PARP Inhibition for Triple Negative Breast Cancer (ER-/PR-/HER2-)With BRCA1/2 Mutations

Breast Cancer Clinical Trial

Official title:

PARP Inhibition After Preoperative Chemotherapy in Patients With Triple Negative Breast Cancer or ER/PR +, HER2 Negative With Known BRCA1/2 Mutations: Hoosier Oncology Group BRE09-146

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01074970
• Other study ID #: BRE09-146
• Status: Completed
• Phase: Phase 2
• Start date: February 2010
• Est. completion date: December 15, 2018

Study information

• Verified date: February 2020
• Source: Hoosier Cancer Research Network
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this trial is to evaluate 2-year disease-free survival in this patient population treated with single agent cisplatin and patients treated with cisplatin in combination with Rucaparib following preoperative chemotherapy. Side effects and tolerability of this treatment in patients with residual disease following preoperative chemotherapy will also be observed and characterized.

Description:

OUTLINE: This is a multi-center study.

Safety Run-in will be for the first 12 patients on study only (6 in cohort 1 and 6 in cohort 2). Patients in the safety run will be included in the efficacy analysis on intent to treat basis:

Cisplatin 75 mg/m2 IV D1 every 3 weeks x 4 cycles; Rucaparib 16-30 mg IV D 1,2,3 every 3 weeks x 4 cycles

If cycle 1 is well tolerated, the dose of Rucaparib will be escalated from 16 mg to 24 mg for subsequent cycles in the cohort 1, and 24 mg to 30 mg in the cohort 2.

If ≤ 1 of 6 patients in cohort 1 experiences DLT, cohort 2 will commence. If 2 or more of 6 patients in cohort 1 experience DLT, the study will be suspended and an amendment to explore lower doses will be considered.

If ≤ 1 of 6 patients in cohort 2 experiences DLT, the randomized portion of the study will commence. If 2 or more of 6 patients experience DLT, the study will be suspended and an amendment to proceed with the randomized portion at the cohort 2 dose (24 mg) will be considered.

During the randomized portion of the study, patients will be randomized to either Arm A or Arm B.

Stratification factors:

• Anthracycline vs. not

• Residual LN involvement vs. No Residual LN involvement

Arm A (Cisplatin Monotherapy) Cisplatin 75 mg/m2 IV D1 every 3 weeks x 4 cycles

Arm B (Combination Therapy) Cisplatin 75 mg/m2 IV D1 every 3 weeks x 4 cycles; Rucaparib 16-30 mg IV D1,2,3 every 3 weeks x 4 cycles

Rucaparib maintenance 30 mg IV weekly x 24 weeks

ECOG Performance Status 0-1

Life Expectancy: Not Specified

Hematopoietic:

• Hemoglobin (Hgb) > 9.0 g/dL

• Platelets > 100 K/ mm3

• Absolute neutrophil count (ANC) > 1.5 K/mm3

Hepatic:

• Bilirubin < upper limit of normal (except in patients with documented Gilbert's disease, who must have a total bilirubin < 3.0 mg/dL)

• Aspartate aminotransferase (AST, SGOT) < 2.5 x ULN

• Alanine aminotransferase (ALT, SGPT) < 2.5 x ULN

Renal:

• Calculated creatinine clearance of > 50 cc/min using the Cockcroft-Gault formula

Cardiovascular:

• Left ventricular ejection fraction within normal limits.

• Patients with an unstable angina or myocardial infarction within 12 months of study entry are excluded.

• No clinically significant arrhythmia or baseline ECG abnormalities in the opinion of the treating investigator.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 135
• Est. completion date: December 15, 2018
• Est. primary completion date: December 15, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Must have histologically or cytologically confirmed triple negative (ER-/PR-/HER2-) invasive breast cancer, stage I-III at diagnosis (AJCC 6th edition) based on initial evaluation by clinical examination and/or breast imaging. NOTE: Patients with ER+ and/or PR+ may enroll ONLY if they are known carriers of a deleterious mutation in BRCA1 or BRCA2. Patients with HER2+ tumors may not enroll regardless of BRCA status.

• Must have completed preoperative (neoadjuvant) chemotherapy. NOTE: Acceptable preoperative regimens include an anthracycline or a taxane, or both. Patients may NOT have received cisplatin as part of their neoadjuvant therapy regimen. Patients who received preoperative therapy as part of a clinical trial may enroll. No adjuvant chemotherapy after surgery other than that specified in this protocol is allowed. Adjuvant bisphosphonate use is allowed.

• Must have completed definitive resection of primary tumor. The last surgery for breast cancer must have been completed at least 14 days prior to registration for protocol therapy.

• Must have significant residual invasive disease at the time of definitive surgery following preoperative chemotherapy. Significant residual disease is defined at least one of the following:

• Miller-Payne response in the breast of 0-25.

• Residual Cancer Burden (RBC) classification II or III6

• Residual carcinoma in one or more regional lymph nodes that would meet AJCC 6th edition criteria for N1 - N3 disease.

• Alternatively, if Miller-Payne or RCB grading is not available, the patient will be eligible if the pathology report indicates that the area of residual invasive disease in the breast measures at least 2 cm following preoperative therapy. The presence of DCIS without invasion does not qualify as residual disease in the breast.

• Whole breast radiotherapy is required for patients who underwent breast conserving therapy, including lumpectomy or partial mastectomy. Patients receiving adjuvant radiation therapy must have completed radiotherapy at least 14 days prior to registration for protocol therapy.

• Written informed consent and HIPAA authorization for release of personal health information.

