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Assessing the Efficacy of Paclitaxel and Olaparib in Comparison to Paclitaxel / Carboplatin Followed by Epirubicin/Cyclophosphamide as Neoadjuvant Chemotherapy in Patients With HER2-negative Early Breast Cancer and Homologous Recombination Deficiency

NCT02789332

Description:

This is a multicenter, prospective, randomized, open-label phase II study evaluating the efficacy and safety of PO→EC as neoadjuvant treatment of operable and locally advanced breast cancer in patients with HR deficiency. Patients will be randomized to receive - paclitaxel 80 mg/m² iv weekly in combination with olaparib tablets 100 mg (4X25mg) twice daily for 12 weeks (65 patients) or - paclitaxel 80 mg/m² iv weekly in combination with carboplatin AUC 2 iv weekly for 12 weeks (37 patients) both followed by 4 cycles of epirubicin 90 mg/m² and cyclophosphamide 600 mg/m² (EC) either every 3 or every 2 weeks followed by surgery. The control arm was chosen to allow direct comparison with one of the currently considered standard of care regimen.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Unknown status

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Assessing the Efficacy of Paclitaxel and Olaparib in Comparison to Paclitaxel / Carboplatin Followed by Epirubicin/Cyclophosphamide as Neoadjuvant Chemotherapy in Patients With HER2-negative Early Breast Cancer and Homologous Recombination Deficiency
  • Official Title: A Randomized Phase II Trial to Assess the Efficacy of Paclitaxel and Olaparib in Comparison to Paclitaxel / Carboplatin Followed by Epirubicin/Cyclophosphamide as Neoadjuvant Chemotherapy in Patients With HER2-negative Early Breast Cancer and Homologous Recombination Deficiency (HRD Patients With Deleterious BRCA1/2 Tumor or Germline Mutation and/or HRD Score High)

Clinical Trial IDs

  • ORG STUDY ID: GBG90
  • NCT ID: NCT02789332

Conditions

  • Breast Cancer
  • Triple Negative Breast Neoplasms
  • HRpos Breast Neoplasms
  • BRCA 1 /2 and / or HRD

Interventions

DrugSynonymsArms
PwOPaclitaxel Olaparib over 12 weeksPaclitaxel with Olaparib (PwO)
PwCbPaclitaxel Carboplatin over 12 weeks, Control arm currently considered standard of care regimenPaclitaxel with Carboplatin (PwCb)
ECEpirubicin 90 mg/m² and Cyclophosphamide 600 mg/m² (EC) either every 3 or every 2 weeksPaclitaxel with Carboplatin (PwCb)

Purpose

This is a multicenter, prospective, randomized, open-label phase II study evaluating the efficacy and safety of PO→EC as neoadjuvant treatment of operable and locally advanced breast cancer in patients with HR deficiency. Patients will be randomized to receive - paclitaxel 80 mg/m² iv weekly in combination with olaparib tablets 100 mg (4X25mg) twice daily for 12 weeks (65 patients) or - paclitaxel 80 mg/m² iv weekly in combination with carboplatin AUC 2 iv weekly for 12 weeks (37 patients) both followed by 4 cycles of epirubicin 90 mg/m² and cyclophosphamide 600 mg/m² (EC) either every 3 or every 2 weeks followed by surgery. The control arm was chosen to allow direct comparison with one of the currently considered standard of care regimen.

Detailed Description

      The efficacy of olaparib in germline HRD score high with or without BRCA 1/2 mutation
      carriers with breast cancer is not well described

        -  The efficacy and safety of olaparib included in a standard of care regimen like
           paclitaxel weekly followed by epirubicin and cyclophosphamide (Pw-->EC) is unknown

        -  Carboplatin increased the pCR rate in patients with triple-negative breast cancer (TNBC)
           in two randomized phase II neoadjuvant studies when added to an anthracycline,
           cyclophosphamide and paclitaxel (GeparSixto, CALBG 40603). pCR rates were even higher in
           patients with germline BRCA 1 or 2 mutations (ypT0/is ypN0 65%) and with HRD score high
           (ypT0/is ypN0 63%).

        -  The TNT study showed a doubling in response rate for patients receiving carboplatin vs
           docetaxel in patients with germline BRCA 1 or 2 mutations.

        -  There is a high correlation between tumor and germline BRCA 1/2 mutations.

        -  Data from Geparsixto study showed that triple negative breast patients have an HR
           deficiency in about 70% (67% have a high HRD and 30% have a tBRCA mutation)

        -  About 5% of tBRCA patients have a low HRD score

        -  gBRCA2 patients are older when diagnosed and are more likely to have an HRpos tumor.

        -  The GeparOLA study aims to support the decision for a phase III study exploring the
           addition of olaparib to a Pw-->EC schedule by providing an estimate on the pCR rate in
           the targeted population but also by providing estimate comparison to paclitaxel and
           carboplatin followed by epirubicin and cyclophosphamide (PCb-->EC) as carboplatin is
           more and more considered a standard option of care in HR deficient patients (tBRCA 1/2
           mutations and/or HRD score high).
    

