Clinical Trials /

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

NCT03150576

Description:

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).

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2/Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Platinum and Polyadenosine 5'Diphosphoribose Polymerisation (PARP) Inhibitor for Neoadjuvant Treatment of Triple Negative Breast Cancer (TNBC) and/or Germline BRCA (gBRCA) Positive Breast Cancer
  • 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 IDs

  • ORG STUDY ID: A093777
  • NCT ID: NCT03150576

Conditions

  • Breast Cancer

Interventions

DrugSynonymsArms
OlaparibLynparzaResearch 1
Paclitaxel and CarboplatinTaxol and ParaplatinControl

Purpose

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 527 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.

      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.
    

Trial Arms

NameTypeDescriptionInterventions
ControlActive Comparator4 cycles of: Paclitaxel 80mg/m2 Day 1, 8 & 15, every 3 weeks, Carboplatin area under the curve (AUC) 5 Day 1, every 3 weeks
  • Paclitaxel and Carboplatin
Research 1Experimental4 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
  • Olaparib
  • Paclitaxel and Carboplatin
Research 2Experimental4 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
  • Olaparib
  • Paclitaxel and Carboplatin

Eligibility Criteria

        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).
      
Maximum Eligible Age:70 Years
Minimum Eligible Age:16 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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.
Safety Issue:
Description:Primary outcome measure - safety of the addition of olaparib to three weekly carboplatin/weekly paclitaxel chemotherapy.

Secondary Outcome Measures

Measure:pCR at surgery - assessed by review of histopathology slides
Time Frame:Up to 2 years after last patient randomised
Safety Issue:
Description:pCR at surgery assessed by central pathology review of the diagnosis and surgery slides.
Measure:Relapse-Free Survival (RFS)
Time Frame:Up to 10 years after last patient is randomised
Safety Issue:
Description:Relapse Free Survival (RFS), calculated from date of randomisation to date of first relapse or date of death from all causes, whichever occurs first.
Measure:Breast cancer specific survival (BCSS)
Time Frame:Up to 10 years after last patient is randomised
Safety Issue:
Description:Breast cancer specific survival (BCSS), calculated from date of randomisation to date of death from breast cancer.
Measure:Distant disease-free survival
Time Frame:Up to 10 years after last patient is randomised
Safety Issue:
Description: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.
Measure:Local recurrence-free survival
Time Frame:Up to 10 years after last patient is randomised
Safety Issue:
Description: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.
Measure:Overall survival (OS)
Time Frame:Up to 10 years after last patient is randomised
Safety Issue:
Description:Overall survival (OS), calculated from date of randomisation to date of death from all causes.
Measure:Time to second cancer (TTSC)
Time Frame:Up to 10 years after last patient is randomised
Safety Issue:
Description:Time to second cancer (TTSC), calculated from the date of randomisation to the date of diagnosis of second cancer.
Measure:pCR in breast alone
Time Frame:Up to 2 years after last patient is randomised
Safety Issue:
Description:pCR in breast alone
Measure:Residual Cancer Burden (RCB)
Time Frame:Up to 10 years after last patient is randomised
Safety Issue:
Description:Residual Cancer Burden (RCB) I-III will be assessed by central pathology review.
Measure:Radiological response - as assessed by radiological response criteria as per RECIST v1.1
Time Frame:Up to 2 years after last patient is randomised
Safety Issue:
Description:Radiological response after 4th and final cycles
Measure:Treatment related toxicities - as assessed by CTCAE v4.03
Time Frame:Up to 10 years after last patient is randomised
Safety Issue:
Description:Treatment related toxicities
Measure:Quality of Life
Time Frame:Up to 10 years after last patient is randomised
Safety Issue:
Description:Quality of Life (sub-study)

Details

Phase:Phase 2/Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Cambridge University Hospitals NHS Foundation Trust

Trial Keywords

  • Triple negative breast cancer
  • germline BRCA
  • platinum and PARP inhibitor
  • neoadjuvant chemotherapy
  • olaparib

Last Updated

May 10, 2017