Randomised, Phase II/III, 3 Stage Trial to Evaluate the Safety and Efficacy of the Addition of Olaparib to Platinum-based Neoadjuvant Chemotherapy in Breast Cancer Patients With TNBC and/or gBRCA.
Overview
- Phase
- Phase 2
- Intervention
- Paclitaxel and Carboplatin
- Conditions
- Breast Cancer
- Sponsor
- Cambridge University Hospitals NHS Foundation Trust
- Enrollment
- 780
- Locations
- 29
- Primary Endpoint
- Stage 1 - Number of participants with treatment-related adverse events as assessed by NCI CTCAE v4.03.
- Status
- Recruiting
- Last Updated
- 3 years ago
Overview
Brief Summary
This neoadjuvant trial for patients with TNBC and/or gBRCA breast cancer, aims to investigate the safety and efficacy (improvement in pathological Complete Response at surgery) of concurrent platinum-based chemotherapy with olaparib an inhibitor of the PARP enzyme (PARPi).
Detailed Description
Randomised, phase II/III 3 stage trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in breast cancer patients with TNBC and/or gBRCA. Disease under investigation: Breast Cancer Purpose of clinical trial: To establish if the addition of olaparib to neoadjuvant platinum-based chemotherapy for Triple Negative Breast Cancer (TNBC) and/or germline BRCA (gBRCA) breast cancer is safe and improves efficacy. Trial Design: Open label, randomised, 3-stage Phase II/III Sample Size: Minimum of 780 patients (including at least 220 gBRCA patients equally allocated to the control and the selected research arm). Non Investigational Medicinal Products: Prophylactic granulocyte-colony stimulating factor (G-CSF) to be given as per local practice and 3 cycles of anthracyclines as per local practice. Treatment period: A minimum of 21 weeks of chemotherapy followed by surgery. Procedures: Screening \& enrolment Eligible patients with early breast cancer will be registered and consented for screening: BRCA mutation test Tumour Infiltrating Lymphocytes(TILs) score Cytokeratin 5/6 (CK5/6), Epidermal Growth Factor Receptor (EGFR) +/-, Androgen Receptor (AR) status by Immunohistochemistry (IHC). Standard assessment prior to chemotherapy Standard staging to exclude metastatic disease. When eligibility is confirmed, patients will be randomised via a web-based central system which will allocate each patient a unique randomisation number associated with one of the treatment arms. PARTNERing Pathway - For those patients who still have residual disease after receiving neoadjuvant chemotherapy +/- olaparib there is the opportunity to be screened to a sub-study to receive a further two cycles of chemotherapy consisting of Duralumab and AZD6738. End of Trial: For patients, the end of trial is after the last follow-up visit or contact with the research team planned 10 years after surgery. Procedures for safety monitoring during trial: Pharmacovigilance will be performed by the PARTNER Trial Office. Also, the Trial Management Group and the Independent Data and Safety Monitoring Committee will regularly review the patient safety data. Criteria for discontinuation of trial treatment on safety grounds: Severe toxicity or inter-current illness, requiring cessation in the judgement of patient's clinician. Patient within 4 weeks has not recovered from toxicity to an extent that allows further treatment. Patient unable to comply with trial procedures. Disease progression while on trial treatment. Patient becomes pregnant.
Investigators
Prof. Jean Abraham
Professor
University of Cambridge
Eligibility Criteria
Inclusion Criteria
- •Aged between 16 and
- •Written informed consent, willing and able to comply with the Protocol for the duration of the trial including undergoing treatment and scheduled visits and examinations.
- •Histologically confirmed invasive breast cancer.
- •ER-negative\*, and HER2-negative\*\* breast cancer (TNBC). Patients will be eligible with any PR status but PR expression must be scored.
- •Germline BRCA (gBRCA) mutation positive, HER2 negative, and PgR / ER of any status.
- •T1, T2 or T3 tumours.
- •T4 tumour of any size with direct extension to (a) chest wall or (b) skin. OR Inflammatory carcinoma with tumour of any size. OR
- •Other Locally Advanced Disease:
- •Involvement of ipsilateral large or fixed axillary lymph nodes, or infra or supraclavicular nodes (\>10mm diameter or clinical N2 or N3) and primary breast tumour of any diameter.
- •Involvement of ipsilateral large or fixed axillary lymph nodes, or infra or supraclavicular nodes (\>10mm diameter, or clinical N2 or N3), without a primary breast tumour identified, the presence of breast cancer in a Lymph Node (LN) must be histopathologically confirmed by LN biopsy.
Exclusion Criteria
- •T0 tumour in absence of axillary node \>10mm.
- •TNBC with a non-basal phenotype which strongly expresses Androgen Receptor.
