ABT-888 and Temozolomide for Metastatic Breast Cancer and BRCA1/2 Breast Cancer

Study Description

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Brief Summary:

The purpose of this research study is to find out if the combination of ABT-888 and temozolomide is safe and effective in treating patients with metastatic breast cancer. ABT-888 works by obstructing a DNA enzyme called poly (ADP-ribose) polymerase (PARP) which helps repair cancer cells damaged by chemotherapy. By blocking the PARP enzyme, the cancer cells are unable to repair themselves and as a result die. The other drug in this study is temozolomide. Temozolomide is designed to damage DNA in order to prevent cancer cells from reproducing. Because PARP inhibitors, such as ABT-888, prevent cancer cells from repairing their own DNA, they enhance the potential of chemotherapy therapy like temozolomide to induce cell death. The combination of ABT-888 and temozolomide has been used in a clinical trial for treatment of other cancers and information for this research study suggests that the combination may help to inhibit growth in breast cancer.

ONLY THE EXPANSION COHORT BELOW IS RECRUITING:

BRCA CARRIER EXPANSION COHORT: The purpose of the expansion cohort is to further evaluate the activity and safety of this combination in BRCA mutation carriers with metastatic breast cancer.

Condition or disease	Intervention/treatment	Phase
Breast Cancer; Metastatic Breast Cancer; BRCA1 Gene Mutation; brca2 Gene Mutation	Drug: ABT-888; Drug: temozolomide	Phase 2

Detailed Description:

• Each treatment cycle lasts 28 days. Participants will be given a supply of ABT-88 in the form of capsules which they will take twice daily on days 1-7 of each cycle. Temozolomide is also in capsule form and will be taken once daily on days 1-5 of each cycle.
• Participants will come into the clinic on day 1 of each cycle and will have the following tests and procedures performed: physical examination, vital signs and blood tests.
• On day 15 of cycles 1 and 2 and day 22 of each cycle, participants will have blood work done.
• An assessment fo the tumor by CT scan of the participants chest, abdomen and pelvis will be done every 2 cycles.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	64 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase 2 Study of ABT-888 and Temozolomide for Metastatic Breast Cancer and an Expansion Cohort in BRCA1/2 Mutation Carriers
Study Start Date :	November 2009
Estimated Primary Completion Date :	June 2019
Estimated Study Completion Date :	June 2020

Arms and Interventions

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Arm	Intervention/treatment
Experimental: TMZ/ABT888; Combination therapy with temozolomide and veliparib	Drug: ABT-888; Capsules taken orally twice a day on days 1-7 of each 28 day cycle; Other Name: veliparib Drug: temozolomide; capsules taken orally once a day on days 1 through 5 of a 28 day cycle; Other Name: TMZ

Outcome Measures

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Primary Outcome Measures :

1. To determine the objective response rate (ORR) of ABT-888 and temozolomide (TMZ) in metastatic breast cancer. [ Time Frame: 2 years ]
2. To determine Safety and Efficacy in an Expansion Cohort of BRCA1/2 Mutation Carriers. [ Time Frame: 2 years ]
   An expansion cohort of 20 additional patients with BRCA1/2 Deleterious Mutations will be evaluated to further assess safety and efficacy of the combination of ABT888 and Temozolomide in metastatic breast cancer.

Secondary Outcome Measures :

1. To further characterize the safety and tolerability of ABT-888 and TMZ in patients with metastatic breast cancer. [ Time Frame: 2 years ]
2. To evaluate progression free survival. [ Time Frame: 5 years ]
3. To evaluate the clinical benefit rate. [ Time Frame: 2 years ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Histologically or cytologically confirmed breast cancer that is metastatic (Stage IV) or locally advanced recurrent breast cancer that is unresectable and for which standard curative or palliative measures do not exist or are no longer effective.
• Measurable disease by RECIST criteria
• All immunohistochemical subtypes of breast cancer are eligible. HER2 positive breast cancer must have progressed on prior standard HER2 therapy or have a contraindication to anti-HER2 therapy.
• Must have at least 1 prior chemotherapy regimen for metastatic disease, with no limit on total number of prior therapies.
• 18 years of age or older
• Life expectancy of at least 12 weeks
• ECOG Performance Status of 0, 1, or 2
• Normal organ and marrow function as outlined in the protocol
• Archived tissue block or 25 unstained slides (from primary and/or metastatic tumor) if available for correlative exploratory studies. Absence of available tissue will not exclude the subjects from participating.
• CNS metastases are allowed if they are clinically stable without current evidence of symptomatic progression and do not require steroids, whole brain radiation therapy, or stereotactic radiosurgery. This may include brain metastases not previously treated if they are clinically stable as described above.
• Women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation.
• Women of child-bearing potential must have a negative pregnancy test within 14 days of registration.
• Patients must be progressing on their current therapy
• Prior exposure to single agent PARP inhibitor is allowed, but no prior exposure to PARP with a combination of chemotherapy is allowed.

Exclusion Criteria:

• Participants who have had chemotherapy, biologic therapy, small molecule targeted therapy or radiotherapy within 14 days prior to entering the study or those who have not recovered from adverse events due to agents administered more than 2 weeks earlier. Anti-cancer hormonal therapy must be stopped 24 hours prior to starting study treatment.
• Participants may not be receiving any other investigational agents.
• Prior therapy with TMZ is allowed except if participant has a history of allergic reactions attributed to TMZ, or if therapy was discontinued due to intolerance of or toxicity from TMZ.
• Leptomeningeal disease
• CNS involvement requiring steroids (except for patients who recently completed brain radiation and are on stable or tapering doses of steroids).
• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, recent myocardial infarction, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements, or other comorbid condition that investigator believes may compromise participant's safe and effective participation in the trial.
• Concurrent radiation therapy is not permitted while on study
• Concurrent anti-cancer therapy is not permitted on study
• Pregnant and breast feeding women
• History of uncontrolled seizure disorder
• Individuals with a history of other malignancies are eligible if they meet the following criteria: a) the other malignancy was treated with curative intent and is deemed by the investigator to be at low risk of recurrence , AND b) a metastatic lesion has been histologically confirmed as breast cancer, c) individuals with the following cancers are eligible if diagnosed and treated: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin.

EXPANSION COHORT:

An expansion cohort will have the same eligibility requirements with the following notable exceptions:

• Patients must have known deleterious mutation of BRCA1/2
• Prior PARP inhibitor combinations with chemotherapy are allowed
• Any number of prior therapies is allowed, including first line

Contacts and Locations

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Locations

United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02115
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02115

Sponsors and Collaborators

Steven Isakoff, MD, PhD

Dana-Farber Cancer Institute

Beth Israel Deaconess Medical Center

Abbott

Investigators

Principal Investigator:	Steven Isakoff, MD, PhD	Massachusetts General Hospital

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Steven Isakoff, MD, PhD, Attending Physician, Massachusetts General Hospital
ClinicalTrials.gov Identifier:	NCT01009788 History of Changes
Other Study ID Numbers:	09-261
First Posted:	November 9, 2009
Last Update Posted:	April 9, 2018
Last Verified:	April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Keywords provided by Steven Isakoff, MD, PhD, Massachusetts General Hospital:

ABT-888; temozolomide; TMZ

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Temozolomide; Dacarbazine	Veliparib; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Poly(ADP-ribose) Polymerase Inhibitors; Enzyme Inhibitors