| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with triple negative or HRpositive, early breast cancer |
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| E.1.1.1 | Medical condition in easily understood language |
Patients with an illness associated with a very aggressive form of breast cancer, however they are chemosensitive and the chromosomal instability might be a suitable target for Olaparib.
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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 | 10006187 |
| E.1.2 | Term | 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 assess the pathological complete response (pCR=ypT0/is ypN0) rate of neoadjuvant treatment of olaparib and paclitaxel followed by epirubicin and cyclophosphamide (PO→EC) inneoadjuvant breast cancer patients with early breast cancer and HR deficient tumors defined as either tBRCA1/2 mutation or HRD score high or known gBRCA mutation. |
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| E.2.2 | Secondary objectives of the trial |
• 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)
• To assess the pCR rates (ypT0/is, ypN0) in the stratified subgroups
• To determine other pCR rates (ypT0 ypN0; ypT0 ypN0/+; ypT0/is ypN0/+; ypT(any) ypN0)
• To assess the pCR rate in HRD high with vs without tBRCA mutation
• To determine the response rates of the breast tumor and axillary nodes based on physical examination and imaging tests (sonography, mammography, or MRI)
• To determine the breast conservation rate
• To assess the toxicity and compliance
• To correlate co-occurring mutations detected by next generation sequencing in lymphocytes or in tumors cells with pCR (exploratory)
• Potential biomarkers predicting safety and compliance for breast cancer |
• Bestimmung der pCR-Raten von POEC und PCb EC
• Bestimmung der pCR Raten (ypT0/is, ypN0) in den stratifizierten Subgruppen
• Bestimmung der Raten von ypT0 ypN0; ypT0 ypN0/+; ypT0/is ypN0/+; ypT(jedes Stadium) ypN0; bei POEC und Vergleich mit PbEC.
• Bestimmung der pCR Rate bei HRD high mit und ohne tBRCA Mutation
• Bestimmung der Ansprechrate des Brusttumors und der axillären Lymphknoten anhand körperlicher Untersuchung und bildgebender Verfahren (Sonographie, Mammographie oder MRT) bei POEC und Vergleich mit PCbEC.
• Bestimmung der Rate der brusterhaltenden Therapie bei POEC und Vergleich mit PCbEC.
• Bestimmung von Toxizität und Compliance bei POEC und Vergleich mit PCbEC.
• Evaluation genomweiter Single Nucleotide Polymorphismen (SNPs), stromaler TILs, PARP, 53BP1, REV7 und weiterer Biomarker zur Behandlung von Brustkrebs. |
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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 |
| Genetic Markers from peripheral blood to predict tumor biology, treatment response and prognosis |
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| E.3 | Principal 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. |
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| E.4 | Principal 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 |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
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.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Pathological response will be assessed considering all removed breast and lymphatic tissues from all surgeries after NACT. pCR rate will be assessed approximately 25 weeks after randomization. |
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| E.5.2 | Secondary end point(s) |
Other pCR definition
ypT0 ypN0 is defined as no microscopic evidence of residual invasive and no non-invasive viable tumor cells in all resected specimens of the breast and axilla.
ypT0 ypN0/+ is defined as no microscopic evidence of residual invasive or non-invasive viable tumor cells in all resected specimens of the breast;
ypT0/is ypN0/+ is defined as no microscopic evidence of residual invasive viable tumor cells in all resected specimens of the breast; patients with a sentinel node biopsy prior to treatment start will be evaluated for ypT(any) ypN0 similarly to the description given for the primary endpoint.
Breast conservation is defined as tumorectomy, segmentectomy or quadrantectomy as a most radical surgery.
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 with the following priority: MRI, mammography, computed tomogram. The same imaging method should be considered for the measurement before, during and after treatment.
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. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Most secondary objectives will be assessed approximately 25 weeks after randomization. LRRFS, RRFS, LRFS, DDFS, IDFS and OS are defined as the time period between registration and first event |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| 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 | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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 | No |
| 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 | 35 |
| 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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| last visit of the last subject, LVLS |
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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 | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
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