Trial Arms

NameTypeDescriptionInterventions
Paclitaxel with Carboplatin (PwCb)Active Comparatorpaclitaxel 80 mg/m² iv weekly in combination with carboplatin AUC 2 iv weekly for 12 weeks (37 patients) followed by 4 cycles of epirubicin 90 mg/m² and cyclophosphamide 600 mg/m² (EC) either every 3 or every 2 weeks followed by surgery.
  • PwCb
  • EC
Paclitaxel with Olaparib (PwO)Experimentalpaclitaxel 80 mg/m² iv weekly in combination with olaparib tablets 100 mg twice daily for 12 weeks (65 patients) followed by 4 cycles of epirubicin 90 mg/m² and cyclophosphamide 600 mg/m² (EC) either every 3 or every 2 weeks followed by surgery.
  • PwO
  • EC

Eligibility Criteria

        Inclusion Criteria:

          1. Written informed consent for all study specific procedures according to local
             regulatory requirements prior to beginning specific protocol procedures.

          2. Complete baseline documentation must be sent to GBG Forschungs GmbH.

          3. Unilateral or bilateral primary carcinoma of the breast, confirmed histologically by
             core biopsy. Fine-needle aspiration alone is not sufficient. Incisional biopsy is not
             allowed. In case of bilateral cancer, the investigator has to decide prospectively
             which side will be evaluated for the primary endpoint.

          4. Centrally confirmed negative HER2-status. Centrally confirmed estrogen and
             progesterone receptor, and Ki-67 status detected on core biopsy. ER/PR positive is
             defined as ≥1% stained cells and HER2-positive is defined as IHC 3+ or in-situ
             hybridisation (ISH) ratio ≥2.0. Formalin-fixed, paraffin-embedded (FFPE) breast tissue
             from core biopsy has therefore to be sent to the Dept. of Pathology at the Charité,
             Berlin prior to randomization.

          5. Centrally confirmed tumor Homologous Recombinant Deficiency score (tBRCA
             positive/mutated and/or HRD high). Patients with known gBRCA and/or tBRCA status can
             be enrolled prior to the central test results available.

          6. Tumor lesion in the breast with a palpable size of > 2 cm or a sonographical size of
             >1 cm in maximum diameter. If the tumor is not detectable with sonography mammography
             assessment can be considered. The lesion has to be measurable in two dimensions,
             preferably by sonography. In case of inflammatory disease, the extent of inflammation
             can be used as measurable lesion.

          7. Patients must be in the following stages of disease:

               -  cT2 - cT4a-d or

               -  cT1c and cN+ or cT1c and pNSLN+ or

               -  cT1c and ER-neg and PR-neg or

               -  cT1c and Ki67>20% In patients with multifocal or multicentric breast cancer, the
                  largest lesion should be measured and at least one lesion has to meet the above
                  criteria

          8. Age > 18 years.

          9. Karnofsky Performance status index ≥ 80%.

         10. Normal cardiac function must be confirmed by ECG and cardiac ultrasound (LVEF or
             shortening fraction) within 3 months prior to randomization. Results must be above the
             normal limit of the institution.

         11. Laboratory requirements:

             Hematology

               -  Absolute neutrophil count (ANC) ≥2.0 x 109 / L and

               -  Platelets ≥100 x 109 / L and

               -  Hemoglobin ≥10 g/dL (≥ 6.2 mmol/L) Hepatic function

               -  Total bilirubin ≥1.5x UNL and

               -  ASAT (SGOT) and ALAT (SGPT) ≥1.5x UNL and

               -  Alkaline phosphatase ≥2.5x UNL.

         12. Negative pregnancy test (urine or serum) within 14 days prior to randomization for all
             women of childbearing potential.

         13. Complete staging work-up within 3 months prior to randomization. All patients must
             have bilateral mammography, breast ultrasound (≥21 days, and in no case exceed 6 weeks
             prior to randomization) (Note MRI/ CT scan may be used as an alternative imaging
             technique). In case of high risk according to guidelines: chest X-ray (PA and lateral)
             or as an alternative breast MRI/CT, abdominal ultrasound or CT scan or MRI, and bone
             scan in case of high risk for primary metastasis according to guidelines. In case of
             positive bone scan, bone X-ray or CT scan is mandatory. Other tests may be performed
             as clinically indicated.

         14. Male or female patients

         15. Patients must be available and compliant for central diagnostics, treatment and
             follow-up.

        Exclusion Criteria:

          1. Prior chemotherapy for any malignancy within 5 years.

          2. Prior radiation therapy for breast cancer within 5 years.

          3. Pregnant or lactating patients. Patients of childbearing potential must implement
             adequate non-hormonal contraceptive measures (barrier methods, intrauterine
             contraceptive devices, sterilization) during study treatment.

