A Randomized Phase II Trial to Assess the Efficacy of Paclitaxel and Olaparib in Comparison to Paclitaxel / Carboplatin Followed by Epirubicin/Cyclophosphamide as Neoadjuvant Chemotherapy in Patients With HER2-negative Early Breast Cancer and Homologous Recombination Deficiency (HRD Patients With Deleterious BRCA1/2 Tumor or Germline Mutation and/or HRD Score High)
Overview
- Phase
- Phase 2
- Intervention
- PwCb
- Conditions
- Breast Cancer
- Sponsor
- German Breast Group
- Enrollment
- 107
- Locations
- 12
- Primary Endpoint
- response by pCR =ypT0/is ypN0
- Status
- Completed
- Last Updated
- 6 years ago
Overview
Brief Summary
This is a multicenter, prospective, randomized, open-label phase II study evaluating the efficacy and safety of PO→EC as neoadjuvant treatment of operable and locally advanced breast cancer in patients with HR deficiency. Patients will be randomized to receive
- paclitaxel 80 mg/m² iv weekly in combination with olaparib tablets 100 mg (4X25mg) twice daily for 12 weeks (65 patients) or
- paclitaxel 80 mg/m² iv weekly in combination with carboplatin AUC 2 iv weekly for 12 weeks (37 patients) both followed by 4 cycles of epirubicin 90 mg/m² and cyclophosphamide 600 mg/m² (EC) either every 3 or every 2 weeks followed by surgery.
The control arm was chosen to allow direct comparison with one of the currently considered standard of care regimen.
Detailed Description
The efficacy of olaparib in germline HRD score high with or without BRCA 1/2 mutation carriers with breast cancer is not well described * The efficacy and safety of olaparib included in a standard of care regimen like paclitaxel weekly followed by epirubicin and cyclophosphamide (Pw--\>EC) is unknown * Carboplatin increased the pCR rate in patients with triple-negative breast cancer (TNBC) in two randomized phase II neoadjuvant studies when added to an anthracycline, cyclophosphamide and paclitaxel (GeparSixto, CALBG 40603). pCR rates were even higher in patients with germline BRCA 1 or 2 mutations (ypT0/is ypN0 65%) and with HRD score high (ypT0/is ypN0 63%). * The TNT study showed a doubling in response rate for patients receiving carboplatin vs docetaxel in patients with germline BRCA 1 or 2 mutations. * There is a high correlation between tumor and germline BRCA 1/2 mutations. * Data from Geparsixto study showed that triple negative breast patients have an HR deficiency in about 70% (67% have a high HRD and 30% have a tBRCA mutation) * About 5% of tBRCA patients have a low HRD score * gBRCA2 patients are older when diagnosed and are more likely to have an HRpos tumor. * The GeparOLA study aims to support the decision for a phase III study exploring the addition of olaparib to a Pw--\>EC schedule by providing an estimate on the pCR rate in the targeted population but also by providing estimate comparison to paclitaxel and carboplatin followed by epirubicin and cyclophosphamide (PCb--\>EC) as carboplatin is more and more considered a standard option of care in HR deficient patients (tBRCA 1/2 mutations and/or HRD score high).
Investigators
Eligibility Criteria
Inclusion Criteria
- •Written informed consent for all study specific procedures according to local regulatory requirements prior to beginning specific protocol procedures.
- •Complete baseline documentation must be sent to GBG Forschungs GmbH.
- •Unilateral or bilateral primary carcinoma of the breast, confirmed histologically by core biopsy. Fine-needle aspiration alone is not sufficient. Incisional biopsy is not allowed. In case of bilateral cancer, the investigator has to decide prospectively which side will be evaluated for the primary endpoint.
- •Centrally confirmed negative HER2-status. Centrally confirmed estrogen and progesterone receptor, and Ki-67 status detected on core biopsy. ER/PR positive is defined as ≥1% stained cells and HER2-positive is defined as IHC 3+ or in-situ hybridisation (ISH) ratio ≥2.
- •Formalin-fixed, paraffin-embedded (FFPE) breast tissue from core biopsy has therefore to be sent to the Dept. of Pathology at the Charité, Berlin prior to randomization.
- •Centrally confirmed tumor Homologous Recombinant Deficiency score (tBRCA positive/mutated and/or HRD high). Patients with known gBRCA and/or tBRCA status can be enrolled prior to the central test results available.
- •Tumor lesion in the breast with a palpable size of \> 2 cm or a sonographical size of \>1 cm in maximum diameter. If the tumor is not detectable with sonography mammography assessment can be considered. The lesion has to be measurable in two dimensions, preferably by sonography. In case of inflammatory disease, the extent of inflammation can be used as measurable lesion.
- •Patients must be in the following stages of disease:
- •cT2 - cT4a-d or
- •cT1c and cN+ or cT1c and pNSLN+ or
Exclusion Criteria
- •Prior chemotherapy for any malignancy within 5 years.
- •Prior radiation therapy for breast cancer within 5 years.
