Breast Cancer
Conditions
Keywords
PARP inhibition + breast cancer, breast cancer, PARP inhibitor, Triple negative
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.
Interventions
DRUGCisplatin
Cisplatin 75 mg/m2 IV infusion over 60 minutes, D1 every 21 days for 4 cycles
DRUGRucaparib
Rucaparib 24mg C1,30mg C2-4, D1,2,3 every 21 days for 4 cycles
Sponsors
Clovis Oncology, Inc.
Hoosier Cancer Research Network
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Two-year Disease Free Survival | 24 months | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Five-year Disease Free Survival | 60 months | To evaluate 5-year 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 |
| Overall Survival | 60 months | To determine 5-year overall survival |
| Summarize Grade 2,3, # 4 Toxicities | 12 months | To characterize the side effects and tolerability of cisplatin and cisplatin plus Rucaparib in patients with residual disease following preoperative chemotherapy by summarizing Grade 2,3, # 4 toxicities according to CTCAE v3.0 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A: Cisplatin Monotherapy Cisplatin 75 mg/m2 IV infusion over 60 minutes, D1 every 21 days for 4 cycles | 65 |
| Arm B: Combination Therapy Cisplatin 75 mg/m2 IV infusion over 60 minutes, D1 every 21 days for 4 cycles
Rucaparib 24mg C1,30mg C2-4, D1,2,3 every 21 days for 4 cycles | 57 |
| Safety Cohort 1: Rucaparib 24 mg With Cisplatin Cisplatin 75 mg/m2 IV infusion over 60 minutes, D1 every 21 days for 4 cycles
Rucaparib 16mg C1,30mg C2-4, D1,2,3 every 21 days for 4 cycles | 7 |
| Safety Cohort 2: Rucaparib 30 mg With Cisplatin Cisplatin 75 mg/m2 IV infusion over 60 minutes, D1 every 21 days for 4 cycles
Rucaparib 24mg C1,30mg C2-4, D1,2,3 every 21 days for 4 cycles | 6 |
| Total | 135 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 4 | 3 |
| Overall Study | Disease progression during treatment | 3 | 1 | 2 | 9 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 0 |
| Overall Study | Never Treated | 0 | 0 | 8 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 6 | 4 |
Baseline characteristics
| Characteristic | Arm B: Combination Therapy | Total | Safety Cohort 2: Rucaparib 30 mg With Cisplatin | Arm A: Cisplatin Monotherapy | Safety Cohort 1: Rucaparib 24 mg With Cisplatin |
|---|---|---|---|---|---|
| Age, Continuous | 47 years | 47 years | 49 years | 48 years | 46 years |
| BRCA2 Status Known at Entry No | 55 Participants | 131 Participants | 6 Participants | 63 Participants | 7 Participants |
| BRCA2 Status Known at Entry Yes | 2 Participants | 4 Participants | 0 Participants | 2 Participants | 0 Participants |
| ECOG Performance Score ECOG PS 0 | 49 Participants | 104 Participants | 3 Participants | 52 Participants | 0 Participants |
| ECOG Performance Score ECOG PS 1 | 8 Participants | 24 Participants | 3 Participants | 13 Participants | 0 Participants |
| ECOG Performance Score Not Collected or Available | 0 Participants | 7 Participants | 0 Participants | 0 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 9 Participants | 0 Participants | 6 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 48 Participants | 117 Participants | 5 Participants | 57 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 6 Participants | 9 Participants | 1 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 4 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 26 Participants | 1 Participants | 13 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 5 Participants | 0 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) White | 41 Participants | 100 Participants | 5 Participants | 49 Participants | 5 Participants |
