AZD2281 Plus Carboplatin to Treat Breast and Ovarian Cancer

Background:

AZD2281 (KU-0059436) is an oral PARP-1 and PART-2 inhibitor that affects tumor growth by
impairing the ability of the cell to repair damaged DNA. Carboplatin causes covalent
cross-linking of DNA with stalled replication forks that would usually be repaired through
nucleotide excision repair and homologous recombination (HR).

Sporadic breast (triple negative) and ovarian cancers have been shown to exhibit a BRCA1-like
phenotype.

BRCA1/2 proteins have a critical function in the homologous DNA repair pathway. BRCA1/2
mutation carriers are at high risk for breast and ovarian cancer, and increased risk of
pancreatic cancer and prostate cancer. Mutation carriers have been shown to have increased
susceptibility to DNA damaging agents, such as the platinums.

BRCA1/2 deficient cells have been shown to be sensitive to PARP inhibition alone and in
combination with DNA damaging agents.

Combining these two agents in a background of impaired HR in BRCA1/2 mutation potitive
malignancies may result in synergistic anti-tumor effect.

Objectives:

Determine the safety and toxicity of the combination of AZD2281 and carboplatin in
BRCA1/2-associated or familial recurrent breast and ovarian cancer patients (cohort 1, Group
A), non-high risk serous ovarian cancer patients (Group B), and non-high risk triple negative
breast cancer patients (Group C).

Determine pharmacodynamics, estimates of biochemical changes in the apoptosis and PARP signal
transduction pathways in tumor and stromal cells in response to treatment of an expansion
cohort (cohort 2) at the MTD in a pilot fashion.

Eligibility:

Adults with breast or ovarian CA that is metastatic or unresectable and for which standard
curativetherapies do not exist or are no longer effective.

Documented deleterious BRCA1/2 mutation or a BRCAPRO score of greater than or equal to 30%.

Non-high risk serous ovarian cancer (negative family history, BRCAPRO score of less than or
equal to 20% or negative BRCA1/2 mutation test).

Documented ER negative, PR negative, Her2neu negative breast cancer (negative family history
and/or BRCAPRO score less than or equal to 10% (or negative BRCA1/2 mutation test).

Patients must be off prior chemotherapy, radiation therapy, hormonal therapy, or biological
therapy for at least 4 weeks.

All patients enrolling in cohort 2 must have at least one lesion amenable to biopsy.

ECOG performance status 0-2 and adequate organ and marrow function.

Design:

Patients will receive AZD2281 for days 1-7 of each 21 day cycle to maximize PARP inhibition
with carboplatin administration on day 2. Carboplatin will then be administered q3weeks and
with continuation AZD2281 BID on days 1-7 of each 21 day cycle.

AZD2281 or carboplatin will be escalated sequentially in Cohort 1 (Groups A, B, and C), and
after the maximum tolerated dose is determined, Cohort 2 will be enrolled for assessment of
translational endpoints.

Patients will be evaluated for toxicity in clinic every 3 weeks and every other cycle for
response using RECIST criteria. The clinic visit will be changed to every 4 weeks when
patients continue to stay on the study longer than two years with no or minimal disease.
Imaging studies will be obtained every 3 cycles for patients who stay on the study longer
than four years. The clinic visit will be changed to every two months (+/- 7 days) and the
imaging studies will be obtained every four months (+/- 7 days) for patients who stay on the
study longer than five years.

Tumor biopsies and plasma and serum samples will be obtained from patients in Cohort 2 before
treatment (biopsy mandatory), prior to treatment on cycle 2, day 1, and at time of disease
progression (biopsies optional). Tumor biopsies (optional) will also be taken from "super
responders" in Cohort 1 who have had a durable response longer than two years.

A minimum of 84 and a maximum of 101 patients will be needed to achieve the objectives of the
trial.

- INCLUSION CRITERIA:

Patients must have breast and/or epithelial ovarian cancer, primary peritoneal cancer,
and/or fallopian tube cancer histologically or cytologically confirmed at the NCI that is
metastatic or unresectable and for which standard curative measures do not exist or are no

longer effective.

All patients in cohort 1 must have measurable and/or evaluable disease.

Patients in the expansion cohort 2 must have safely biopsible disease as determine by an
interventional radiologist and must agree to the first mandatory biopsy (the other two
biopsies optional).