- •Pregnant or lactating patients. Patients of childbearing potential must implement adequate non-hormonal contraceptive measures (barrier methods, intrauterine contraceptive devices, sterilization) during study treatment.
- •Inadequate general condition (not fit for anthracycline-taxane-targeted agents-based chemotherapy).
- •Previous malignant disease without being disease-free for less than 5 years (except CIS of the cervix and non-melanomatous skin cancer).
- •Known or suspected congestive heart failure (\>NYHA I) and / or coronary heart disease, angina pectoris requiring antianginal medication, previous history of myocardial infarction, evidence of transmural infarction on ECG, uncontrolled or poorly controlled arterial hypertension (i.e. BP \>140 / 90 mm Hg under treatment with two antihypertensive drugs), rhythm abnormalities requiring permanent treatment, clinically significant valvular heart disease.
- •History of significant neurological or psychiatric disorders including psychotic disorders, dementia or seizures that would prohibit the understanding and giving of informed consent.
- •Patients currently in an institution by order of jurisdictional or governmental grounds.
- •Currently active infection.
- •Definite contraindications for the use of corticosteroids.
Arms & Interventions
Paclitaxel with Carboplatin (PwCb)
paclitaxel 80 mg/m² iv weekly in combination with carboplatin AUC 2 iv weekly for 12 weeks (37 patients) followed by 4 cycles of epirubicin 90 mg/m² and cyclophosphamide 600 mg/m² (EC) either every 3 or every 2 weeks followed by surgery.
Intervention: PwCb
Paclitaxel with Carboplatin (PwCb)
paclitaxel 80 mg/m² iv weekly in combination with carboplatin AUC 2 iv weekly for 12 weeks (37 patients) followed by 4 cycles of epirubicin 90 mg/m² and cyclophosphamide 600 mg/m² (EC) either every 3 or every 2 weeks followed by surgery.
Intervention: EC
Paclitaxel with Carboplatin (PwCb)
paclitaxel 80 mg/m² iv weekly in combination with carboplatin AUC 2 iv weekly for 12 weeks (37 patients) followed by 4 cycles of epirubicin 90 mg/m² and cyclophosphamide 600 mg/m² (EC) either every 3 or every 2 weeks followed by surgery.
Intervention: Surgery after neoadjuvant Therapy
Paclitaxel with Carboplatin (PwCb)
paclitaxel 80 mg/m² iv weekly in combination with carboplatin AUC 2 iv weekly for 12 weeks (37 patients) followed by 4 cycles of epirubicin 90 mg/m² and cyclophosphamide 600 mg/m² (EC) either every 3 or every 2 weeks followed by surgery.
Intervention: Stratification
Paclitaxel with Olaparib (PwO)
paclitaxel 80 mg/m² iv weekly in combination with olaparib tablets 100 mg twice daily for 12 weeks (65 patients) followed by 4 cycles of epirubicin 90 mg/m² and cyclophosphamide 600 mg/m² (EC) either every 3 or every 2 weeks followed by surgery.
Intervention: PwO
Paclitaxel with Olaparib (PwO)
paclitaxel 80 mg/m² iv weekly in combination with olaparib tablets 100 mg twice daily for 12 weeks (65 patients) followed by 4 cycles of epirubicin 90 mg/m² and cyclophosphamide 600 mg/m² (EC) either every 3 or every 2 weeks followed by surgery.
Intervention: EC
Paclitaxel with Olaparib (PwO)
paclitaxel 80 mg/m² iv weekly in combination with olaparib tablets 100 mg twice daily for 12 weeks (65 patients) followed by 4 cycles of epirubicin 90 mg/m² and cyclophosphamide 600 mg/m² (EC) either every 3 or every 2 weeks followed by surgery.
Intervention: Surgery after neoadjuvant Therapy
Paclitaxel with Olaparib (PwO)
paclitaxel 80 mg/m² iv weekly in combination with olaparib tablets 100 mg twice daily for 12 weeks (65 patients) followed by 4 cycles of epirubicin 90 mg/m² and cyclophosphamide 600 mg/m² (EC) either every 3 or every 2 weeks followed by surgery.
Intervention: Stratification
Outcomes
Primary Outcomes
response by pCR =ypT0/is ypN0
Time Frame: 24 weeks
Assess the efficacy of olaparib in HER2-negative early Breast Cancer and HRD (BRCA 1/2 mutations and/or HRD positive). Pathological complete response of breast and lymph nodes (ypT0/is ypN0) defined as no microscopic evidence of residual invasive viable tumor cells in all resected specimens of the breast and axilla. Pathological response will be assessed considering all removed breast and lymphatic tissues from all surgeries.
Secondary Outcomes
- response by pCR =ypT0/is ypN0(12 weeks)
- Breast Conservation rate(24 weeks)
- Response rate by sono and/or mammo(24 weeks)
- response by pCR =ypT0/is ypN0 in stratified subgroups(24 weeks)
- response by pCR according to other definitions(24 weeks)
- response by pCR in HRD high versus tBRCA(24 weeks)
- Toxicity of treatment(24 weeks)