ABCSG 45 Details *

A prospective, open, randomized, phase II study of carboplatin/ olaparib in the pre-operative treatment of patients with triple-negative primary breast cancer which exhibit the features of positive homologous recombination deficiency (HRD) status

Start: 06/2019
Coordinating Investigator: Christian Singer, Vienna
Sample size: 90 (national)
Design:
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ABCSG 45

Primary objective:

To compare the efficacy of 6 cycles of pre-operative carboplatin / olaparib with 6 cycles of pre-operative taxane/ anthracycline-based chemotherapy (TAC) in tumors exhibiting positive homologous recombination deficiency (HRD) status when measured by centrally assessed RCB at the time of surgery

Secondary objective:

  • To compare the efficacy of 6 cycles of pre-operative carboplatin/ olaparib with 6 cycles of pre-operative taxane/ anthracycline-based chemotherapy (TAC) in tumors exhibiting positive HRD status when measured by pCR at the time of surgery.
  • To compare patient-reported quality of life (QoL) and sexual health (SH) in patients treated with pre-operative carboplatin/ olaparib vs. patients treated with pre-operative TAC overall and by subgroups defined by menopausal status (only women) or age at randomization at multiple pre-specified time points.

Inclusion criteria:

  1. Signed informed consent prior to any study specific assessments and procedures
  2. Patients must be >18 years of age
  3. Pre-menopausal (including peri-menopausal) and postmenopausal women and men with core-biopsied, early primary triple-negative (according to local standards) invasive breast cancer
  4. Positive HRD status (centrally assessed) in core-biopsy sample of the breast
  5. Absence of distant metastasis (M0) as assessed according to institutional standards within 90 days prior to randomization
  6. Unilateral early invasive TNBC patients. In case the tumor is multicentric and/ or multifocal, all histopathologically examined tumors must meet pathologic criteria for TNBC
  7. Willingness to undergo adequate lymph node procedures (e.g., sentinel/ axillary lymph node dissection) according to institutional standards
  8. Patients must have normal organ and bone marrow function measured within 28 days prior to randomization as defined below:
    • Haemoglobin (Hb) ≥10.0 g/dL
    • Absolute neutrophil count (ANC) ≥1.5 x 109/L
    • Absence of known Myelodysplastic Syndrome (MDS)/ Acute Myeloid Leukaemia (AML) and no features suggestive of MDS/ AML on peripheral blood smear
    • White blood cell (WBC) count ≥ 3.0 x 109/L
    • Platelet count ≥100 x 109/L
    • Total bilirubin ≤1.5 x institutional upper limit of normal (ULN)
    • AST (SGOT)/ ALT (SGPT) ≤2.5 x institutional ULN
  9. ECOG performance status 0-1
  10. Negative pregnancy test (serum or urine) max. 28 days prior to randomization for women with childbearing potential:
    • Pregnancy testing does not need to be pursued in patients who are judged as postmenopausal before randomization, as determined by local practice, or who have undergone bilateral oophorectomy, total hysterectomy, or bilateral tubal ligation
  11. Women of childbearing potential and male patients randomized into treatment Arm A or B must use adequate contraception for the duration of protocol treatment and for 3 months after the last dose of (N)IMP. Adequate contraception is defined as one highly effective form (i.e. total abstinence, (fe)male sterilization) OR two effective forms (e.g. non-hormonal intrauterine device (IUD) and condom/ occlusive cap with spermicidal foam/ gel/ film/ cream/ suppository)
  12. Patient is willing and able to comply with the protocol for the duration of the study, including undergoing treatment, scheduled visits and examinations

Exclusion criteria:

  1. Involvement in the planning and/ or conduct of the study (applies to both AstraZeneca/ ABCSG staff and/ or staff at the study site)
  2. Previous randomization in the present study
  3. Participation in another clinical study with an investigational product during the last 6 months (i.e. 183 days) prior to randomization
  4. Any previous treatment with a PARP inhibitor, including olaparib
  5. Prior ipsilateral invasive breast cancer and/ or ipsilateral Ductal Carcinoma in Situ (DCIS) and/ or prior chemotherapy for any breast cancer
    • Patients with contralateral invasive breast cancer and/ or contralateral DCIS diagnosed ≥5 years prior to randomization if curatively treated without chemotherapy are eligible
  6. Bilateral invasive breast cancer
  7. Patients with second primary malignancy are ineligible except for the following:
    • Adequately treated non-metastatic, non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, stage 1 grade 1 endometrial carcinoma or
    • Other curatively treated malignancies diagnosed ≥5 years prior to randomization with no evidence of disease for at least 5 years
  8. Other severe acute and/ or chronic medical and/ or psychiatric condition and/ or laboratory abnormality that would impart, in the judgment of the Investigator, risk associated with study participation or (N)IMP administration, or which, in the judgment of the Investigator, would make the patient inappropriate for participation in this study
  9. Concomitant use of known strong or moderate Cytochrome P450 3A4 (CYP3A4) inhibitors and inducers.
  10. Resting ECG with QTc >470 msec and/ or family history of long QT syndrome
    • However, ECG measurement can be repeated within 24 hours and patient is ineligible if none of these repeated measurements demonstrate QTc ≤470 msec
  11. Echocardiography (ECHO) and/ or multigated acquisition (MUGA) scan with <50% Left Ventricular Ejection Fraction (LVEF)
  12. Whole blood transfusions within 120 days prior to randomization
  13. Major surgery within 14 days prior to randomization and/ or patients with insufficient recovery from any major surgery per physician’s assessment at the time of randomization
  14. Any medical condition rendering the patient unfit for pre-operative chemotherapy with TAC or carboplatin/ olaparib
  15. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the (N)IMP
  16. Pregnant or breast feeding women
  17. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV) or patients who are receiving antiretroviral therapy
  18. Patients with known active hepatic disease (i.e. Hepatitis B or C)
  19. Patients with a known hypersensitivity to olaparib, platins, taxanes, epirubicin, or cyclophosphamide
  20. Patients with uncontrolled seizures
  21. Previous allogeneic bone marrow transplant
  22. Known ≥ grade 2 peripheral neuropathy

* studyinformation based on protocol version 1.1