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

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)

SECONDARY 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 courses 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 course 2 and continuing in subsequent courses, patients also receive
sirolimus PO on day -2. Treatment repeats every 21 days for 10 courses 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 courses 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

- Within 14 days prior to registration: 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

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