- •Previous or concomitant chemotherapy or biological agents used for the treatment of cancer in the last 5 years.
- •Malignancy within the last 5 years except: adequately treated non-melanoma skin cancer; curatively treated in situ cancer of the cervix; ductal carcinoma in situ (DCIS); Stage 1, grade 1 endometrial carcinoma; or other solid tumours including lymphomas (without bone marrow involvement) curatively treated with no evidence of disease for ≥5 years.
- •Patients with myelodysplastic syndrome/acute myeloid leukaemia.
- •Evidence of distant metastasis apparent prior to randomisation.
- •Patients with uncontrolled seizures.
- •Pre-existing sensory or motor neuropathy of CTCAE v4.03, grade ≥
- •Concomitant use of known potent CYP3A4 inhibitors and inducers. Consider wash-out periods.
- •Pregnant or breast feeding women.
Arms & Interventions
Control
4 cycles of: Paclitaxel 80mg/m2 Day 1, 8 \& 15, every 3 weeks, Carboplatin area under the curve (AUC) 5 Day 1, every 3 weeks
Intervention: Paclitaxel and Carboplatin
Research 1
4 cycles of: Paclitaxel 80mg/m2 on Days 1, 8 \& 15 every 3 weeks, Carboplatin AUC 5 Day 1, every 3 weeks, Olaparib oral 150mg twice daily, Day -2 to Day 10 every 3 weeks
Intervention: Olaparib
Research 1
4 cycles of: Paclitaxel 80mg/m2 on Days 1, 8 \& 15 every 3 weeks, Carboplatin AUC 5 Day 1, every 3 weeks, Olaparib oral 150mg twice daily, Day -2 to Day 10 every 3 weeks
Intervention: Paclitaxel and Carboplatin
Research 2
4 cycles of: Paclitaxel 80mg/m2 on Days 1, 8 \& 15 every 3 weeks, Carboplatin AUC 5 Day 1, every 3 weeks, Olaparib oral 150mg twice daily, Day 3 to Day 14 every 3 weeks
Intervention: Olaparib
Research 2
4 cycles of: Paclitaxel 80mg/m2 on Days 1, 8 \& 15 every 3 weeks, Carboplatin AUC 5 Day 1, every 3 weeks, Olaparib oral 150mg twice daily, Day 3 to Day 14 every 3 weeks
Intervention: Paclitaxel and Carboplatin
Outcomes
Primary Outcomes
Stage 1 - Number of participants with treatment-related adverse events as assessed by NCI CTCAE v4.03.
Time Frame: 1 year - when first 25 patients in each research arm who had received at least one dose of Olaparib protocol treatment have completed their protocol treatment.
Primary outcome measure - safety of the addition of olaparib to three weekly carboplatin/weekly paclitaxel chemotherapy.
Stage 2 - pCR rate and completion rate of Olaparib treatment as per protocol.
Time Frame: 15 months - when pathological complete response (pCR) is available for 53 patients in each of two research arms.
Primary outcome measure - pCR in each of the two research arms. At the end of stage 2, one of the research treatments will be dropped using the 'pick the winner' method.
Stage 3 - Efficacy analysis based on pCR at surgery. To be assessed by central review of pathology reports.
Time Frame: 5.5 years - October 2021 approx.
Primary outcome measure - pCR at surgery after neoadjuvant treatment. pCR rates after neoadjuvant chemotherapy +/- olaparib, defined as no residual invasive carcinoma within the breast (Ductal Carcinoma in situ permitted) AND no evidence of metastatic disease within the lymph nodes.
Secondary Outcomes
- pCR in breast alone(Up to 2 years after last patient is randomised)
- pCR at surgery - assessed by review of histopathology slides(Up to 2 years after last patient randomised)
- PARTNERing Pathway(2 cycles (each lasting 28 days))
- Distant disease-free survival(Up to 10 years after last patient is randomised)
- Residual Cancer Burden (RCB)(Up to 10 years after last patient is randomised)
- Breast cancer specific survival (BCSS)(Up to 10 years after last patient is randomised)
- Overall survival (OS)(Up to 10 years after last patient is randomised)
- Relapse-Free Survival (RFS)(Up to 10 years after last patient is randomised)
- Local recurrence-free survival(Up to 10 years after last patient is randomised)
- Time to second cancer (TTSC)(Up to 10 years after last patient is randomised)
- Treatment related toxicities - as assessed by CTCAE v4.03(Up to 10 years after last patient is randomised)
- Radiological response - as assessed by radiological response criteria as per RECIST v1.1(Up to 2 years after last patient is randomised)
- Quality of Life Questionnaire(Up to 10 years after last patient is randomised)