaries of adverse events, vital signs, physical examinations, and clinical laboratory test data. Adverse events will then be quantified via CTCAE 4.0.
Time frame: Up to 3 years
Percentage of Patients With Reduction in Prostate Specific Antigen According to the Prostate Cancer Working Group 2 (PCWG2) Criteria (Phases I and II)
PSA decline from the level at registration will be quantified for each patient and proportion of patients with PSA decline divided by the total number of patients enrolled in study will be described.
Time frame: Baseline to up to 3 years
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