Sirolimus, Docetaxel, and Carboplatin in Treating Patients With Metastatic Castration-Resistant Prostate Cancer

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