Clinical trial NCT01074970: PARP Inhibition for Triple Negative Breast Cancer (ER-/PR-/HER2-)With BRCA1/2 Mutations
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Breast Cancer
Keywords: PARP inhibition + breast cancer
breast cancer
PARP inhibitor
Triple negative
Lead sponsor: Hoosier Cancer Research Network
Sponsor class: OTHER
Collaborators: name: Clovis Oncology, Inc.
First posted: 2010-02-24
Enrollment: 135
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Two-year Disease Free Survival
timeFrame: 24 months
Secondary outcomes:
measure: Five-year Disease Free Survival
timeFrame: 60 months
measure: Overall Survival
timeFrame: 60 months
measure: Summarize Grade 2,3, # 4 Toxicities
timeFrame: 12 months
Other outcomes:
Locations:
city: Fullerton
country: United States
facility: St. Jude Heritage Healthcare
state: California
city: Los Angeles
country: United States
facility: University of California Los Angeles
state: California
city: Santa Maria
country: United States
facility: Central Coast Medical Oncology Corporation
state: California
city: Aurora
country: United States
facility: University of Colorado Cancer Center
state: Colorado
city: Hollywood
country: United States
facility: Memorial Cancer Institute Breast Cancer Center
state: Florida
city: Miami
country: United States
facility: University of Miami, Sylvester Comprehensive Cancer Center
state: Florida
city: Fort Wayne
country: United States
facility: Fort Wayne Oncology & Hematology, Inc
state: Indiana
city: Indianapolis
country: United States
facility: Indiana University Melvin and Bren Simon Cancer Center
state: Indiana
city: Indianapolis
country: United States
facility: Community Regional Cancer Center
state: Indiana
city: Lafayette
country: United States
facility: Horizon Oncology Research, Inc./IU Health Arnett
state: Indiana
city: Munster
country: United States
facility: Monroe Medical Associates
state: Indiana
city: South Bend
country: United States
facility: Northern Indiana Cancer Research Consortium
state: Indiana
city: Wyoming
country: United States
facility: Metro Health Cancer Care
state: Michigan
city: Saint Louis
country: United States
facility: Siteman Cancer Center
state: Missouri
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers of Nevada
state: Nevada
city: Cherry Hill
country: United States
facility: The Center for Cancer & Hematologic Disease
state: New Jersey
city: Mount Holly
country: United States
facility: Virtua Health Cancer Program
state: New Jersey
city: Vineland
country: United States
facility: South Jersey Health Care
state: New Jersey
city: Albuquerque
country: United States
facility: Presbyterian Medical Group
state: New Mexico
city: Albuquerque
country: United States
facility: University of New Mexico Cancer Center: Albuquerque
state: New Mexico
city: Asheville
country: United States
facility: HOPE a Women's Cancer Center
state: North Carolina
city: Cleveland
country: United States
facility: Seidman Cancer Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health Sciences University
state: Oregon
city: Harrisburg
country: United States
facility: Pinnacle Health Fox Chase Regional Cancer Center
state: Pennsylvania
city: Sellersville
country: United States
facility: Bux-Mont Oncology Hematology Associates (FCCC) at Grand View Hospital
state: Pennsylvania
city: Memphis
country: United States
facility: The West Clinic
state: Tennessee
city: Norfolk
country: United States
facility: Virginia Oncology Associates
state: Virginia
Study officials:
affiliation: Hoosier Cancer Research Network
name: Kathy D. Miller, M.D.
role: STUDY_CHAIR
References:
citation: 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)
citation: 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^)
citation: 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)