Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase I Combination Study of AZD2281 and Cisplatin Plus Gemcitabine in Adults With Solid Tumors
Brief Summary: Background:

* AZD2281 is an experimental drug in a class of agents called PARP inhibitors. PARP is a protein that is involved in repairing DNA damage; PARP inhibitors interfere with that process.
* Cisplatin and gemcitabine are approved by the United States Food and Drug Administration to treat certain cancers.

Objectives:

* To determine the optimum doses of AZD2281, cisplatin and gemcitabine in combination that can safely be given to patients with solid tumor cancers.
* To evaluate the response of the tumor to the drug combination and determine the side effects of the treatment.

Eligibility:

-Patients 18 years or older with an advanced solid tumor cancer for whom standard treatments are not effective.

Design:

* In this dose escalation study, the first small group of patients receives the smallest study doses of the study drugs. Subsequent groups receive incrementally higher doses as long as the preceding group does not experience unacceptable side effects. When the highest safe dose is determined, additional patients entering the study receive that dose.
* Patients receive treatment in 21-day cycles as follows:
* Days 1-4: AZD2281 by mouth twice a day
* Day 3: gemcitabine thorough a vein over 1 hour; then cisplatin through a vein over 1 hour.
* Day 10: gemcitabine through a vein over 1 hour.
* Evaluations during treatment include the following:
* Physical examination, vital signs check and blood tests every 3 weeks.
* CT scans every 6 weeks to evaluate the tumor.
* Treatment may continue until it is no longer beneficial.


Options:
A: * 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.
B: Inclusion Criteria:

* Histologically confirmed diagnosis of metastatic breast cancer (Stage IV)
* Estrogen Receptor \[ER\] negative, PgR negative and HER2 less than 3+ expression by immunohistochemistry (IHC)
* No more than 1 prior chemotherapy received for treating this metastatic breast cancer
* No more than 1 prior anthracycline and/or taxane regimen (either adjuvant or metastatic setting)
* Other protocol-defined inclusion criteria may apply

Exclusion Criteria:

* Prior platinum agent
* Prior mitomycin
* Known history of brain metastases
* Other protocol-defined exclusion criteria may apply
C: * 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
D: Inclusion Criteria:

* Male or female patients with a histologically or cytologically diagnosed malignant solid tumour
* Adequate bone marrow, hepatic and renal function
* Performance status of no more than 2 ( ECOG scale).

Exclusion Criteria:

* Any chemotherapy, radiotherapy ( except palliative), endocrine or immunotherapy within 4 weeks prior to entry
* Major surgery with 4 weeks of entering the study and must have recovered from effects of the major surgery
* More than two previous courses of platinum-containing chemotherapy
* Heavily pre-treated patients(\> 2 courses of previous chemotherapy and/or extensive irradiation leading to bone marrow deficiency) will be excluded from the study

Answer: A