          4. Inadequate general condition (not fit for anthracycline-taxane-targeted agents-based
             chemotherapy).

          5. Previous malignant disease without being disease-free for less than 5 years (except
             CIS of the cervix and non-melanomatous skin cancer).

          6. Known or suspected congestive heart failure (>NYHA I) and / or coronary heart disease,
             angina pectoris requiring antianginal medication, previous history of myocardial
             infarction, evidence of transmural infarction on ECG, uncontrolled or poorly
             controlled arterial hypertension (i.e. BP >140 / 90 mm Hg under treatment with two
             antihypertensive drugs), rhythm abnormalities requiring permanent treatment,
             clinically significant valvular heart disease.

          7. History of significant neurological or psychiatric disorders including psychotic
             disorders, dementia or seizures that would prohibit the understanding and giving of
             informed consent.

          8. Patients currently in an institution by order of jurisdictional or governmental
             grounds.

          9. Currently active infection.

         10. Definite contraindications for the use of corticosteroids.

         11. Known hypersensitivity reaction to one of the compounds or incorporated substances
             used in this protocol.

         12. Concurrent treatment with:

               -  chronic corticosteroids unless initiated > 6 months prior to study entry and at
                  low dose (10 mg or less methylprednisolone or equivalent).

               -  sex hormones. Prior treatment must be stopped before study entry.

               -  other experimental drugs or any other anti-cancer therapy.

         13. Participation in another clinical trial with any investigational, not marketed drug
             within 30 days prior to study entry.

         14. Prior use of a PARP-Inhibitor
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:response by pCR =ypT0/is ypN0
Time Frame:24 weeks
Safety Issue:
Description:Assess the efficacy of olaparib in HER2-negative early Breast Cancer and HRD (BRCA 1/2 mutations and/or HRD positive). Pathological complete response of breast and lymph nodes (ypT0/is ypN0) defined as no microscopic evidence of residual invasive viable tumor cells in all resected specimens of the breast and axilla. Pathological response will be assessed considering all removed breast and lymphatic tissues from all surgeries.

Secondary Outcome Measures

Measure:response by pCR =ypT0/is ypN0
Time Frame:12 weeks
Safety Issue:
Description:To assess the pCR rates of patients receiving PO→EC and the pCR rates of patients receiving paclitaxel and carboplatin followed by EC (PCb→EC)
Measure:response by pCR =ypT0/is ypN0 in stratified subgroups
Time Frame:24 weeks
Safety Issue:
Description:To assess the pCR rates (ypT0/is, ypN0) in the stratified subgroups
Measure:response by pCR according to other definitions
Time Frame:24 weeks
Safety Issue:
Description:To determine other pCR rates (ypT0 ypN0; ypT0 ypN0/+; ypT0/is ypN0/+; ypT(any) ypN0) of patients receiving PO→EC and to compare them with the pCR rates of patients receiving PCb→EC.
Measure:response by pCR in HRD high versus tBRCA
Time Frame:24 weeks
Safety Issue:
Description:To assess the pCR rate in HRD high with vs without tBRCA mutation
Measure:Response rate by sono and/or mammo
Time Frame:12 weeks
Safety Issue:
Description:To determine the response rates of the breast tumor and axillary nodes based on physical examination and imaging tests (sonography, mammography, or MRI) with PO→EC and to compare it with PCb→EC. Clinical (c) and imaging (i) response will be assessed after EC and before surgery by physical examination and imaging tests. Sonography is the preferred examination, however, if sonography appears not to provide valid results or is not performed, other imaging tests will be considered.
Measure:Response rate by sono and/or mammo
Time Frame:24 weeks
Safety Issue:
Description:To determine the response rates of the breast tumor and axillary nodes based on physical examination and imaging tests (sonography, mammography, or MRI) with PO→EC and to compare it with PCb→EC. Clinical (c) and imaging (i) response will be assessed after EC and before surgery by physical examination and imaging tests. Sonography is the preferred examination, however, if sonography appears not to provide valid results or is not performed, other imaging tests will be considered.
Measure:Breast Conservation rate
Time Frame:24 weeks
Safety Issue:
Description:To determine the breast conservation rate with PO→EC and to compare it with PCb→EC. Breast conservation is defined as tumorectomy, segmentectomy or quadrantectomy as a most radical surgery.
Measure:Toxicity of treatment
Time Frame:24 weeks
Safety Issue:
Description:To assess the toxicity and compliance of PO→EC and to compare it with PCb→EC. Tolerability and safety will be assessed on the basis of adverse events, serious adverse events, adverse events of special interest and treatment discontinuations. Safety by toxicity grades is defined by the NCI-CTCAE version 4.0.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:German Breast Group

Trial Keywords

  • carboplatin
  • olaparib
  • pCR
  • neoadjuvant
  • triple-negative
  • hormonreceptor-positive
  • BRCA1/2
  • HRD, homologous recominant deficient
  • breast cancer
  • genetic testing (somatic and germline mutations)

Last Updated

June 26, 2017