AZD2281 and Cisplatin Plus Gemcitabine to Treat Solid Tumor Cancers

Background:

- Poly (ADP-ribose) polymerase-enzyme (PARP-1) recognizes and rapidly binds to DNA single-
and double-strand breaks and has been shown to participate in other DNA-related
functions, including gene amplification, cell division, differentiation, apoptosis, and
DNA base-excision repair.

- Increased PARP activity is one of the mechanisms by which tumor cells avoid apoptosis
caused by DNA damaging agents, and drug resistance has been linked to higher expressions
of PARP in cancer cells. This differential expression of PARP supports the observed
selectivity of PARP inhibitors to affect proliferating tumor cells. AZD2281 is an orally
administered potent inhibitor of PARP-1 and PARP-2, and its combination with cisplatin
and gemcitabine may overcome some of the resistance associated with these agents.

Primary Objectives:

- Establish the safety, tolerability, and maximum tolerated dose (MTD) of AZD2281 in
combination with cisplatin and gemcitabine in patients with solid tumors.

- Evaluate the effect of cisplatin-gemcitabine, with or without AZD2281, on PAR and gamma-
H2AX levels in tumor biopsies and peripheral blood mononuclear cells (PBMCs) pre- and
post-treatment.

Secondary Objectives:

- Evaluate the pharmacokinetics (PK) of AZD2281 with and without cisplatin and gemcitabine.

Eligibility:

- Patients (greater than or equal to 18 years) must have histologically confirmed solid
tumor malignancy that is metastatic or unresectable for which standard curative measures
do not exist, or are associated with minimal patient survival benefit.

- Patients who have previously received cisplatin or gemcitabine, or both, are eligible.

Design:

- Cycle 1 and subsequent cycles: AZD2281 will be administered orally every 12 hours (Q 12
hours) on day 1, while gemcitabine will be administered intravenously (IV) over 1 hour
(600 mg/m(2)/hour) on day 1 and 8 of each cycle and cisplatin over 1 hour on day 1 after
gemcitabine.

- Dose escalation will proceed in cohorts of 3 6 patients to a minimum of 27 and a maximum
of 42 patients.

- Patients will have a maximum of six cycles of treatment.

- Tumor biopsies will be collected in cycle 1 only, while blood for PBMC samples will be
collected in cycle 1 and before drug administration, 24 and 48 hours post
administration, in cycle 2, day 1. If Dose Level 3 is achieved additional time points
will be collected in cycle 1, day 8 - before drug administration, 6, 24 and 48 hours

post.

- INCLUSION CRITERIA:

Patients must have histologically confirmed (by the NIH pathology department) solid tumor
malignancy that is metastatic or unresectable for which standard curative measures do not
exist, or are associated with minimal patient survival benefit.

- To minimize the risk of bone marrow toxicity in this population, patients must have
had no more than two prior severely myelosuppressive cytotoxic chemotherapy regimens.

- Any prior therapy must have been completed greater than 2 weeks prior to enrollment on
the protocol in patients participating in a phase 0 (eIND]) study, or greater than or
equal to 4 weeks in patients participating in a regulatory IND study, and the
participants must have recovered to eligibility levels (CTCAE Grade less than or equal
to 1) from prior toxicity. Prior radiation or surgery should have been completed
greater than or equal to 4 weeks prior to study enrollment and all associated
toxicities resolved to eligibility levels (prior irradiated tumors will be considered
for biopsy if signs of disease progression are present).

- Age greater than or equal to18 years. Because no dosing or AE data are currently
available on the use of AZD2281 in patients less than 18 years of age, children are
excluded from this study, but may be eligible for future pediatric Phase I combination
trials.

- Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2
(Karnofsky greater than or equal to 60 percent).

- Life expectancy greater than or equal to 3 months.

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

- Absolute neutrophil count greater than or equal to 1,500/microL

- Platelets greater than or equal to 100,000/microL

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

- AST(SGOT)/ALT(SGPT) less than or equal to 2.5 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/minute for patients with
creatinine levels greater than 1.5 times institutional upper limit of normal.

- The effects of AZD2281 on the developing human fetus are unknown. For this
reason, and because cisplatin and gemcitabine used in this trial 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
completion of study. Should a woman become pregnant or suspect she is pregnant
while participating in this study, she should inform her treating physician
immediately.

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

- Patients who have previously received cisplatin or gemcitabine, or both, are
eligible to enter the trial.

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 AEs due to agents administered more than 4 weeks earlier. Patients must
be greater than or equal to 2 weeks since any investigational agent was administered
as part of an exploratory IND study and should have recovered to eligibility levels
from any toxicity.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, prolonged QTc interval (greater than 500 msec), or psychiatric
illness/social situations that would limit compliance with study requirements.

- In the Food and Drug Administration (FDA) Use-in-Pregnancy Ratings for Drugs,
cisplatin and gemcitabine are classified as category D drugs, indicating that
investigational or postmarketing data show risk to the fetus. For this reason, 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 completion of study. Should a woman
become pregnant or suspect she is pregnant while participating in this study, she
should inform her treating physician immediately. Because there is a risk for AEs in
nursing infants secondary to treatment of the mother with these drugs, breastfeeding
should be discontinued while the patient is on this trial and for 30 days after
completion of treatment on this trial.

- Patients with known brain metastases are excluded from this clinical trial, with the
exception of patients whose brain metastatic disease status remains stable for greater
than or equal to 1 month after treatment of the brain metastases without steroids
(except for maintenance replacement doses of steroids) or anti-seizure medications.

- Patients with clinically significant illnesses which could compromise participation in
the study, including, but not limited to, active or uncontrolled infection, immune
deficiencies or confirmed diagnosis of HIV infection, Hepatitis B, Hepatitis C,
uncontrolled diabetes, uncontrolled hypertension, symptomatic congestive heart
failure, unstable angina pectoris, myocardial infarction within the past 6 months,
uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would
limit compliance with study requirements are excluded from this trial.

- Patients with lymphomas and primary CNS malignancies are excluded from this study.