Ph Ib/IIa Study of Cabazitaxel Plus Bavituximab in Castration-resistant Prostate Cancer

• Measurement of PSA response rate [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]
  To estimate the PSA response rate from cabazitaxel + bavituximab therapy in CRPC patients previously treated with docetaxel. PSA response rate will be assessed at multiple time points during the 24 wks of study treatment.
• Objective response rate by RECIST for patients with measurable disease [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]
  To estimate the objective response rate from cabazitaxel + bavituximab therapy in CRPC patients previously treated with docetaxel. Objective response rate will be assessed at day 85, 169
• Overall survival [ Time Frame: 24+ weeks ] [ Designated as safety issue: Yes ]
  To estimate the overall survival in subjects with CRPC (previously treated with docetaxel) following cabazitaxel + bavituximab therapy. Overall survival will be assessed continually during the duration of the study.
• Grade 3 or 4 Toxicity [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]
  To document the toxicity of cabazitaxel + bavituximab therapy in CRPC patients previously treated with docetaxel. Toxicity will be assessed continually during the 24 wks of study therapy.
• Progression-free survival (PFS) [ Time Frame: 24+ weeks ] [ Designated as safety issue: No ]
  Determination of progression-free survival in subjects treated with cabazitaxel + bavituximab for CRPC previously treated with docetaxel. PFS will be assessed continually during the entire study.

• Measurement of PSA response rate [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
  To estimate the PSA response rate from cabazitaxel + bavituximab therapy in CRPC patients previously treated with docetaxel.
• Objective response rate by RECIST for patients with measurable disease [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
  To estimate the objective response rate from cabazitaxel + bavituximab therapy in CRPC patients previously treated with docetaxel.
• Overall survival [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
  To estimate the overall survival in subjects with CRPC (previously treated with docetaxel) following cabazitaxel + bavituximab therapy.
• Grade 3 or 4 Toxicity [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
  To document the toxicity of cabazitaxel + bavituximab therapy in CRPC patients previously treated with docetaxel

This is a Phase Ib/IIa Study of Cabazitaxel plus Bavituximab in patients with castration-resistant prostate cancer (CRPC). The current study is designed to determine if the addition of bavituximab to cabazitaxel will improve progression free survival (PFS) or overall survival (OS). In addition, the Lead Researcher is requiring the collection of urine, and blood specimens for future research.

This study will enroll patients with CRPC, who have been previously treated with docetaxel or a docetaxel-containing regimen. Patients may be intolerant of, or resistant to, docetaxel, or may have been previously treated with the agent without definite disease progression during therapy.

Patients must meet the study eligibility criteria and must be competent to give informed consent.

Cabazitaxel will be administered IV on day 1 of each 21-day treatment cycle. Bavituximab (3 mg/kg) will be administered as an intravenous (IV) infusion on a weekly basis (Cycle 1 Day 2, all other cycles Day 1; day 8, day 15). Patients will receive cabazitaxel (day 1) plus bavituximab weekly of each 21-day cycle for up to 8 cycles.

Up to 31 patients will be enrolled to ensure 28 evaluable subjects. The accrual period is expected to be between 12 to 18 months (1-1.5 years).

Subjects will remain on the treatment phase of the study until any of the following events occur:

• Disease progression as evidenced by an increase in the prostate-specific antigen (PSA) level, worsening of pain, or disease progression by Response Evaluation Criteria in Solid Tumors (RECIST)
• Completion of 8 cycles of cabazitaxel-bavituximab therapy (day 169)
• Development of toxicity that, in the investigator's judgment, precludes further study participation
• Significant protocol violations or noncompliance on the part of the patient or investigator
• The investigator's judgment that discontinuation is in the patient's best interest
• Initiation of alternative antineoplastic treatments.
• Refusal of the patient to continue treatment or follow-up
• Loss to follow-up

After completion of the treatment phase, subjects will remain on the followup phase of the study until any of the following events occur:

• Refusal of the patient to continue treatment or follow-up
• Loss to follow-up
• Death
• The investigator's judgment that discontinuation is in the patient's best interest

• Prostate Cancer
• Prostatic Neoplasms

Inclusion Criteria:

• Written informed consent has been obtained.
• Adults 18 years of age or older with a life expectancy of at least 3 months.
• Histologically confirmed castration-resistant prostate cancer (CRPC). Patient must have demonstrated a rising PSA level above the androgen-deprivation therapy (ADT) nadir, on at least two determinations four weeks or more apart. ADT is defined as treatment with a Luteinizing-hormone-releasing hormone (LHRH) agonist or orchiectomy.
• Treatment with only one prior chemotherapy regimen, which must contain docetaxel as a single agent or in combination with other agents. Patients may be intolerant of, or resistant to, the cytotoxic drug combination.
• Patients on ADT must be willing to continue ADT for the duration of their participation in this protocol. ADT cannot be initiated, and ADT dose/agents may not be changed during the study.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
• Adequate hematologic function (absolute neutrophil count [ANC] ≥ 1,500 cells/μL; hemoglobin ≥ 8 g/dL, platelets ≥ 100,000/μL).
• Adequate renal function (serum creatinine ≤ 1.5 mg/dL or calculated creatinine clearance ≥ 60 mL/min).
• Adequate hepatic function (bilirubin ≤ 1.0 x upper limit of normal [ULN], alanine aminotransferase [ALT] ≤ 1.5 x ULN, aspartate aminotransferase [AST] ≤ 1.5 x ULN).
• Prothrombin time (PT) / international normalized ratio (INR) ≤ 1.5 × ULN.
• Activated partial thromboplastin (aPTT) time ≤ 1.5 × ULN.
• Prostate-specific antigen (PSA) level of at least 2 ng/mL.
• New York Heart Association classification I or II.
• All patients of reproductive potential must agree to use an approved form of contraception (as determined by the investigator).

Exclusion Criteria:

• Known history of bleeding diathesis or coagulopathy (e.g., von Willebrand disease or hemophilia).
• Any history of thromboembolic events (e.g., deep vein thrombosis or pulmonary thromboembolism); central venous catheter-related thrombosis > 6 months before Screening is allowed.
• Ongoing therapy with oral or parenteral anticoagulants; patients on low-dose anticoagulants to maintain patency of central venous catheters are eligible.
• Grade 2 or higher peripheral neuropathy (e.g., numbness, tingling, and/or pain in distal extremities).
• Radiotherapy (teletherapy or brachytherapy) , chemotherapy or estrogen agonist within 28 days before Study Day 1.
• Systemic radiotherapy (Sm-153, Sr-89) within 56 days before study day 1.
• Symptomatic or clinically active brain metastases.
• Major surgery within 28 days of Study Day 1.
• Uncontrolled intercurrent disease (eg, diabetes, hypertension, thyroid disease).
• Any history of cerebrovascular accident, or transient ischemic attack at any time, or history of symptomatic coronary artery disease < 6 months before screening.
• A history of any condition requiring anti-platelet therapy (eg, phosphodiesterase inhibitors, adenosine diphosphate receptor antagonists), with the exception of general cardiovascular prophylaxis with aspirin (≤ 325 mg/day).
• Serious non-healing wound (including wound healing by secondary intention, ulcer, or bone fracture).
• Known chronic infection with human immunodeficiency virus (HIV) or viral hepatitis.
• Contraindication to intravenous (IV) contrast media.