| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Breast Cancer in patients with operable Triple Negative or luminal B/HER2 normal patients |
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| E.1.1.1 | Medical condition in easily understood language |
| Breast Cancer in patients with operable Triple Negative or luminal B/HER2 normal patients |
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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 | 17.1 |
| 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 compare the pathologic complete response (pCR) rate in the breast (ypT0/is ypN0/+) in patients with operable Triple Negative or luminal B/HER2 normal breast cancer treated with either cabazitaxel or weekly paclitaxel. |
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| E.2.2 | Secondary objectives of the trial |
• pCR rates per arm separately for the stratified subpopulations.
• Objective response rate (ORR) in the breast according to WHO criteria.
• pCR rate defined as ypT0 ypN0.
• pCR rate defined as ypT0/is ypN0.
• pCR rate in the axillary lymph nodes (ypN0).
• To determine the pCR rate and local recurrence free survival (LRFS) in patients with a clinical complete response (cCR) and a negative core biopsy before surgery.
• Breast conservation surgery rate.
• To assess the toxicity (NCI CTCAE V4.03) and compliance in both arms.
• Invasive loco-regional recurrence free survival (LRRFS), distant-disease-free survival (DDFS), invasive disease-free survival (IDFS), and overall survival (OS).
• To explore the biomarkers and profiles potentially predicting response to treatment
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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 |
1) Pharmacogenetic Substudy (Version 3 - 23.07.2012)
Primary objective:
• To associate the germline genotype of the patient with the treatment response in both randomization arms.
Secondary endpoints:
• To associate the germline genotype of the patient with the long term prognosis of the patients in both randomization arms.
• To associate the germline genotype of the patient with the molecular profile of the tumors.
• To associate the germline genotype with the toxicities under therapy in both randomization arms
2) Surgical Substudy in patients with high probability for pCR (Version 3 - 23.07.2012)
If it can be shown at an interim analysis that the positive predictive value for a pCR of a negative (≥3) core biopsies before surgery in patients with complete clinical response is >90%, these patients might opt for having no further breast surgery
3) Substudy on ovarian study (Version 3 - 23.07.2012)
Primary objective:
• To evaluate the rate of premature ovarian failure 2 years after end of chemotherapy defined as no regular menstruation and FSH >15mIE/ml and E2 < 30 (50pg/ml) .
Secondary objectives:
• To evaluate rate of menstruation prior to chemotherapy, at month 6*, 12, 18, 24, 30.
• To evaluate FSH, E2, AMH prior to therapy and at 6*, 12, 18, 24, 30 months.
• To evaluate the follicle count prior to therapy and at 6*, 12, 18, 24, 30 months.
• To assess the menopausal symptom score prior to therapy and at 6*, 12, 18, 24, 30 months.
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| E.3 | Principal inclusion criteria |
• Written informed consent for all study 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.
• Tumor lesion in the breast with a palpable size of => 2 cm or a sonographical size of => 1 cm in maximum diameter. The lesion has to be measurable in two dimensions, preferably by sonography.
• Patients must be in the following stages of disease:
- cT3 or
- cT2 or
- cT1c and cN+ or
- cT1c and pNSLN+.
• In patients with multifocal or multicentric breast cancer, the largest lesion should be evaluated.
• Centrally confirmed triple negative or luminal B/HER2-normal subtype. ER- and PgR-negative defined as <1% stained cells. HER-2 negative defined as IHC 0+, 1+ or IHC 2+ and FISH/SISH/CISH (ratio <2.0) negative. Luminal B defined as ER or PgR + and > 14% Ki-67 stained cells. The formalin-fixed, paraffin-embedded (FFPE) breast tissue block from the diagnostic core biopsy has therefore to be sent to the Dept. of Pathology at the Charité, Berlin prior to randomization.
• Age => 18 years.
• Eastern Cooperative Oncology Group (ECOG) Performance Status: 0 or 1 (see Appendix A).
• Laboratory requirements:
- Hemoglobin > 9.0 g/dL
-Absolute neutrophil count > 1.5 x 109/L,
- Platelet count > 100 x 109/L,
- AST/SGOT and/or ALT/SGPT < 2.5 x ULN;
- Total bilirubin < 1.0 x ULN,
- Serum creatinine < 1.5 x ULN. If creatinine 1.0 - 1.5 x ULN, creatinine clearance will be calculated according to CKD-EPI formula and patients with creatinine clearance < 60 mL/min should be excluded (see Appendix 2 for formula).
• 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), breast MRI (optional), chest X-ray (PA and lateral), abdominal ultrasound or CT scan or MRI, and bone scan done. In case of positive bone scan, bone X-ray is mandatory. Other tests may be performed as clinically indicated.
• Patients must be available and compliant for central diagnostics, treatment and follow-up
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| E.4 | Principal exclusion criteria |
• Any prior treatment for primary breast cancer including radiation therapy
• History of ipsi/ or contra-lateral invasive breast cancer
• Locally advanced disease including N3 and metastatic disease
• Patients in the following stages of disease are not allowed:
- cT4
• Prior malignancy without being disease-free for more than 5 years (except carcinoma in situ of the cervix or other in situ cancer (e.g. bladder cancer) and adequately treated basal cell carcinoma of the skin.
