Docetaxel and Carboplatin for Patients With mCRPC and DNA-Repair Deficiencies

This is a phase 2 study of the combination of docetaxel and carboplatin in patients with
germline inactivation of genes in the homologous recombination pathway, including BRCA1,
BRCA2, and ATM.

PRIMARY OBJECTIVE To assess rate of 50% Prostate Specific Androgen (PSA) decline to docetaxel
and carboplatin

EXPLORATORY OBJECTIVES To assess PSA response duration to docetaxel and carboplatin To assess
response of measurable disease To assess time to progression of bone lesions or measurable
disease (RECIST) To assess response to docetaxel and carboplatin in patients with germline
alterations or somatic alterations of DNA repair pathway genes (BRCA1, BRCA2, ATM)

Inclusion Criteria

Patients meeting the following inclusion criteria will be eligible to participate in this
study:

1. 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.

2. Age > 18 years

3. Histologically or cytologically confirmed adenocarcinoma of the prostate

4. 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.

5. Castration resistant prostate cancer as defined by serum testosterone < 50ng/ml and
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 (Response Evaluation Criteria in
Solid Tumors).

- Progression of metastatic bone disease on bone scan with > 2 new lesions.

6. Prior therapy with abiraterone acetate, enzalutamide, or docetaxel. There is no limit
to the number of prior treatment regimens.

7. Presence of metastatic disease on scans.

8. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2.

9. Life expectancy >12 weeks.

10. 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 has been disease-free
for at least one year (any prior chemotherapy is allowed).

11. Patients must have adequate organ and marrow function as defined below obtained within
14 days prior to start of therapy:

1. Absolute neutrophil count >1.5 x 109 cells/L

2. Hgb > 9.0 g/dL

3. Platelets >100,000 x 109/L

4. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total
bilirubin levels < 1.5 x Upper Limit of Normal (ULN)

12. Presence of germline inactivation of BRCA1, BRCA2, or ATM (see section 1.1).

13. Patients with clearly deleterious germline mutations of other genes involved in
homologous DNA repair may be included at the investigator's discretion.

14. Patients with homozygous inactivation of genes involved in homologous recombination
from primary or metastatic tumor as assessed by a Clinical Laboratory Improvement
Amendments (CLIA) level assay for DNA sequencing may be included.

Exclusion Criteria

Patients who meet any of the following criteria will be excluded from the study:

1. Currently receiving active therapy for other neoplastic disorders.

2. Histologic evidence of small cell carcinoma (morphology alone - immunohistochemical
evidence of neuroendocrine differentiation without morphologic evidence is not
exclusionary).

3. Prior treatment with platinum-based chemotherapy for prostate cancer.

4. Known parenchymal brain metastasis.

5. Active or symptomatic viral hepatitis or chronic liver disease.

6. 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 or cardiac ejection fraction
measurement of < 35 % at baseline, if done.

7. Treatment with an investigational therapeutic within 30 days of Cycle 1.

8. Patients with dementia/psychiatric illness/social situations limiting compliance with
study requirements or understanding and/or giving of informed consent are not eligible

9. Any medical conditions, which, in the opinion of the investigators, would jeopardize
either the patient or the integrity of the data obtained are not eligible.