| Region of Enrollment United States | 57 participants | 135 participants | 6 participants | 65 participants | 7 participants |
| Sex: Female, Male Female | 57 Participants | 135 Participants | 6 Participants | 65 Participants | 7 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 26 / 66 | 25 / 63 | 5 / 7 |
| other Total, other adverse events | 56 / 65 | 61 / 63 | 7 / 7 |
| serious Total, serious adverse events | 1 / 65 | 6 / 63 | 1 / 7 |
Outcome results
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
Time frame: 24 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Cisplatin Monotherapy | Two-year Disease Free Survival | 54.2 percentage of participants |
| Arm B: Combination Therapy | Two-year Disease Free Survival | 64.1 percentage of participants |
Secondary
Five-year Disease Free Survival
To evaluate 5-year 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
Time frame: 60 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Cisplatin Monotherapy | Five-year Disease Free Survival | 38.3 percentage of participants |
| Arm B: Combination Therapy | Five-year Disease Free Survival | 50.1 percentage of participants |
Secondary
Overall Survival
To determine 5-year overall survival
Time frame: 60 months
Population: Data for this secondary objective was not collected or analyzed
Secondary
Summarize Grade 2,3, # 4 Toxicities
To characterize the side effects and tolerability of cisplatin and cisplatin plus Rucaparib in patients with residual disease following preoperative chemotherapy by summarizing Grade 2,3, # 4 toxicities according to CTCAE v3.0
Time frame: 12 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: Cisplatin Monotherapy | Summarize Grade 2,3, # 4 Toxicities | Vomiting Gr 2 | 5 participants |
| Arm A: Cisplatin Monotherapy | Summarize Grade 2,3, # 4 Toxicities | Neutropenia Gr 2 | 16 participants |
| Arm A: Cisplatin Monotherapy | Summarize Grade 2,3, # 4 Toxicities | Neutropenia Gr 3 | 11 participants |
| Arm A: Cisplatin Monotherapy | Summarize Grade 2,3, # 4 Toxicities | Neutropenia Gr 4 | 0 participants |
| Arm A: Cisplatin Monotherapy | Summarize Grade 2,3, # 4 Toxicities | Neutropenic fever Gr 2 | 1 participants |
| Arm A: Cisplatin Monotherapy | Summarize Grade 2,3, # 4 Toxicities | Anemia Gr 2 | 5 participants |
| Arm A: Cisplatin Monotherapy | Summarize Grade 2,3, # 4 Toxicities | Thrombocytopenia Gr 2 | 2 participants |
| Arm A: Cisplatin Monotherapy | Summarize Grade 2,3, # 4 Toxicities | Thrombocytopenia Gr 3 | 0 participants |
| Arm A: Cisplatin Monotherapy | Summarize Grade 2,3, # 4 Toxicities | Nausea Gr 2 | 13 participants |
| Arm A: Cisplatin Monotherapy | Summarize Grade 2,3, # 4 Toxicities | Nausea Gr 3 | 0 participants |
| Arm A: Cisplatin Monotherapy | Summarize Grade 2,3, # 4 Toxicities | Anorexia Gr 2 | 3 participants |
| Arm A: Cisplatin Monotherapy | Summarize Grade 2,3, # 4 Toxicities | Fatigue Gr 2 | 14 participants |
| Arm A: Cisplatin Monotherapy | Summarize Grade 2,3, # 4 Toxicities | Fatigue Gr 3 | 3 participants |
| Arm A: Cisplatin Monotherapy | Summarize Grade 2,3, # 4 Toxicities | Fatigue Gr 4 | 1 participants |
| Arm A: Cisplatin Monotherapy | Summarize Grade 2,3, # 4 Toxicities | Tinnitus Gr 2 | 16 participants |
| Arm A: Cisplatin Monotherapy | Summarize Grade 2,3, # 4 Toxicities | Tinnitus Gr 3 | 1 participants |
