Phase I Cabazitaxel, Mitoxantrone, and Prednisone Metastatic Castration-Resistant Prostate Cancer

This is a Phase I, open label, dose-finding, multicenter clinical trial to establish the
maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of cabazitaxel (25 mg/m2 IV
q21 days) in combination with mitoxantrone (4-12 mg/m2 IV q21 days) and prednisone (5mg
orally BID) in patients with metastatic CRPC who have not undergone prior chemotherapy for
metastatic disease.

Up to five cohorts will be enrolled to determine the MTD and DLT profile of this combination.
An accelerated titration design method is being used in order to minimize the number of
patients exposed to subtherapeutic doses of mitoxantrone.

Inclusion Criteria:

1. Histologically confirmed adenocarcinoma of the prostate.

2. Progressive metastatic prostate cancer (positive bone scan or measurable disease)
despite castrate levels of testosterone (either from orchiectomy or LHRH agonist therapy).

3. Patients may have either non-measurable disease OR measurable disease

4. All patients must have a PSA ≥ 2 ng/mL.

5. Progressive disease based on any one of the following:

1. transaxial imaging

2. a rise in PSA

3. radionuclide bone scan

Patients whose sole manifestation of progression is an increase in disease-related
symptoms are not eligible.

1. For patients with measurable disease, progression will be defined by the RECIST
criteria.

2. For patients with non-measurable disease, a positive bone scan and elevated PSA
will be required. PSA evidence for progressive prostate cancer during or after
first-line chemotherapy consists of a PSA level of at least 2 ng/ml which has
risen on at least 2 successive occasions, at least one week apart. If the
confirmatory PSA (#3) value is less (i.e., #3b) than the screening PSA (#2)
value, then an additional test for rising PSA (#4) will be required to document
progression for the purposes of eligibility.

3. Radionuclide bone scan: new metastatic lesions

6. Testosterone < 50 ng/dL. Patients must continue primary androgen deprivation
with an LHRH analogue if they have not undergone orchiectomy.

7. ECOG Performance Status 0 -2.

8. Required Laboratory values:

1. Creatinine < 1.5 x upper limits of normal (ULN). If Cr. > 1.5 x ULN, then
calculated creatinine clearance > 40cc/min.

2. ALT and AST within normal limits

3. Absolute neutrophil count > 2,000/mm3

4. Platelets > 100,000/ mm3

5. Hemoglobin > 8.0 gm/dL

6. Total bilirubin within normal limits

9. Ejection fraction by MUGA scan or echocardiogram ≥ lower limit of
institutional normal.

10. Patients receiving hormonal therapy (i.e. any dose of megestrol acetate
(Megace), Proscar (finasteride), any herbal product known to decrease PSA levels
(e.g., Saw Palmetto and PC-SPES) other than LHRH agonist/antagonist or a stable
dose of corticosteroid from a prior chemotherapy regimen must discontinue the
agent for at least 4 weeks prior to enrollment. Progressive disease must be
documented after discontinuation of the hormonal therapy.

11. No other systemic therapies for prostate cancer within 28 days prior to
initiation of this protocol.

12. Prior radiation therapy completed ≥ 4 weeks prior to enrollment.

13. No history of radiopharmaceuticals (strontium, samarium) for prostate cancer
treatment.

14. Patients must agree to use adequate contraception (hormonal or barrier method
of birth control) prior to study entry, for the duration of study participation
and for 3 months after discontinuing therapy. Should a patient's sexual partner
become pregnant or suspect she is pregnant while the patient is participating in
this study, he should inform the treating physician immediately.

15. Life expectancy > 12 weeks.

16. Age ≥ 18 years

17. Inclusion of Minorities: Men and members of all ethnic groups are eligible
for this trial.

Exclusion Criteria:

1. Patients with significant cardiovascular disease including congestive heart
failure (NYHA class III or IV), active angina pectoris or myocardial
infarction within 6 months.

2. Patients with serious intercurrent infections, or nonmalignant medical
illnesses that are uncontrolled or whose control may be jeopardized by the
complications of this therapy.

3. Patients with psychiatric illness/social situations that would limit
compliance with study requirements.

4. Patients with pre-existing neuropathy greater than CTCAE Grade 1 (motor or
sensory).

5. Patients with known prior severe hypersensitivity reactions to cabazitaxel
or other agents containing polysorbate 80.

6. Patients with known active brain metastases are excluded because of their
poor prognosis. Head CT is NOT routinely required prior to enrollment.
Patients with treated, asymptomatic brain metastasis will be eligible for
enrollment.

7. Patients with a "currently active" second malignancy other than non-melanoma
skin cancer are excluded. [Patients are not considered to have a "currently
active" malignancy if they have completed therapy and are considered by
their physician to be at less than 30% risk of relapse.]

8. Concurrent use of moderate to strong CYP3A4 inhibitors is not allowed.