Pilot Trial of BMN 673, an Oral PARP Inhibitor, in Patients With Advanced Solid Tumors and Deleterious BRCA Mutations

Background:

- The poly (ADP-ribose) polymerase (PARP) family of enzymes is critical for maintaining
genomic stability by regulating a variety of DNA damage repair mechanisms.

- Talazoparib (BMN 673) is a PARP inhibitor with greater in vitro activity than any other
PARP inhibitor currently in development. Talazoparib (BMN 673) has been shown to cause
single-agent synthetic lethality in BRCA1/2- and PTEN-deficient cell lines, and has
potent antitumor activity in animal models of tumors harboring mutations in DNA repair
pathways.

- Talazoparib (BMN 673) is showing promising single-agent activity in patients with
advanced ovarian and breast cancer harboring deleterious BRCA mutations.

- This pilot study will evaluate the pharmacodynamic effects of talazoparib (BMN 673) on
DNA damage and apoptosis markers in tumor biopsy tissue.

Primary Objective:

-Determine the pharmacodynamic effect of talazoparib (BMN 673) in tumor biopsies from
patients with advanced ovarian, breast, or other solid tumor and deleterious BRCA mutations.

Secondary Objectives:

-Determine the response rate (CR + PR) of treatment with talazoparib (BMN 673) in patients
with deleterious BRCA mutations.

Eligibility:

- Adult patients with documented deleterious BRCA 1 or 2 mutations with histologically
confirmed ovarian, primary peritoneal, breast, prostate, pancreas, gastric or other
solid tumor whose disease has progressed following at least one standard therapy or who
have no acceptable standard treatment options.

- No major surgery, radiation, or chemotherapy within 4 weeks prior to study enrollment,
and recovered from toxicities of prior therapies to at least eligibility levels.

- Age greater than or equal to 18 years of age; ECOG performance status less than equal to
2

- Adequate organ function.

- Willingness to undergo tumor biopsies.

Study Design:

- Talazoparib (BMN 673) will be administered orally each day in 28-day cycles.

- Dosing will be at the established recommended Phase II dose of 1000 microgram/day each
day for 28 days.

- To meet the primary, pharmacodynamic endpoint of the trial, we plan to accrue a total of
12 patients with matched, evaluable baseline and day 8 biopsies. To allow for some
patients whose biopsies will not be evaluable (i.e., will contain <5% tumor content),
the accrual ceiling is 24 patients. The number of patients evaluable for objective
response, while relevant to the secondary objective of the trial, will not be considered
in determining completion of accrual.

- Tumor biopsies will be mandatory at baseline (pre-dose), and then approximately 3-6
hours post talazoparib (BMN 673) on day 8. One optional tumor biopsy may also be
collected either on day 1 (+/- 2 days) of the cycle following any restaging at which a
10-19% increase in tumor volume is observed (according to RECIST criteria) if the
patient has been on study for at least 4 cycles, or at time of disease progression.

- INCLUSION CRITERIA:

Adult patients with documented deleterious BRCA 1 or 2 mutations with histologically
confirmed ovarian, primary peritoneal, breast, prostate, pancreas, gastric or other solid
tumor whose disease has progressed following at least one standard therapy or who have no
acceptable standard treatment options.

Patients should be either platinum-naive or should have received platinum-based therapy at
least 6 months or greater prior to the time of enrollment; patients who received platinum
as part of adjuvant therapy should not have had recurrent disease within 6 months of
completing adjuvant therapy.

Patients with metastatic disease must have received at least one line of standard of care
(SOC) treatment for metastatic disease prior to enrollment

- Age greater than or equal to 18 years of age.

- ECOG performance status less than or equal to 2

- Life expectancy of greater than 3 months.

- Patients must have normal organ and marrow function as defined below:

- leukocytes greater than or equal to 3,000/mcL

- absolute neutrophil count greater than or equal to 1,500/mcL

- platelets greater than or equal to 100,000/mcL

- total bilirubin less than or equal to 1.5 times institutional upper limit of normal

- AST(SGOT)/ALT(SGPT) less than or equal to 3 times institutional upper limit of normal

- creatinine less than or equal to 1.5 times institutional upper limit of normal

OR

-creatinine clearance greater than or equal to 60 mL/min/1.73 m(2) for patients with
creatinine levels above institutional normal.

The effects of BMN 673 on the developing human fetus are unknown. For this reason and
because PARP inhibitors are known to be teratogenic, women of childbearing potential and
men must agree to use adequate contraception (hormonal or barrier method of birth control;
abstinence) prior to study entry, for the duration of study participation, and for 30 days
after completing study treatment. Should a woman become pregnant or suspect she is pregnant
while she or her partner is participating in this study, she should inform her treating
physician immediately. Men treated or enrolled on this protocol must also agree to use
adequate contraception prior to the study, for the duration of study participation, and for
3 months after completion of BMN 673 administration.

- Patients must be able to swallow whole tablets or capsules. Nasogastric or G-tube
administration is not allowed. Any gastrointestinal disease which would impair ability
to swallow, retain, or absorb drug is not allowed.

- Ability to understand and the willingness to sign a written informed consent document.

- Patients with HER2-positive advanced breast cancer or ovarian cancer should have
received at least two lines of systemic therapy in the advanced setting.

EXCLUSION CRITERIA:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier.
Patients who have had prior treatment with any PARP inhibitors are ineligible.

- Patients who are receiving any other investigational agents.

- Patients with known active brain metastases or carcinomatous meningitis are excluded
from this clinical trial. Patients whose brain metastatic disease status has remained
stable for greater than or equal to 4 weeks following treatment of brain metastases
are eligible to participate at the discretion of the principal investigator.

- Eligibility of subjects receiving any medications or substances with the potential to
affect the activity or pharmacokinetics of BMN 673 will be determined following review
by the principal investigator.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Pregnant women are excluded from this study because the effects of the study drugs on
the developing fetus are unknown.

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with BMN 673. In addition, these
patients are at increased risk of lethal infections when treated with marrow
suppressive therapy. Appropriate studies will be undertaken in patients receiving
combination antiretroviral therapy when indicated.

- Patients who require use of coumarin-derivative anticoagulants such as warfarin are
excluded. Low molecular weight heparin is permitted for prophylactic or therapeutic
use. Low-dose warfarin (less than or equal to 1 mg/day) is permitted.

- Women who are currently lactating