Cabazitaxel With or Without Carboplatin in Treating Patients With Previously Treated Metastatic Castration-Resistant Prostate Cancer

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dosage (MTD) of cabazitaxel-carboplatin in the phase I
portion of the study.

II. To evaluate progression free survival achieved with cabazitaxel-carboplatin versus
cabazitaxel alone in men with metastatic castration resistant prostate cancer (mCRPC) in the
phase II portion of the study.

SECONDARY OBJECTIVES:

I. To assess prostate-specific antigen (PSA) response rate (percentage of patients with > 50
% decline).

II. To correlate changes in bone specific alkaline phosphatase and urine n-telopeptides with
response.

III. To evaluate overall survival. IV. To evaluate safety and toxicity. V. To evaluate
influence of the anaplastic phenotype on response to therapy. VI. To collect and archive
serum, plasma, and urine samples in study patients for later hypothesis generating
associations.

OUTLINE: This is a phase I, dose-escalation study followed by a randomized phase II study.

PHASE I: Patients receive cabazitaxel intravenously (IV) over 60-90 minutes and carboplatin
IV over 60-90 minutes on day 1. Treatment repeats every 21 days for up to 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 cabazitaxel IV over 60-90 minutes on day 1. Treatment repeats every
21 days for up to 10 courses in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive cabazitaxel IV over 60-90 minutes and carboplatin IV over 60-90
minutes on day 1. Treatment repeats every 21 days for up to 10 courses in the absence of
disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months.

Inclusion Criteria:

- Histologic evidence of prostate adenocarcinoma

- In addition to patients with adenocarcinoma, patients with "anaplastic" features are
also eligible as defined by at least one of the following: a) histologic evidence of
small cell prostate cancer (patients with small cell carcinoma on histology are not
required to demonstrate castration-resistant progression); b) any of the following
metastatic presentations: (i) exclusive visceral metastases; (ii) radiographically
predominant lytic bone metastases identified by plain X-ray or computed tomography
(CT) scan; (iii) bulky (>= 5 cm in longest dimension) lymphadenopathy (iv) bulky (>= 5
cm) tumor mass in the prostate/pelvis (v) low PSA (=< 10 ng/ml) at initial
presentation (prior to androgen ablation or at symptomatic progression in the
castrate-setting) plus high volume (>= 20) bone metastases; (vi) elevated serum
lactate dehydrogenase (LDH) (>= 2 x ULN) or elevated serum carcinoembryonic antigen
(CEA) (>= 2 x upper limit of normal [ULN]) in the absence of other etiologies; (vii)
short interval (=< 180 days) to castrate-resistant progression following initiation of
hormonal therapy

- Castration-resistant prostate cancer; patients must have surgical or ongoing chemical
castration (with luteinizing-hormone-releasing hormone [LHRH] agonists or LHRH
antagonists), with a baseline testosterone level < 50 ng/dL

- Metastatic disease; patients must have evidence for metastatic prostate cancer by bone
scan and/or CT/magnetic resonance imaging (MRI) (i.e., soft tissue, visceral, lymph
node); if lymph node, visceral and/or soft-tissue metastases are the only evidence of
metastasis, at least one lesion must be >= 1.5 cm in diameter

- Patients may have received prior treatment with androgen ablative therapies (such as
bicalutamide, ketoconazole, diethylstilbestrol [DES], abiraterone, Xtandi, ARN-509)
and/or "targeted" therapies (such as tyrosine kinase inhibitors); androgen ablative
therapies must be discontinued >= 3 days prior to initiation of study treatment with
the exception of abiraterone and/or enzalutamide, which may be continued during study
treatment per the practice preference of the treating physician; patients who are
predicted to benefit from an antiandrogen withdrawal response should be tested for
this possibility before being considered for eligibility to this study; targeted
therapies must be discontinued >= 2 weeks before initiation of study treatment

- Both chemotherapy-naive and patients previously treated with chemotherapy are
eligible; chemotherapy pretreated patients may have received a maximum of two prior
systemic cytotoxic chemotherapies completed at least 3 weeks prior to initiation of
study treatment

