Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase I Study With an Expansion Cohort of the PARP Inhibitor AZD2281 (KU-0059436) Combined With Carboplatin in Breast and Ovarian Cancer in BRCA1/2 Mutation Carriers (Familial Breast and Ovarian Cancer) and Sporadic Triple Negative Breast Cancer and Ovarian Cancer
Brief Summary: Background:

* Carboplatin is approved by the Food and Drug Administration to treat cancer.
* 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.

Objectives:

* To determine the optimum doses of AZD2281 and carboplatin that can safely be used in patients with breast and ovarian cancer.
* To evaluate the response of the tumor to the drug combination and determine the side effects of the treatment.

Eligibility:

-Patients 18 years of age or older with breast or ovarian cancer who have a family history of cancer or who have a BRCA1 or BRCA2 mutation.

Design:

* In this dose escalation study, the first small group of patients receives the smallest study doses of AZD2281 and carboplatin. Subsequent groups receive incrementally higher doses of first AZD2281 and then carboplatin as long as the preceding group has not experienced unacceptable side effects. When the highest safe dose is determined, additional patients receive that dose.
* Patients receive treatment in 21-day cycles as follows: AZD2281 by mouth twice a day every day; carboplatin thorough a vein on day 8 of each cycle. Treatment may continue until it is no longer beneficial.
* Evaluations during treatment include the following:
* Physical examination 1 week after starting treatment and then every 3 weeks.
* Blood tests weekly for the first 4 weeks of treatment and then every 3 weeks.
* CT scans or other imaging tests such as ultrasound or MRI every 6 weeks to evaluate the tumor.


Options:
A: 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
B: * 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
C: 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
D: Inclusion Criteria:

1. Females with age between 18 and 70 years old
2. Histological proven unresectable recurrent or advanced breast cancer
3. Triple-negative for estrogen receptor (ER), progestogen receptor (PR), and human epithelial receptor-2 (HER2) by immunohistochemistry (IHC) test. For patients with ER negative, PR negative, Her2 two plus, a negative Her2 gene amplification should be verified with FISH test. Her2 one plus may consider FISH verification.
4. No prior chemotherapy for metastatic breast cancer. Prior use of taxanes in the adjuvant/neoadjuvant setting is acceptable if completed 6 months prior to enrollment
5. At least one measurable disease according to the response evaluation criteria in solid tumor (RECIST)
6. Performance status not more than 1
7. All patients enrolled are required to have adequate hematologic, hepatic, and renal function
8. Life expectancy greater than 12 weeks
9. No serious medical history of heart, lung, liver and kidney
10. Provision of written informed consent prior to any study specific procedures
11. Patients with good compliance

Exclusion Criteria:

1. Pregnant or lactating women (female patients of child-bearing potential must have a negative serum pregnancy test within 14 days of first day of drug dosing, or, if positive, a pregnancy ruled out by ultrasound)
2. Women of child-bearing potential, unwilling to use adequate contraceptive protection during the course of the study
3. Treatment with radiotherapy at the axial skeleton within 4 weeks before the first treatment or has not recovered from all toxicities of previously administered radiotherapy
4. Treatment with an investigational product within 4 weeks before the first treatment
5. Symptomatic central nervous system metastases, except for patients with stable and asymptomatic brain metastases who have completed a course of cranial irradiation, and have at least one measurable lesion outside the brain. Radiotherapy should be completed within 4 weeks prior to the registration
6. Other active malignancies (including other hematologic malignancies) or other malignancies within the last 5 years, except for cured nonmelanoma skin cancer or cervical intraepithelial neoplasia.
7. Patient having a history of clinically significant cardiovascular, hepatic, respiratory or renal diseases, clinically significant hematological and endocrinal abnormalities, clinically significant neurological or psychiatric conditions
8. Uncontrolled serious infection

Answer: B