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

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

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.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Cisplatin; Drug: Rucaparib

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 135
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Fullerton, California, United States, 92835
      • St. Jude Heritage Healthcare
    • Los Angeles, California, United States, 90095
      • University of California Los Angeles
    • Santa Maria, California, United States, 93454
      • Central Coast Medical Oncology Corporation
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Cancer Center
  • Florida
    • Hollywood, Florida, United States, 33021
      • Memorial Cancer Institute Breast Cancer Center
    • Miami, Florida, United States, 33136
      • University of Miami, Sylvester Comprehensive Cancer Center
  • Indiana
    • Fort Wayne, Indiana, United States, 46815
      • Fort Wayne Oncology & Hematology, Inc
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Melvin and Bren Simon Cancer Center
    • Indianapolis, Indiana, United States, 46256
      • Community Regional Cancer Center
    • Lafayette, Indiana, United States, 47905
      • Horizon Oncology Research, Inc./IU Health Arnett
    • Munster, Indiana, United States, 46321
      • Monroe Medical Associates
    • South Bend, Indiana, United States, 46601
      • Northern Indiana Cancer Research Consortium
  • Michigan
    • Wyoming, Michigan, United States, 49519
      • Metro Health Cancer Care
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Siteman Cancer Center
  • Nevada
    • Las Vegas, Nevada, United States, 89128
      • Comprehensive Cancer Centers of Nevada
  • New Jersey
    • Cherry Hill, New Jersey, United States, 08003
      • The Center for Cancer & Hematologic Disease
    • Mount Holly, New Jersey, United States, 08060
      • Virtua Health Cancer Program
    • Vineland, New Jersey, United States, 08360
      • South Jersey Health Care
  • New Mexico
    • Albuquerque, New Mexico, United States, 87110
      • Presbyterian Medical Group
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico Cancer Center: Albuquerque
  • North Carolina
    • Asheville, North Carolina, United States, 28806
      • Hope A Women's Cancer Center
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Seidman Cancer Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health Sciences University
  • Pennsylvania
    • Harrisburg, Pennsylvania, United States, 17110
      • Pinnacle Health Fox Chase Regional Cancer Center
    • Sellersville, Pennsylvania, United States, 18960
      • Bux-Mont Oncology Hematology Associates (FCCC) at Grand View Hospital
  • Tennessee
    • Memphis, Tennessee, United States, 38138
      • The West Clinic
  • Virginia
    • Norfolk, Virginia, United States, 23502
      • Virginia Oncology Associates

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm A: Cisplatin Monotherapy; Cisplatin 75 mg/m2 IV infusion over 60 minutes, D1 every 21 days for 4 cycles	Drug: Cisplatin; Cisplatin 75 mg/m2 IV infusion over 60 minutes, D1 every 21 days for 4 cycles
Active Comparator: Arm B: Combination Therapy; Rucaparib 24mg C1,30mg C2-4, D1,2,3 every 21 days for 4 cycles Cisplatin 75 mg/m2 IV infusion over 60 minutes, D1 every 21 days for 4 cycles	Drug: Cisplatin; Cisplatin 75 mg/m2 IV infusion over 60 minutes, D1 every 21 days for 4 cycles; Drug: Rucaparib; Rucaparib 24mg C1,30mg C2-4, D1,2,3 every 21 days for 4 cycles

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
One-year Disease Free Survival	To evaluate 1-year DFS	12 months
Overall Survival	To determine 5-year overall survival	60 months
Pharmacokinetic Data	To collect limited pharmacokinetic data, in patients receiving study drug to compliment ongoing PK analyses in other trials with Rucaparib	12 months
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

Collaborators and Investigators

• Sponsor: Hoosier Cancer Research Network
• Collaborators: Clovis Oncology, Inc.
• Investigators: Study Chair: Kathy D. Miller, M.D., Hoosier Cancer Research Network

Publications and helpful links

General Publications

• 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)
• Kalra M, Tong Y, Jones DR, Walsh T, Danso MA, Ma CX, Silverman P, King MC, Badve SS, Perkins SM, Miller KD. Cisplatin +/- rucaparib after preoperative chemotherapy in patients with triple-negative or BRCA mutated breast cancer. NPJ Breast Cancer. 2021 Mar 22;7(1):29. doi: 10.1038/s41523-021-00240-w.
• 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 Oncology Group BRE09-146. J Clin Oncol 33:5s, 2015 (suppl; abstr 1082)

Helpful Links

• Hoosier Cancer Research Network Homepage

Study record dates

Study Major Dates

• Study Start: February 1, 2010
• Primary Completion (Actual): December 15, 2018
• Study Completion (Actual): December 15, 2018

Study Registration Dates

• First Submitted: February 23, 2010
• First Submitted That Met QC Criteria: February 23, 2010
• First Posted (Estimate): February 24, 2010

Study Record Updates

• Last Update Posted (Actual): February 11, 2020
• Last Update Submitted That Met QC Criteria: February 10, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: breast cancer; PARP inhibitor; Triple negative; PARP inhibition + breast cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Triple Negative Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Poly(ADP-ribose) Polymerase Inhibitors; Cisplatin; Rucaparib
• Other Study ID Numbers: BRE09-146