- Patients must have documented evidence of progressive disease as defined by any of the
following: a) PSA progression: minimum of 2 rising values (3 measurements) obtained a
minimum of 7 days apart with the last result being at least >= 2.0 ng/mL; b) new or
increasing non-bone disease (by Response Evaluation Criteria In Solid Tumors
[RECIST]); c) positive bone scan with 2 or more new lesions (Prostate Cancer Working
Group [PCWG2])

- For purposes of stratification, patients will be categorized as "responders" or
"non-responders" based on their response to prior docetaxel-based therapy; a)
responders will have demonstrated objective responses to first-line docetaxel as
determined by any of the following: 1. decrease in PSA level >= 50% from baseline,
maintained for >= 6 weeks; 2. partial or complete response in lymph nodes and soft
tissue metastases by RECIST; responders must have received >= 225 mg/m^2 (~ 3 cycles)
of docetaxel; b) patients not meeting response criteria above will be considered as
non-responders; we anticipate 2 general categories of non-responders based on the
following disease phenotypes: 1. progressive disease on therapy without any objective
evidence of response ("primary-resistant disease"); progressive disease on therapy
with prior objective evidence of response, but response duration is =< 6 weeks
("docetaxel refractory disease"); non-responders are eligible even if they have
received < 225 mg/m^2 of docetaxel

- If present, peripheral neuropathy must be =< grade 2

- Absolute neutrophil count (ANC) >= 1,500/ml (unless due to bone marrow infiltration by
tumor in which case ANC >= 500/ml are allowed) (within 14 days before registration)

- Platelets >= 100,000/ml (unless due to bone marrow infiltration by tumor in which case
>= 50,000/ml are allowed) (within 14 days before registration)

- Total bilirubin =< upper limit of normal with the exception of isolated
hyperbilirubinemia due to Gilbert's syndrome or if the patient has liver metastases
and/or acute tumor-associated illness =< 4 x ULN (within 14 days before registration)

- Serum glutamic-pyruvic transaminase (SGPT), (alanine aminotransferase [ALT]) AND/OR
serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =<
1.5 x the ULN or if patient has liver metastases and/or acute tumor-associated
illness, =< 4 x ULN (within 14 days before registration)

- Patient has creatinine clearance >= 30 ml/min using the Cockcroft-Gault equation
(within 14 days before registration)

- Men whose partner is a woman of childbearing potential must be willing to consent to
using effective contraception while on treatment and for at least 3 months thereafter

- Patient or his legally authorized representative must provide written informed consent

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2

Exclusion Criteria:

- Radiation therapy (including palliative radiotherapy to a metastatic lesion) within 14
days or major surgery (e.g., open abdominal, pelvic, thoracic, orthopedic or
neurosurgery) within 28 days of the date of the first dose

- Samarium-153 within 28 days of registration, or strontium-89 within 12 weeks (84 days)
of registration; patients who have received 2 or more doses of bone-seeking
radioisotopes are not eligible

- Current treatment on another therapeutic clinical trial

- Prior treatment with cabazitaxel and/or carboplatin

- Impending complication from bone metastases (fracture and/or cord compression);
properly treated or stabilized fractures and/or cord compression is allowed

- Presence of ongoing urinary obstruction (e.g., urinary retention, hydronephrosis)
requiring medical intervention; properly treated urinary obstruction is allowed

- Patient has an uncontrolled intercurrent illness (e.g., uncontrolled diabetes,
uncontrolled hypertension)

- Patient has another serious medical or psychiatric illness that could, in the
investigator's opinion, potentially interfere with the patient's ability to provide
informed consent or with the completion of treatment according to this protocol

- Patients with a history of severe hypersensitivity reaction to JEVTANA® (cabazitaxel)
or other drugs formulated with polysorbate 80

- Patients with an active second malignancy that could, in the investigator's opinion,
potentially interfere with the patient's ability to participate and/or complete this
trial