BRCA1 Mutation, BRCA2 Mutation, BRCA-Associated Breast Carcinoma, BRCA Mutation, Breast Cancer, Breast Neoplasms, Triple Negative Breast Cancer, Triple Negative Breast Neoplasms
Conditions
Keywords
BRCA1 protein, BRCA2 protein
Brief summary
This is a Phase II, single-arm, open label study to evaluate Olaparib plus Pembrolizumab following platinum-based chemotherapy plus Pembrolizumab as neoadjuvant therapy for germline BRCA (gBRCA) 1/2 mutated triple negative breast cancer (TNBC). Pembrolizumab in combination with weekly paclitaxel and carboplatin (treatment 1) is followed by Pembrolizumab in combination with Olaparib (treatment 2) in neoadjuvant setting and Pembrolizumab in combination with Olaparib in adjuvant setting will be studied
Interventions
DRUGPembrolizumab
200 mg fixed dose, IV, every 3 weeks (Q3W), on Days 1 of Cycles 1-4
DRUGPaclitaxel
80 mg/m2, IV, weekly, on Days 1, 8, 15 of Cycles 1-4
DRUGCarboplatin
Area under the curve (AUC 1.5), intravenously (IV), weekly, on Days 1, 8, 15 of Cycles 1-4
DRUGOlaparib
300 mg BID (twice daily) orally
PROCEDUREDefinitive Surgery
Each subject will undergo definitive surgery 3-6 weeks after conclusion of the last cycle of the neoadjuvant treatment.
Sponsors
Merck Sharp & Dohme LLC
Okayama University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male/female subjects who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of invasive breast cancer * Have histologically confirmed TNBC, as defined by the most recent ASCO/CAP guidelines. * Confirmed germline BRCA 1/2 mutated. * Have previously untreated locally advanced non-metastatic (M0) TNBC defined as the following combined primary tumor (T) and regional lymph node (N) staging per AJCC for breast cancer staging criteria version 7 as assessed by the investigator based on radiological and/or clinical assessment: 1. T1c, N1-N2 2. T2, N0-N2 3. T3, N0-N2 4. T4a-d, N0-N2 * It has been confirmed that there is no distant metastasis to each organ by the following tests. Chest: Contrast CT or FDG-PET/CT Abdominal: Contract CT\* or FDG-PET/CT Bone: Bone scintigraphy or FDG-PET/CT Brain: In the case of no central nervous system symptoms, examination for brain metastasis is not required. * The subject (or legally acceptable representative if applicable) provides written informed consent for the trial. * Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. * Have adequate organ function as defined in the protocol. Specimens must be collected within 10 days prior to the start of study treatment.
Exclusion criteria
* Subjects who has a positive urine pregnancy test within 72 hours prior to registration * Has diagnosed as inflammatory breast cancer. * Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor . * Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. * Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention. * Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. * Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years. * Has severe hypersensitivity (≥Grade 3) to pembrolizumab and investigational drugs used in this study and/or any of their excipients. * Has active autoimmune disease that has required systemic treatment in the past 2 years * Has a history of (non-infectious) pneumonitis/interstitial lung disease . * Has an active infection requiring systemic therapy. * Has a known history of Human Immunodeficiency Virus (HIV) infection. * Has a known history of Hepatitis B (defined as Hepatitis B surface antigen \[HbsAg\] reactive) or known active Hepatitis C virus (defined as HCV RNA \[qualitative\] is detected) infection. * Has a known history of active TB (Bacillus Tuberculosis). * Has a history or current evidence of any condition, therapy, or laboratory abnormality. * Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. * Is pregnant or breastfeeding, or expecting to conceive or father children. * Has had an allogenic tissue/solid organ transplant. * Has received pre-treatment with Olaparib or other PARP inhibitors. * Has significant cardiovascular disease * Has a resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible cardiac conditions. * Subject has myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or with features suggestive of MDS/AML. * Subject received colony-stimulating factors within 28 days prior to the first dose of study intervention. * Subject is considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. * Is either unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption. * Is, in the judgement of the investigator, unlikely to comply with the study procedures, restrictions, and requirements of the study. * Is currently receiving either strong or moderate inhibitors of cytochrome P450 (CYP)3A4 that cannot be discontinued for the duration of the study. * Is currently receiving either strong or moderate inducers of CYP3A4 that cannot be discontinued for the duration of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pathological Complete Response (pCR) Rate (ypT0/TisypN0) | From 27 weeks up to 30 weeks | Pathological complete response rate (ypT0/TisypN0) is defined as the proportion of subjects without residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy by AJCC staging criteria (7th edition) assessed by the local pathologist at the time of definitive surgery. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pathological Complete Response (pCR) Rate (ypT0/is) | From 27 weeks up to 30 weeks | Pathological complete response rate (ypT0/is) is defined as the proportion of subjects without residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen regardless of regional lymph nodes status following completion of neoadjuvant systemic therapy by AJCC staging criteria (7th edition) assessed by the local pathologist at the time of definitive surgery. |
| Pathological Complete Response (pCR) Rate (ypT0/Tis ypN0) | From 27 weeks Up to 30 weeks | Pathological complete response rate (ypT0/TisypN0) is defined as the proportion of subjects without residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy by AJCC staging criteria (7th edition) assessed by the local pathologist at the time of definitive surgery. |
| Three-Year Overall Survival (3-year OS) | Up to 3 years | The Proportion of Three Year-Overall Survival (3y-OS) is defined as the proportion of survival subjects without death due to any cause at 3 years from registration. Subjects without documented death at the time of the analysis will be censored at the date of the last follow-up. |
| Residual Cancer Burden 0/1 | From 27 weeks up to 30 weeks | Residual Cancer Burden (RCB) 0/1 rate is defined as the proportion of subjects on evaluation from routine pathologic sections of the primary breast tumor and the regional lymph nodes after the completion of neoadjuvant therapy assessed by the local pathologist at the time of definitive surgery. Six variables are included in a calculation formula. The calculated RCB index value can also be categorized as one of four RCB classes (0 - 3). The calculation formula and detailed description can be found at a dedicated Web site: http://www.mdanderson.org/breastcancer\_RCB. |
| Three-Year Disease Free Survival (3-year DFS) | Up to 3 years | The Proportion of Three-Year Disease Free Survival (3y-DFS) is defined as the proportion of survival subjects without metastatic disease and secondary malignancy at 3 years from registration. Subjects without documented metastatic disease and secondary malignancy at the time of the analysis will be censored at the date of the last follow-up. |
| AEs/SAEs and treatment discontinuation due to AEs/SAEs | Up to 3 years | Safety measurements are the incidence of, causality of, and outcome of AEs/SAEs; and changes in vital sign measurements and laboratory values. |
| Three-Year Distant Metastatic Free Survival (3-year DMFS) | Up to 3 years | The Proportion of Three-Year Distant Metastatic Free Survival (3y-DMFS) is defined as the proportion of survival subjects without distant metastatic disease at 3 years from registration. Subjects without documented distant metastatic disease at the time of the analysis will be censored at the date of the last follow-up. |
Countries
Japan
Contacts
Primary ContactYuko Takahashi, MD., PhD.
Backup ContactHironobu TAN, PhD.
Outcome results
None listed