| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Early invasive triple negative breast cancer with positive HRD status (acc. to Myriad mychoice© test) |
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| E.1.1.1 | Medical condition in easily understood language |
| Early invasive triple negative breast cancer with positive HRD status |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10075566 |
| E.1.2 | Term | Triple negative breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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. |
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| E.2.2 | Secondary objectives of the trial |
• 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.
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Study title sub-study:
Adjuvant olaparib in Patients with triple-negative primary breast cancer and positive homologous recombination deficiency (HRD) status, who have received at least 4 cycles of neoadjuvant treatment with olaparib/carboplatin or taxane/anthracycline
Date & Version of sub-study:
Protocol Version 3.0 (15 Feb-2023) -> Appendix F: Olaparib Adjuvant Substudy
Objectives:
Explorative objective: to evaluate safety and tolerability of adjuvant olaparib treatment for 1 year after neoadjuvant treatment with at least 4 cycles of olaparib in combination with carboplatin or at least 4 cycles of standard chemotherapy TAC, followed by definitive surgery.
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| E.3 | Principal 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 (incl. peri-menopausal) and postmenopausal women and men with core-biopsied, early primary triple-negative (acc. 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 acc. to institutional standards within 90 days prior to randomization
6. Unilateral early invasive TNBC patients.
7. Willingness to undergo adequate lymph node procedures (e.g., sentinel/ axillary lymph node dissection) acc. 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 (*For patients randomized according to protocol version 2.0, peripheral blood smear only has to be performed if haematology assessment during screening shows abnormalities that require further clarification)
• 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
• Serum creatinine ≤1.5 x institutional ULN or creatinine clearance using the Cockcroft-Gault equation ≥51 mL/min
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 6 months after the last dose of (N)IMP for women and 3 months for male patients. 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, incl. undergoing treatment, scheduled visits and examinations |
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| E.4 | Principal 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) inducers. For further details refer to Appendix B
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, anthracyclines, or cyclophosphamide
20. Patients with uncontrolled seizures
21. Previous allogeneic bone marrow transplant
22. Known ≥ grade 2 peripheral neuropathy |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Histo-pathological response to pre-operative carboplatin/olaparib compared with pre-operative TAC-based chemotherapy when measured by centrally assessed RCB (RCB-0/I versus RCB-II/III). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
• Occurrence of pCR at the time of surgery.
• Quality of Life and sexual health scores and changes from baseline as measured using EORTC QLQ-C30, EORTC QLQ-BR45 and EORTC SHQ-C22.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| pCR at the time of surgery. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| patient-reported quality of life (QoL) and sexual health (SH) |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 7 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 7 |
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