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).
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.
Patients will self-administer Olaparib by mouth. Olaparib tablets should be taken twice daily at the same time each day approximately 12 hours apart.
Paclitaxel I.V. 80mg/m2 in 0.9% sodium chloride 500ml or according to local practice, will be given over 60 minutes on days 1, 8 \& 15, every 3 weeks for 4 cycles. Carboplatin I.V. AUC5 in 5% dextrose 500ml or according to local practice, over 30-60minutes on day 1 every 3 weeks for 4 cycles.
Stage 1 - Number of participants with treatment-related adverse events as assessed by NCI CTCAE v4.03.
Primary outcome measure - safety of the addition of olaparib to three weekly carboplatin/weekly paclitaxel chemotherapy.
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.
Stage 2 - pCR rate and completion rate of Olaparib treatment as per protocol.
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.
Time frame: 15 months - when pathological complete response (pCR) is available for 53 patients in each of two research arms.
Stage 3 - Efficacy analysis based on pCR at surgery. To be assessed by central review of pathology reports.
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.
Time frame: 5.5 years - October 2021 approx.
pCR at surgery - assessed by review of histopathology slides
pCR at surgery assessed by central pathology review of the diagnosis and surgery slides.
Time frame: Up to 2 years after last patient randomised
PARTNERing Pathway
For those patients who still have residual disease after receiving neoadjuvant chemotherapy there is the opportunity to receive a further two cycles of Duralumab and AZD6738. Durvalumab I.V will be administered on cycle 1, day 1 and cycle 2, day 1. AZD6738 will be self administered by patients by mouth twice a day for 7 days beginning on cycle 1, day 22 and cycle 2, day 22.
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Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
780
Cambridge University Hospitals NHS Foundation Trust & the University of Cambridge
Cambridge, Cambridgeshire, United Kingdom
RECRUITINGQueen's Hospital
Burton-on-Trent, Derby, United Kingdom
RECRUITINGThe Christie
Manchester, Lancs, United Kingdom
RECRUITINGPinderfields General Hospital
Wakefield, Yorkshire, United Kingdom
RECRUITINGUniversity Hospital Ayr
Ayr, United Kingdom
RECRUITINGBasingstoke and North Hampshire Hospital
Basingstoke, United Kingdom
RECRUITINGBedford General Hospital
Bedford, United Kingdom
RECRUITINGRoyal Bournemouth Hospital
Bournemouth, United Kingdom
RECRUITINGBristol Haematology & Cancer Centre
Bristol, United Kingdom
RECRUITINGWest Suffolk Hospital
Bury St Edmunds, United Kingdom
RECRUITING...and 20 more locations
Time frame: 2 cycles (each lasting 28 days)
Relapse-Free Survival (RFS)
Relapse Free Survival (RFS), calculated from date of randomisation to date of first relapse or date of death from all causes, whichever occurs first.
Time frame: Up to 10 years after last patient is randomised
Breast cancer specific survival (BCSS)
Breast cancer specific survival (BCSS), calculated from date of randomisation to date of death from breast cancer.
Time frame: Up to 10 years after last patient is randomised
Distant disease-free survival
Distant disease-free survival, calculated from date of randomisation to date of the first distant disease relapse or date of death from all causes, whichever occurs first.
Time frame: Up to 10 years after last patient is randomised
Local recurrence-free survival
Local recurrence-free survival, calculated from date of randomisation to date of the first local recurrence or date of death from all causes, whichever occurs first.
Time frame: Up to 10 years after last patient is randomised
Overall survival (OS)
Overall survival (OS), calculated from date of randomisation to date of death from all causes.
Time frame: Up to 10 years after last patient is randomised
Time to second cancer (TTSC)
Time to second cancer (TTSC), calculated from the date of randomisation to the date of diagnosis of second cancer.
Time frame: Up to 10 years after last patient is randomised
pCR in breast alone
pCR in breast alone
Time frame: Up to 2 years after last patient is randomised
Residual Cancer Burden (RCB)
Residual Cancer Burden (RCB) I-III will be assessed by central pathology review.
Time frame: Up to 10 years after last patient is randomised
Radiological response - as assessed by radiological response criteria as per RECIST v1.1
Radiological response after 4th and final cycles
Time frame: Up to 2 years after last patient is randomised
Treatment related toxicities - as assessed by CTCAE v4.03
Treatment related toxicities
Time frame: Up to 10 years after last patient is randomised
Quality of Life Questionnaire
Quality of Life (sub-study). Questionnaire to be completed by patient prior to start of treatment, following cycle 4 and cycle 7, following surgery and then annually for two years to document long-term effects on quality of life.
Time frame: Up to 10 years after last patient is randomised