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

A Phase 2 Study of ABT-888 and Temozolomide for Metastatic Breast Cancer and an Expansion Cohort in BRCA1/2 Mutation Carriers

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.

Study Overview

• Status: Completed
• Conditions: Breast Cancer; Metastatic Breast Cancer; BRCA1 Gene Mutation; brca2 Gene Mutation
• Intervention / Treatment: Drug: ABT-888; Drug: temozolomide

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 Type: Interventional
• Enrollment (Actual): 63
• Phase: Phase 2

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TMZ/ABT888 Primary Cohort; Primary cohort included patients unselected for BRCA1/2 mutations or breast cancer subtype. Combination therapy with temozolomide and veliparib (28 day cycle) Veliparib 30-40 mg orally twice/day days 1-7 Temozolomide 150 mg/m^2 orally once daily days 1-5, increased to 200 mg/m^2 starting cycle 2 as tolerated	Drug: ABT-888; Capsules (30-40 mg) taken orally twice a day on days 1-7 of each 28 day cycle; Other Names: veliparib; Drug: temozolomide; Capsules (150 mg/m^2 initially, and 200 mg/m^2 starting cycle 2 if tolerated) taken orally once a day on days 1 through 5 of a 28 day cycle; Other Names: TMZ
Experimental: TMZ/ABT888 Expansion Cohort; Expansion cohort included patients with BRCA1/2 deleterious mutations. Combination therapy with temozolomide and veliparib (28 day cycle) Veliparib 30 mg orally twice/day days 1-7 Temozolomide 150 mg/m^2 orally once daily days 1-5, increased to 200 mg/m^2 starting cycle 2 as tolerated	Drug: ABT-888; Capsules (30-40 mg) taken orally twice a day on days 1-7 of each 28 day cycle; Other Names: veliparib; Drug: temozolomide; Capsules (150 mg/m^2 initially, and 200 mg/m^2 starting cycle 2 if tolerated) taken orally once a day on days 1 through 5 of a 28 day cycle; Other Names: TMZ

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR) of ABT-888 and Temozolomide (TMZ) in Metastatic Breast Cancer	Objective response rate (ORR) is defined as the percentage of enrolled patients who have a partial or complete response per RECIST (Response Evaluation Criteria in Solid Tumors) v1.1 guidelines. A partial response is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. A complete response is defined as disappearance of all target lesions, with any pathological lymph nodes (whether target or non-target) reduced in short axis to <10 mm.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival	Progression free survival is defined as the length of time from enrollment until disease progression, death, or date of last patient contact. Progressive disease was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Progressive disease is defined as at least a 20% increase (at least 5 mm) in the sum of the LD of target lesions in comparison with the lowest sum achieved on study or the appearance of one or more new lesions, and/or unequivocal progression of non-target lesions.	5 years
Clinical Benefit Rate	Clinical benefit rate (CBR) is defined as the percentage of patients who achieve a partial or complete response or stable disease by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. A partial response is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. A complete response is defined as disappearance of all target lesions, with any pathological lymph nodes (whether target or non-target) reduced in short axis to <10 mm. Progressive disease is defined as at least a 20% increase (at least 5 mm) in the sum of the LD of target lesions in comparison with the lowest sum achieved on study or the appearance of one or more new lesions, and/or unequivocal progression of non-target lesions.	Four months

Collaborators and Investigators

• Sponsor: Steven J Isakoff, MD, PhD
• Collaborators: Dana-Farber Cancer Institute; Beth Israel Deaconess Medical Center; Abbott
• Investigators: Principal Investigator: Steven Isakoff, MD, PhD, Massachusetts General Hospital

Publications and helpful links

General Publications

• Xu J, Keenan TE, Overmoyer B, Tung NM, Gelman RS, Habin K, Garber JE, Ellisen LW, Winer EP, Goss PE, Yeap BY, Chabner BA, Isakoff SJ. Phase II trial of veliparib and temozolomide in metastatic breast cancer patients with and without BRCA1/2 mutations. Breast Cancer Res Treat. 2021 Oct;189(3):641-651. doi: 10.1007/s10549-021-06292-7. Epub 2021 Aug 20.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2009
• Primary Completion (Actual): September 1, 2012
• Study Completion (Actual): September 1, 2015

Study Registration Dates

• First Submitted: November 5, 2009
• First Submitted That Met QC Criteria: November 6, 2009
• First Posted (Estimated): November 9, 2009

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 26, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: ABT-888; temozolomide; TMZ
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Breast Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents, Alkylating; Alkylating Agents; Temozolomide; Veliparib
• Other Study ID Numbers: 09-261

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No