| Arm A: Cisplatin Monotherapy | Summarize Grade 2,3, # 4 Toxicities | Nephropathy Gr 2 | 1 participants |
| Arm A: Cisplatin Monotherapy | Summarize Grade 2,3, # 4 Toxicities | Neuropathy Gr 2 | 1 participants |
| Arm A: Cisplatin Monotherapy | Summarize Grade 2,3, # 4 Toxicities | Neuropathy Gr 3 | 0 participants |
| Arm A: Cisplatin Monotherapy | Summarize Grade 2,3, # 4 Toxicities | Dysguesia Gr 2 | 3 participants |
| Arm A: Cisplatin Monotherapy | Summarize Grade 2,3, # 4 Toxicities | Vomiting Gr 3 | 0 participants |
| Arm A: Cisplatin Monotherapy | Summarize Grade 2,3, # 4 Toxicities | Hepatic abnormality Gr 3 | 1 participants |
| Arm A: Cisplatin Monotherapy | Summarize Grade 2,3, # 4 Toxicities | Hepatic abnormality Gr 4 | 1 participants |
| Arm A: Cisplatin Monotherapy | Summarize Grade 2,3, # 4 Toxicities | Rash Gr 2 | 2 participants |
| Arm A: Cisplatin Monotherapy | Summarize Grade 2,3, # 4 Toxicities | Headache Gr 2 | 2 participants |
| Arm B: Combination Therapy | Summarize Grade 2,3, # 4 Toxicities | Vomiting Gr 2 | 7 participants |
| Arm B: Combination Therapy | Summarize Grade 2,3, # 4 Toxicities | Fatigue Gr 4 | 0 participants |
| Arm B: Combination Therapy | Summarize Grade 2,3, # 4 Toxicities | Neutropenia Gr 2 | 13 participants |
| Arm B: Combination Therapy | Summarize Grade 2,3, # 4 Toxicities | Headache Gr 2 | 5 participants |
| Arm B: Combination Therapy | Summarize Grade 2,3, # 4 Toxicities | Neutropenia Gr 3 | 16 participants |
| Arm B: Combination Therapy | Summarize Grade 2,3, # 4 Toxicities | Tinnitus Gr 2 | 12 participants |
| Arm B: Combination Therapy | Summarize Grade 2,3, # 4 Toxicities | Neutropenia Gr 4 | 1 participants |
| Arm B: Combination Therapy | Summarize Grade 2,3, # 4 Toxicities | Vomiting Gr 3 | 3 participants |
| Arm B: Combination Therapy | Summarize Grade 2,3, # 4 Toxicities | Neutropenic fever Gr 2 | 1 participants |
| Arm B: Combination Therapy | Summarize Grade 2,3, # 4 Toxicities | Tinnitus Gr 3 | 1 participants |
| Arm B: Combination Therapy | Summarize Grade 2,3, # 4 Toxicities | Anemia Gr 2 | 7 participants |
| Arm B: Combination Therapy | Summarize Grade 2,3, # 4 Toxicities | Rash Gr 2 | 2 participants |
| Arm B: Combination Therapy | Summarize Grade 2,3, # 4 Toxicities | Thrombocytopenia Gr 2 | 0 participants |
| Arm B: Combination Therapy | Summarize Grade 2,3, # 4 Toxicities | Nephropathy Gr 2 | 2 participants |
| Arm B: Combination Therapy | Summarize Grade 2,3, # 4 Toxicities | Thrombocytopenia Gr 3 | 2 participants |
| Arm B: Combination Therapy | Summarize Grade 2,3, # 4 Toxicities | Hepatic abnormality Gr 3 | 3 participants |
| Arm B: Combination Therapy | Summarize Grade 2,3, # 4 Toxicities | Nausea Gr 2 | 16 participants |
| Arm B: Combination Therapy | Summarize Grade 2,3, # 4 Toxicities | Neuropathy Gr 2 | 3 participants |
| Arm B: Combination Therapy | Summarize Grade 2,3, # 4 Toxicities | Nausea Gr 3 | 3 participants |
| Arm B: Combination Therapy | Summarize Grade 2,3, # 4 Toxicities | Dysguesia Gr 2 | 1 participants |
| Arm B: Combination Therapy | Summarize Grade 2,3, # 4 Toxicities | Anorexia Gr 2 | 7 participants |
| Arm B: Combination Therapy | Summarize Grade 2,3, # 4 Toxicities | Neuropathy Gr 3 | 1 participants |
| Arm B: Combination Therapy | Summarize Grade 2,3, # 4 Toxicities | Fatigue Gr 2 | 11 participants |
| Arm B: Combination Therapy | Summarize Grade 2,3, # 4 Toxicities | Hepatic abnormality Gr 4 | 0 participants |
| Arm B: Combination Therapy | Summarize Grade 2,3, # 4 Toxicities | Fatigue Gr 3 | 6 participants |