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

Breast Cancer Clinical Trial

— PARTNER  

Official title:

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.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03150576
• Other study ID #: PARTNER
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: May 2016
• Est. completion date: June 2034

Study information

• Verified date: November 2022
• Source: Cambridge University Hospitals NHS Foundation Trust
• Contact: CCTC A Cambridge Cancer Trials Centre
• Phone: +44 (0)1223 348071
• Email: cuh.partner[@]nhs.net
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 780
• Est. completion date: June 2034
• Est. primary completion date: June 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years to 70 Years

Eligibility

Inclusion Criteria:

• Aged between 16 and 70.

• 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.

OR

• 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.

OR

Multifocal tumour:

• with at least one tumour with a size>10mm.

• Patients with bilateral disease are eligible to enter the trial provided that both breast disease meets the above criteria.

• Be fit to receive the trial chemotherapy regimen in the opinion of the responsible clinician:

Adequate bone marrow, hepatic, and renal function. ECOG performance status of 0, or 1.

• Treatment should be commenced within 6 weeks of the diagnostic biopsy. In uncommon circumstances, where medically acceptable, treatment is permitted to start within a maximum of 9 weeks of the diagnostic biopsy.

• Availability of the Tumour Infiltrating Lymphocytes score is required.

• Availability of CK 5/6 and EGFR +/- Androgen Receptor IHC score.

• Availability of slides and paraffin embedded tissue blocks from pre-chemotherapy core biopsy and from primary surgical resection is required.

• Women of child-bearing potential (WCBP), defined as not surgically sterilized or not post-menopausal for at least 24 consecutive months if age =55 year or 12 months if age >55 years, must have a negative serum or urine pregnancy test within 14 days prior to randomisation.

• All WCBP and all sexually active male patients as well as their partners must be aware that they should not conceive during the treatment period and therefore should routinely use effective forms of contraception, throughout their participation in the trial and for at least 6 months after the last dose of trial treatment. Please follow the olaparib contraception guidelines.

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 =2.

• Concomitant use of known potent CYP3A4 inhibitors and inducers. Consider wash-out periods.

• Pregnant or breast feeding women.

• Not suitable for neoadjuvant chemotherapy in the opinion of the responsible clinician.

• Major surgery within 14 days of starting trial treatment and patients must have recovered from any effects of any major surgery.

• Any evidence of other disease or any concomitant medical or psychiatric problems which in the opinion of the Investigator would prevent completion of treatment or follow-up. For example:

Evidence of severe or uncontrolled cardiac disease Uncontrolled ventricular arrhythmia Recent myocardial infarction (within 12 months) Active infection including Hepatitis B, Hepatitis C and Human Immunodeficiency virus (HIV). Screening for chronic conditions is not required.

• ECG with mean resting QTc >470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome.

• Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the trial medication

• Known hypersensitivity to olaparib, carboplatin, paclitaxel or their excipients (including cremophor).

• Whole blood transfusions in the last 120 days prior to blood sampling for BRCA test as it may interfere with the results (packed red blood cells and platelet transfusions are acceptable).

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• Olaparib
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 and Carboplatin
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.

Locations

Country	Name	City	State
United Kingdom	University Hospital Ayr	Ayr
United Kingdom	Basingstoke and North Hampshire Hospital	Basingstoke
United Kingdom	Bedford General Hospital	Bedford
United Kingdom	Royal Bournemouth Hospital	Bournemouth
United Kingdom	Bristol Haematology & Cancer Centre	Bristol
United Kingdom	Queen's Hospital	Burton Upon Trent	Derby
United Kingdom	West Suffolk Hospital	Bury Saint Edmunds
United Kingdom	Cambridge University Hospitals NHS Foundation Trust & the University of Cambridge	Cambridge	Cambridgeshire
United Kingdom	Velindre Cancer Centre	Cardiff
United Kingdom	Colchester General Hospital	Colchester
United Kingdom	Russells Hall Hospital	Dudley
United Kingdom	Hinchingbrooke Hospital	Huntingdon
United Kingdom	Ipswich Hospital	Ipswich
United Kingdom	Kidderminster General Hospital	Kidderminster
United Kingdom	University Hospital Crosshouse	Kilmarnock
United Kingdom	Royal Free Hospital	London
United Kingdom	University College London Hospital	London
United Kingdom	The Christie	Manchester	Lancs
United Kingdom	Mount Vernon Cancer Centre	Northwood
United Kingdom	Nottingham City Hospital	Nottingham
United Kingdom	Churchill Hospital	Oxford
United Kingdom	Peterborough City Hospital	Peterborough
United Kingdom	Poole Hospital	Poole
United Kingdom	The Alexandra Hopsital	Redditch
United Kingdom	Queen's Hospital	Romford
United Kingdom	Southampton General Hospital	Southampton
United Kingdom	Singleton Hospital	Swansea
United Kingdom	Pinderfields General Hospital	Wakefield	Yorkshire
United Kingdom	Royal Hampshire County Hospital	Winchester
United Kingdom	Worcestershire Royal Hospital	Worcester

Sponsors (3)

Lead Sponsor	Collaborator
Cambridge University Hospitals NHS Foundation Trust	AstraZeneca, Cancer Research UK

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Discovery and validation of markers that can be correlated with outcomes (pCR and RFS).	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.	Up to 15 years after last patient is randomised
Primary	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.	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	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.	15 months - when pathological complete response (pCR) is available for 53 patients in each of two research arms.
Primary	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.	5.5 years - October 2021 approx.
Secondary	pCR at surgery - assessed by review of histopathology slides	pCR at surgery assessed by central pathology review of the diagnosis and surgery slides.	Up to 2 years after last patient randomised
Secondary	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.	2 cycles (each lasting 28 days)
Secondary	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.	Up to 10 years after last patient is randomised
Secondary	Breast cancer specific survival (BCSS)	Breast cancer specific survival (BCSS), calculated from date of randomisation to date of death from breast cancer.	Up to 10 years after last patient is randomised
Secondary	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.	Up to 10 years after last patient is randomised
Secondary	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.	Up to 10 years after last patient is randomised
Secondary	Overall survival (OS)	Overall survival (OS), calculated from date of randomisation to date of death from all causes.	Up to 10 years after last patient is randomised
Secondary	Time to second cancer (TTSC)	Time to second cancer (TTSC), calculated from the date of randomisation to the date of diagnosis of second cancer.	Up to 10 years after last patient is randomised
Secondary	pCR in breast alone	pCR in breast alone	Up to 2 years after last patient is randomised
Secondary	Residual Cancer Burden (RCB)	Residual Cancer Burden (RCB) I-III will be assessed by central pathology review.	Up to 10 years after last patient is randomised
Secondary	Radiological response - as assessed by radiological response criteria as per RECIST v1.1	Radiological response after 4th and final cycles	Up to 2 years after last patient is randomised
Secondary	Treatment related toxicities - as assessed by CTCAE v4.03	Treatment related toxicities	Up to 10 years after last patient is randomised
Secondary	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.	Up to 10 years after last patient is randomised