• Clinically significant (i.e. active) cardiovascular disease, including cerebrovascular accident (≤6 months before enrolment), myocardial infarction, arterial thrombotic events (≤6 months before enrolment), unstable angina pectoris, New York Heart Association (NYHA) ≥ grade 2 congestive heart failure and/or hypertension, serious cardiac arrhythmia requiring medication during the study and that might interfere with regularity of the study treatment, or not controlled by medication
• Any severe acute or chronic medical condition which could impair the ability of the patient to participate to the study or to comply with the study procedures or interfere with interpretation of study results (such as significant neurological or psychiatric disorders including psychotic disorders, dementia or seizures).
• Active infection.
• Sex hormones. Prior treatment must be stopped before study entry.
• Inability and unwillingness to comply with study visits, treatment, testing, and to comply with the protocol.
• Administration of any live virus vaccine within 8 weeks preceding study entry.
• Use of any investigational agent within 30 days of administration of the first dose of study drug or concurrent treatment on another clinical trial
• Requirement for radiation therapy concurrent with study anticancer treatment. Patients who require breast or chest wall radiation therapy after surgery are eligible
• Pregnancy or breastfeeding women
• Patients with childbearing potential who do not agree to use accepted and effective method of contraception (barrier methods, intrauterine contraceptive devices, sterilization) during the study treatment period and following a period of 6 months after the last study drug administration.
• History of hypersensitivity (grade ≥ 3) to polysorbate 80 or any study drugs or excipients
• Concurrent or planned treatment with potent strong inhibitors or strong inducers of cytochrome P450 3A4/5 (a two-week wash-out period is necessary for patients who are already on these treatments) (see Appendix 3)
• Contraindications to the use of corticosteroid treatment
• Symptomatic peripheral neuropathy grade ≥ 2 (National Cancer Institute Common Terminology Criteria [NCI CTCAE] v.4.03
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| E.5 End points |
| E.5.1 | Primary end point(s) |
- Primary efficacy endpoint is the pCR rate defined as the complete absence of invasive carcinoma on histological examination in the breast irrespective of lymph node involvement (ypT0/Tis, ypN0/+) at the time of definitive surgery and confirmed by independent blinded centralized histology report review.
It will be assessed using all removed breast and lymphatic tissues from all surgeries. Patients in whom success cannot be determined (e.g. patients in whom histology is not evaluable) will be included in the denominator, i.e. these patients will affect the success rate in the same way as treatment failures.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| - After definitive surgery of all patients |
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| E.5.2 | Secondary end point(s) |
1) Secondary short-term efficacy endpoints (ypT0 ypN0; ypT0/is ypN0; ypT(any) ypN0) will be summarized as rates in each treatment group, two-sided 95% confidence intervals will be calculated according to Pearson and Clopper, and the continuity corrected Pearson χ2 test will be performed to evaluate the difference of rates in treatment arms; these tests are considered explorative.
2) Breast conservation rate defined as tumorectomy, segmentectomy or quadrantectomy
3) Clinical (c) and imaging (i) response will be assessed after the 2nd cycle 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 decreasing priority: MRI, mammography, computed tomogram. The same imaging method should be considered for the measurement before, during and after treatment. Tumor response is defined as either a partial response (PR) or complete response (CR) according to WHO criteria (see section 21.7). (CR) is defined as no evidence of disease in the breast using preferably ultrasound and/or MRI, or if not possible, mammography or physical examination. A reduction in the product of the two largest perpendicular diameters of the primary tumor size by 50% or more is defined as partial response (PR), an increase by 25% or more or a new lesion as progressive disease (PD), and the remaining scenarios as no change (NC). Lymphatic nodes are not taken into account. For defined categories of efficacy (complete, partial, stable, or progression), the proportion of patients with success will be determined and appropriate confidence intervals will be calculated.
4) LRRFS, RRFS, LRFS, DDFS, IDFS and OS are defined as the time period between registration and first event (see 15.5, Table 7) and will be analyzed after the end of the study by referring to data from GBG patient’s registry. Progression during neoadjuvant treatment is not considered as events. Curves will be estimated using the Kaplan-Meier method, based on the all randomized and treated patients’ efficacy population. The median survival times (and 95%CIs) will be estimated. Univariate and multivariate Cox-proportional hazards model will be used to adjust hazard ratios for stratification factor and the above defined covariates.
5) Tolerability and Safety: Descriptive statistics for the 2 treatments will be given on the number of patients whose treatment had to be reduced, delayed or permanently stopped. The reason for termination includes aspects of efficacy (e.g. termination due to tumor progression), safety (e.g. termination due to adverse events) and compliance (e.g. termination due to patient's withdrawal of consent). Reasons for premature termination will be categorized according to the main reason and will be presented in frequency tables. Safety by toxicity grades is defined by the NCI-CTCAE version 4.03.
6) Translational research: Exploratory analyses will be performed to identify possible relationships between biomarkers and drug activity. The aim is to identify potential predictive short and long term parameters (pCR, no treatment effect (according to regression score 0-1), RFS, and OS). Missing data on response evaluation will be set to no response
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) After definitive surgery of all patients
2) After definitive surgery of all patients
3) After the 2nd cycle and before surgery
4) Follow up Period
5) End of Study
6) After definitive surgery of all patients
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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 | Yes |
| 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 | 45 |
| 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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| The end of this study is defined as 4 weeks after the last patient had completed her last treatment cycle. The planned end of study is Q-I 2016. |
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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 | |
| E.8.9.1 | In the Member State concerned months | 15 |
| E.8.9.1 | In the Member State concerned days | |
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