• Age > 18 years at the time of consent.

• Must consent to allow submission of archived tumor tissue sample from definitive surgery.

• Must consent to collection of blood samples for PK analysis.

• Women of childbearing potential and males must be willing to use an effective method of contraception from the time consent is signed until 4 weeks after treatment discontinuation.

• Women of childbearing potential must have a negative pregnancy test within 14 days prior to registration for protocol therapy.

• Women must not be breastfeeding.

Exclusion Criteria:

• No stage IV (metastatic) disease, however no specific staging studies are required in the absence of symptoms or physical exam findings that would suggest distant disease.

• No treatment with any investigational agent within 30 days prior to registration for protocol therapy.

• No history of chronic hepatitis B or C

• No clinically significant infections as judged by the treating investigator.

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms
• Triple Negative Breast Neoplasms

Intervention

Drug:
• Cisplatin
Cisplatin 75 mg/m2 IV infusion over 60 minutes, D1 every 21 days for 4 cycles
• Rucaparib
Rucaparib 24mg C1,30mg C2-4, D1,2,3 every 21 days for 4 cycles
• Cisplatin
Cisplatin 75 mg/m2 IV infusion over 60 minutes, D1 every 21 days for 4 cycles

Locations

Country	Name	City	State
United States	Presbyterian Medical Group	Albuquerque	New Mexico
United States	University of New Mexico Cancer Center: Albuquerque	Albuquerque	New Mexico
United States	HOPE a Women's Cancer Center	Asheville	North Carolina
United States	University of Colorado Cancer Center	Aurora	Colorado
United States	The Center for Cancer & Hematologic Disease	Cherry Hill	New Jersey
United States	Seidman Cancer Center	Cleveland	Ohio
United States	Fort Wayne Oncology & Hematology, Inc	Fort Wayne	Indiana
United States	St. Jude Heritage Healthcare	Fullerton	California
United States	Pinnacle Health Fox Chase Regional Cancer Center	Harrisburg	Pennsylvania
United States	Memorial Cancer Institute Breast Cancer Center	Hollywood	Florida
United States	Community Regional Cancer Center	Indianapolis	Indiana
United States	Indiana University Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	Horizon Oncology Research, Inc./IU Health Arnett	Lafayette	Indiana
United States	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada
United States	University of California Los Angeles	Los Angeles	California
United States	The West Clinic	Memphis	Tennessee
United States	University of Miami, Sylvester Comprehensive Cancer Center	Miami	Florida
United States	Virtua Health Cancer Program	Mount Holly	New Jersey
United States	Monroe Medical Associates	Munster	Indiana
United States	Virginia Oncology Associates	Norfolk	Virginia
United States	Oregon Health Sciences University	Portland	Oregon
United States	Siteman Cancer Center	Saint Louis	Missouri
United States	Central Coast Medical Oncology Corporation	Santa Maria	California
United States	Bux-Mont Oncology Hematology Associates (FCCC) at Grand View Hospital	Sellersville	Pennsylvania
United States	Northern Indiana Cancer Research Consortium	South Bend	Indiana
United States	South Jersey Health Care	Vineland	New Jersey
United States	Metro Health Cancer Care	Wyoming	Michigan

Sponsors (2)

Lead Sponsor	Collaborator
Hoosier Cancer Research Network	Clovis Oncology, Inc.

Country where clinical trial is conducted

United States, 

References & Publications (3)

Miller K, Tong Y, Jones DR, Walsh T, Danso MA, Ma CX, Silverman P, King MC, Badve SS, Perkins SM. Cisplatin with or without rucaparib after preoperative chemotherapy in patients with triple negative breast cancer: Final efficacy results of Hoosier Oncolog

S. Dwadasi, Y. Tong, T. Walsh, M.A. Danso, C.X. Ma, P.A Silverman, M.C. King, S.M. Perkins, S.S. Badve, K. Miller. Cisplatin with or without rucaparib after preoperative chemotherapy in patients with triple negative breast cancer: Hoosier Oncology Group BRE09-146. J Clin Oncol 32:5s, 2014 (suppl; abstr 1019^)

S. R. Malireddy, S. M. Perkins, S. S. Badve, G. W. Sledge, K. Miller. PARP inhibition after preoperative chemotherapy in patients with triple negative breast cancer (TNBC) or known BRCA1/2 mutations: Hoosier oncology group BRE09-146. J Clin Oncol 29: 2011 (suppl; abstr TPS130)

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Two-year Disease Free Survival	To evaluate 2-year disease-free survival (DFS), in patients with confirmed TNBC or ER/PR + HER2-, known BRCA1/2 mutations treated with single agent cisplatin and patients treated with cisplatin in combination with Rucaparib following preoperative chemotherapy	24 months
Secondary	Side Effects and Tolerability	To characterize the side effects and tolerability of cisplatin and cisplatin plus Rucaparib in patients with residual disease following preoperative chemotherapy.	12 months
Secondary	One-year Disease Free Survival	To evaluate 1-year DFS	12 months
Secondary	Overall Survival	To determine 5-year overall survival	60 months
Secondary	Pharmacokinetic Data	To collect limited pharmacokinetic data, in patients receiving study drug to compliment ongoing PK analyses in other trials with Rucaparib	12 months
Secondary	Specimen Collection	To collect peripheral blood lymphocytes, archived tumor specimens, and genomic DNA to explore potential correlates of PARP inhibition, recurrence and toxicity.	12 months

External Links

•   Hoosier Cancer Research Network Homepage