Klinische Studien

GeparOla

AcronymISRCTNEudraCTClinicaltrials.govDRKS
GBG 902015-003509-41NCT02789332

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 mutation and/or HRD score high)

Status: Active

Purpose / Objectives

Primary Outcome

 

  • response by pCR =ypT0/is ypN0

Secondary Outcomes

 

  • pCR rate of PO→EC with patients receiving paclitaxel and carboplatin followed by EC (PCb→EC)
      • rates of ypT0 ypN0; ypT0 ypN0/+; ypT0/is ypN0/+; ypT(any) ypN0; and residual cancer burden (RCB)(Tbd) with PO→EC and to compare it with PCb→EC
      • pCR rate only in patients continuing treatment with EC
  • 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
      • breast conservation rate with PO→EC and to compare it with PCb→EC
      • toxicity and compliance of PO→EC and to compare it with PCb→EC
      • To correlate co-occurring mutations detected by next generation sequencing in lymphocytes or in tumors cells with pCR (exploratory)

Diagnosis

Patient attributes

Stage

primary

Age

18-99

Inclusion criteria

  • Written informed consent for all study specific procedures according to local regulatory requirements prior to beginning specific protocol procedures.
  • Complete baseline documentation must be sent to GBG Forschungs GmbH.
  • 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.
  • 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.
  • 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.
  • 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.
    1. Patients must be in the following stages of disease:
    2. 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
  • Age > 18 years.
  • Karnofsky Performance status index ≥ 80%.
  • 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.
    1. Laboratory requirements:
    2. Hematology
    3. 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.
  • Negative pregnancy test (urine or serum) within 14 days prior to randomization for all women of childbearing potential.
  • 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.
  • Male or female patients
  • Patients must be available and compliant for central diagnostics, treatment and follow-up.

Exclusion criteria

  • Prior chemotherapy for any malignancy within 5 years.
  • Prior radiation therapy for breast cancer within 5 years.
  • Pregnant or lactating patients. Patients of childbearing potential must implement adequate non-hormonal contraceptive measures (barrier methods, intrauterine contraceptive devices, sterilization) during study treatment.
  • Inadequate general condition (not fit for anthracycline-taxane-targeted agents-based chemotherapy).
  • Previous malignant disease without being disease-free for less than 5 years (except CIS of the cervix and non-melanomatous skin cancer).
  • 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.
  • History of significant neurological or psychiatric disorders including psychotic disorders, dementia or seizures that would prohibit the understanding and giving of informed consent.
  • Patients currently in an institution by order of jurisdictional or governmental grounds.
  • Currently active infection.
  • Definite contraindications for the use of corticosteroids.
  • Known hypersensitivity reaction to one of the compounds or incorporated substances used in this protocol.
    1. Concurrent treatment with:
    2. 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.
  • Participation in another clinical trial with any investigational, not marketed drug within 30 days prior to study entry.
  • Prior use of a PARP-Inhibitor

 

Trial design

  • Phase II
  • Multicenter
  • Prospective
  • Randomized
  • Two-arm
  • Open Label

Intervention

  • paclitaxel 80 mg/m² iv weekly in combination with olaparib tablets 100 mg (4X25mg) twice daily for 12 weeks
  • 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

Documents (password protected)

Responsibilities in overall trial

Germanbreastgroup - GBG Forschungs GmbH

National Coordinating Investigator

Dr. Sibylle Loibl

Study Sites

Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

Study office

Status

Active

Principal Investigator

Dr. med. Wolfram Malter

Deputy of Principal Investigator

  • Dr. med. Julian Puppe

Subinvestigator

  • Dr. med. Fabinshy Thangarajah

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