Breast cancer patients with locally advanced, unresectable disease must have been
previously treated with standard therapy.

There is no limit on number of prior therapy.

Patients must be at least 6 months from their last platinum exposure.

Platinum-resistant patients may participate.

Patients with allergic reaction to platinums (up to and including grade 3 without a
reaction protocol, and up to and including grade 2 in the face of pretrement, but not
graduated treatment exposure) are still eligible.

Age greater than or equal to 18 years.

ECOG performance status less than or equal to 2 (Karnofsky greater than or equal to 60%).

Life expectancy greater than 3 months.

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

- hemoglobin greater than or equal to 10g/dL

- leukocytesgreater 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 upper limit of normal (ULN) in the absence of
Gilbert s syndrome

- AST(SGOT)/ALT(SGPT) less than or equal to 2.5 X ULN

- creatinine clearance greater than or equal to 60 mL/min by 24-hour urine

OR

- serum creatinine less than or equal to 1.5 mg/dl

- corrected or Ionized Calcium less than or equal to ULN

- potassium within normal limits

A documented deleterious BRCA 1/2 germline mutation or BRCAPRO score of greater than or
equal to 30% for patients enrolling in Group A.

For patients enrolling in the sporadic serous epithelial ovarian cancer group, Group B, a
negative family history (BRCAPRO score less than or equal to 20% or negative BRCA1/2
mutation test).

For patients enrolling in the triple negative breast cancer (ER-/PR- /Her2-) group, Group
B, a negative family history and /or BRCAPRO score less than or equal to 10% or negative
BRCA1/2 mutation test).

The effects of AZD on the developing human fetus are unknown. For this reason and because
platinum agents are known to be teratogenic, men and women of child-bearing potential must
agree to use adequate contraception (hormonal or barrier method of birth control;
abstinence) prior to study entry and for the duration of study participation. Should a
woman become pregnant or suspect she is pregnant while participating in this study, she
should inform her treating physician immediately, Patients of child-bearing potential
should continue on contraception for at least three months following the last dose of
therapy on study.

Toxicities from previous cancer therapies must have recovered to grade 1 (defined by CTC
3.0). Chronic stable grade 2 peripheral neuropathy secondary to neurotoxicity from prior
therapies may be considered on a case by case basis by the Principal Investigator. No
patients with functional impairment due to neuropathy will be eligible for the study.
Hypomagnesemia will not be considered an exclusion criteria. Magnesium levels will be
monitored and replaced as clinically indicated. Ability to understand and the willingness
to sign a written informed consent document.

Female patients with reproductive potential must have a negative urine or serum pregnancy
test within 4 days prior to the start of the study.

EXCLUSION CRITERIA:

Patients who have had chemotherapy, biological therapy, hormonal therapy (with the
exception of raloxifene or others approved for bone health) or radiotherapy within 4 weeks
(6 weeks for nitrosoureas or mitomycin C) prior to entering the study.

Patients may not be receiving any other investigational agents or had them in the previous
28 days.

Patients with known brain metastases diagnosed within 1 year should be excluded from this
clinical trail because of their poor prognosis and because they often develop progressive
neurological dysfunction that would confound the evaluation of neurologic and other adverse
events.

---Patients with brain metastases diagnosed greater than 1 year prior to study entry are
eligible if they received sterilizing therapy to the CNS (resection or radiation) and have
been CNS recurrence-free for a full 1-year period.

Clinically significant bleeding.

Inability to swallow pills.

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 and breast-feeding women.

HIV-positive patients on combination antiretroviral therapy are ineligible because of the
potential for pharmacokinetic interactions with AZD2281. In addition, these patients are at
increased risk of lethal infections when treated with marrow-suppressive therapy such as
carboplatin.

Previous treatment with PARP inhibitor.

Major surgery within the past 28 days.

Patients with locally advanced breast tumors presenting for their initial therapy, or
patients with local (only in breast or chest wall) recurrence only will not be eligible for
this trial

For subjects in the dose-expansion cohorts, history of prior invasive malignancies within
the past 5 years (with the exception of non-melanomatous skin cancers, non-invasive bladder
cancer, stage I endometrial cancer or cervical cancer cured by surgical resection).

Patients with a history of grade 4 allergic reaction to platinums