Terminated due to insufficient funding

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).

Inclusion Criteria:

• Signed informed consent form (ICF) providing agreement to adhere to the dosing schedule, report for all trial visits and authorization, use and release of health and research trial information

• Histologically or cytologically confirmed carcinoma of the prostate (excluding neuroendocrine differentiation or squamous cell histology)

• Ongoing gonadal androgen deprivation therapy with gonadotropin-releasing hormone (GnRH) analogues, antagonists or orchiectomy; patients who have not had an orchiectomy must be maintained on effective GnRH analogue/antagonist therapy

• Castration resistant prostate cancer as defined by serum testosterone < 50 ng/ml and at least one of the following:

  • PSA level of at least 2 ng/ml that has risen on at least 2 successive occasions at least 1 week apart
  • Evaluable disease progression by modified RECIST 1.1
  • Progression of metastatic bone disease on bone scan with > 2 new lesions

• Prior therapy with abiraterone, enzalutamide and/or docetaxel; if a patient has not received docetaxel or cabazitaxel chemotherapy, the patient must be informed of this treatment choice as an alternative; if the patient has received docetaxel or cabazitaxel chemotherapy or refuses one of both of these therapies, this rationale must be documented and the patient is then eligible; patient must be offered and made aware of all Food and Drug Administration (FDA)-approved treatment options; patients with bone only disease may not have received radium-223

• The presence of metastatic disease amenable to computed tomography (CT) or ultrasound guided biopsy; this may include thoracolumbar vertebral bodies, pelvis, femur or humerus or soft tissue or nodal metastasis amenable to biopsy (excluding lung or pleural lesions)

• Agree to participate in biopsy of metastatic lesion during the study at day 21

• Eastern Cooperative Oncology Group (ECOG) performance status of =< 1

• Life expectancy >= 12 weeks

• No prior malignancy is allowed except:

  • Adequately treated basal cell or squamous cell skin cancer or
  • In situ carcinoma of any site or
  • Other adequately treated malignancy for which the patient is currently disease free for at least one year

• Patients with any prior chemotherapy regimens are eligible

• Patients with disease only in the bone may not have received Xofigo/radium 223 to avoid ongoing DNA damage in bone marrow

• Patients who are or are not receiving bisphosphonates or denosumab are eligible; bisphosphonates or denosumab should not be initiated after registration and during active treatment

• Absolute neutrophil count >= 1.5 x 10^9 cells/L (within 14 days prior to registration)

• Hemoglobin (Hgb) >= 9.0 g/dL (within 14 days prior to registration)

• Platelets >= 100,000 x 10^9/L (within 14 days prior to registration)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 1.5 x upper limit of normal (ULN) (within 14 days prior to registration)

• Total bilirubin =< 1.5 x ULN (within 14 days prior to registration)

• Serum creatinine < 1.5 X institutional ULN mg/dL OR estimated glomerular filtration rate (eGFR) >= 50 mL/min (within 14 days prior to registration)

Exclusion Criteria:

• Patients currently receiving active therapy for other neoplastic disorders
• Patients with histologic evidence of small cell carcinoma of the prostate will not be eligible
• Patients with disease only in the bone previously treated with radium-223 will not be eligible
• Known parenchymal brain metastasis
• Active or symptomatic viral hepatitis or chronic liver disease
• Estimated creatinine clearance less than 50 ml/minute
• Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) class II-IV heart disease
• Atrial fibrillation, or other cardiac arrhythmia requiring medical therapy
• Administration of an investigational therapeutic within 30 days of cycle 1, day -2
• Patients with dementia/psychiatric illness/social situations that would limit compliance with study requirements or would prohibit the understanding and/or giving of informed consent
• Patients with medical conditions, which, in the opinion of the investigators, would jeopardize either the patient or the integrity of the data obtained will not be eligible
• Any condition which, in the opinion of the investigator, would preclude participation in this trial
• Patients on anticoagulation therapy which cannot be held for metastatic biopsies