Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Breast Neoplasms

Triple Negative Breast Neoplasms

Breast Diseases

Skin Diseases

Antineoplastic Agents

All Drugs and Chemicals

Paclitaxel

Carboplatin

Albumin-Bound Paclitaxel

Olaparib

Poly(ADP-ribose) Polymerase Inhibitors

Tubulin Modulators

Antimitotic Agents

Enzyme Inhibitors

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

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

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

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.

Paclitaxel and Carboplatin

CCTC A Cambridge Cancer Trials Centre

CCTC Cambridge Cancer Trials Centre

Jean Abraham

First Contact

Mojca Persic

Anne Armstrong

Sreedevi Kumar

Lucy Scott

Sanjay Raj

Shahzeena Aslam

Maria Cidon

Jeremy Braybrooke

Margaret Moody

Annabel Borley

MB Mukesh

Devanshi Tripathi

Cheryl Palmer

Ramachandran Venkitaraman

Mark Churn

Rebecca Roylance

Jackie Newby

Stephanie Sutherland

Stephen Chan

Nicola Levitt

Karen McAdam

Amit Chakrabarti

Emma Staples

Ellen Copson

David Davies

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.

Platinum and Polyadenosine 5'Diphosphoribose Polymerisation Inhibitor for Neoadjuvant Treatment of Triple Negative Breast Cancer and/or Germline BRCA Positive Breast Cancer

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.

All Clinical Trial data will be considered to be shared on formal application to the Trial CI \& TMG, however data affecting or considered as having the potential to affect the integrity or the endpoints of the trial and/or other collaborations will not be shared (or until such time that they no longer are deemed to have an effect).

Discovery and validation of prognostic, pharmacogenetic and pharmacogenomic markers that can be correlated with outcomes (pCR and RFS) in patients randomised to received olaparib compared with those who are not.

Primary outcome measure - safety of the addition of olaparib to three weekly carboplatin/weekly paclitaxel chemotherapy.

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.

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.

pCR at surgery assessed by central pathology review of the diagnosis and surgery slides.

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.

Relapse Free Survival (RFS), calculated from date of randomisation to date of first relapse or date of death from all causes, whichever occurs first.

Breast cancer specific survival (BCSS), calculated from date of randomisation to date of death from breast cancer.

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.

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.

Overall survival (OS), calculated from date of randomisation to date of death from all causes.

Time to second cancer (TTSC), calculated from the date of randomisation to the date of diagnosis of second cancer.

Residual Cancer Burden (RCB) I-III will be assessed by central pathology review.

Radiological response after 4th and final cycles

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.

Spots Global Cancer Trial Database for platinum and parp inhibitor