Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Related Information
Registry Information

Alternate Title

AZD2281 and Carboplatin in Treating Patients With BRCA1/BRCA2-Associated, Hereditary, or Triple Negative Metastatic or Unresectable Breast Cancer or Ovarian Epithelial Cancer

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Biomarker/Laboratory analysis, Treatment	Active	18 and over	NCI	NCI-08-C-0092 08-C-0092, NCI-P07253, NCT00647062

Special Category: NIH Clinical Center trial, NCI Web site featured trial

Objectives

Primary

1. Determine the safety and toxicity of AZD2281 and carboplatin in patients with BRCA1/BRCA2-associated or familial breast or ovarian epithelial cancer, low genetic risk sporadic ovarian serous epithelial cancer, or low genetic risk triple negative breast cancer.
2. Determine the biochemical changes in poly (ADP-ribose) polymerase (PARP) activity and γ-H2AX levels in mononuclear cells and in tumor tissue in response to treatment with this regimen in these patients.

Secondary

1. Assess the clinical activity of this regimen.
2. Evaluate and correlate differences in PARP and XRCC1 polymorphisms with clinical activity and toxicity of this regimen.
3. Evaluate the induction of apoptosis in tumor tissue.
4. Evaluate the pharmacodynamics of this regimen.

Entry Criteria

Disease Characteristics:

• Histologically or cytologically confirmed breast and/or ovarian epithelial cancer, meeting one of the following criteria:
  • Documented deleterious BRCA1/BRCA2 germline mutation or BRCAPRO score ≥ 30%
  • Sporadic ovarian serous epithelial cancer with negative family history, BRCAPRO score ≤ 20%, or negative BRCA1/BRCA2 mutation
  • Triple negative (estrogen receptor negative, progesterone receptor negative, and HER2/neu negative) breast cancer with negative family history and/or BRCAPRO score ≤ 10% or negative BRCA1/2 mutation
• Metastatic or unresectable disease for which standard curative measures do not exist or are no longer effective
  • Patients with locally advanced, unresectable breast cancer must have been previously treated with standard therapy
    • Patients with locally advanced breast cancer presenting for initial therapy are not eligible
  • No local (i.e., only in breast or chest wall) recurrence only
• Measurable and/or evaluable disease
• Disease can be safely biopsied, as determined by an interventional radiologist (cohort 2)
  • Agrees to undergo mandatory biopsy at baseline
• No diagnosis of brain metastases within the past year
  • Patients with brain metastases diagnosed > 1 year ago are eligible provided the patient has undergone resection or radiotherapy for the brain metastases and has had no CNS recurrence for a full year

Prior/Concurrent Therapy:

• See Disease Characteristics
• Recovered from prior therapy (≤ CTC grade 1)
  • Chronic stable grade 2 peripheral neuropathy secondary to neurotoxicity from prior therapy may be allowed at the discretion of the principal investigator
• At least 6 months since prior platinum drugs
  • Patients with platinum-resistant disease are eligible
• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C), biological therapy, hormonal therapy, or radiotherapy
• More than 4 weeks since prior investigational agents
• More than 4 weeks since prior major surgery
• No prior PARP inhibitors
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No other concurrent investigational agents

Patient Characteristics:

• Male or female
• Menopausal status not specified
• ECOG performance status (PS) 0-2 or Karnofsky PS 60-100%
• Life expectancy > 3 months
• Hemoglobin ≥ 10 g/dL
• Leukocytes ≥ 3,000/mcL
• Absolute neutrophil count ≥ 1,500/mcL
• Platelet count ≥ 100,000/mcL
• Total bilirubin normal (in the absence of Gilbert’s syndrome)
• AST/ALT ≤ 2.5 times upper limit of normal (ULN)
• Creatinine clearance ≥ 60 mL/min OR serum creatinine ≤ 1.5 times ULN
• Corrected or ionized calcium normal
• Potassium normal
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for ≥ 3 months after completion of study treatment
• Able to swallow pills
• No history of grade 4 allergic reaction to platinum
  • Patients with ≤ grade 3 (without a reaction protocol) or ≤ grade 2 (in the face of pretreatment, but not graduated treatment exposure) allergic reaction to platinums are eligible
• No functional impairment due to neuropathy
• No clinically significant bleeding
• No concurrent uncontrolled illness including, but not limited to, any of the following:
  • Ongoing or active infection
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Cardiac arrhythmia
  • Psychiatric illness/social situations that would preclude study compliance
• No other invasive malignancies within the past 5 years, except non-melanomatous skin cancer, non-invasive bladder cancer, stage I endometrial cancer, or cervical cancer cured by surgical resection (cohort 2)

Expected Enrollment

Outcomes

Safety and toxicity
Biochemical changes in poly (ADP-ribose) polymerase (PARP) activity and γ-H2AX levels in mononuclear cells and in tumor tissue in response to treatment

Clinical activity
Correlation of differences in PARP and XRCC1 polymorphisms with clinical activity and toxicity
Induction of apoptosis in tumor tissue
Pharmacodynamics
Correlation of BRCA1/BRCA2 mutation with clinical response and ethnicity

Outline

This is a dose-escalation study of AZD2281. Patients are initially enrolled in cohort 1. Once the maximum tolerated dose (MTD) of AZD2281 is determined, additional patients are enrolled in cohort 2 and treated at the MTD.

• Cohort 1 (dose-escalation cohort): Patients receive oral AZD2281 twice daily on days 1-7 and carboplatin* IV over 15-60 minutes on day 2. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

   [Note: *Patients who experience a partial response or stable disease may receive 8-10 courses of carboplatin (more than 10 courses will be at the investigator's discretion); patients with complete response (CR) may receive no more than 2 courses of carboplatin past CR.]

• Cohort 2 (expansion cohort): Patients receive AZD2281 (at the MTD determined in cohort 1) and carboplatin as in cohort 1.

Patients in both cohorts undergo blood sample collection periodically for analysis of PARP inhibition by ELISA. Blood samples from patients in cohort 2 are also analyzed for PARP/XRCC1 polymorphism, γ-H2AX determination by immunofluorescence assay, and pharmacogenomics. Patients in cohort 2 also undergo tumor tissue sample collection at baseline for analysis of apoptosis by TUNEL assay, PARP inhibition by ELISA, γ-H2AX determination by immunofluorescence assay, and tissue proteomics.

After completion of study treatment, patients are followed periodically for 4 weeks.

Trial Contact Information

Trial Lead Organizations

NCI - Center for Cancer Research

Elise Kohn, MD, Principal investigator		Ph: 301-402-2726

U.S.A.
Maryland
	Bethesda
	Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office
		Clinical Trials Office - Warren Grant Magnusen Clinical Center - NCI Clinical Trials Referral Office	Ph:  888-NCI-1937

Related Information

Featured trial article

Registry Information
Official 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
Trial Start Date		2007-12-31
Trial Completion Date		2009-12-31 (estimated)
Registered in ClinicalTrials.gov		NCT00647062
Date Submitted to PDQ		2008-03-20
Information Last Verified		2009-10-06

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