| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with primary breast cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with primary breast cancer |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 pathological complete response (pCR= ypT0/is ypN0) rates of neoadjuvant treatment with sequential, dose-dense, dose-intensified ETC(+HP) vs. weekly PM(Cb)(+HP) in patients with high-risk operable or locally advanced breast cancer.
Only for those patients randomized for the supportive anemia treatment:
To compare the frequency of patients reaching hemoglobin (Hb) levels ≥ 11g/dl 6 weeks after treatment start of a first episode of anemia grade ≥2 (Hb < 10g/dl) between patients receiving supportive treatment for iron deficiency with parental ferric carboxymaltose versus physician’s choice (no supportive treatment, oral iron substitution, erythropoiesis-stimulating agent (ESA), or both).
|
|
| E.2.2 | Secondary objectives of the trial |
• To assess the pCR rates per arm separately for the stratified subpopulations.
• To determine the rates of ypT0 ypN0; ypT0 ypN0/+; ypT0/is ypN0/+; ypT(any) ypN0; and the residual cancer burden (RCB) score.
• To determine the response rates of the breast tumor and axillary nodes based on physical examination and imaging tests (sonography, mammography, or MRI) after treatment in both arms.
• To determine the breast conservation rate after each treatment.
• To assess the toxicity and compliance including incidence of febrile neutropenia, cardiac dysfunction/failure and frequency of dose delays and reductions per arm and subtype.
• To determine loco-regional invasive recurrence free survival (LRRFS), distant-disease-free survival (DDFS), invasive disease-free survival (IDFS), and overall survival (OS) in both arms and according to stratified subpopulations.
|
|
| 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 |
To demonstrate that PET-CT before surgery in addition to conventional presurgical staging methods can decrease the mastectomy rate in patients receiving neoadjuvant chemotherapy for breast cancer (GeparPET substudy).
To evaluate genome wide single nucleotide polymorphisms (SNPs) to detect genes possibly associated with toxicity and efficacy (Pharmacogenetic substudy).
To assess ovarian function measured by amenorrhea rate in correlation with changes in E2, FSH, LH , Anti-Müller Hormone, ultrasound-follicle count in patients aged <45 years.
|
|
| E.3 | Principal inclusion criteria |
• Written informed consent according to local regulatory requirements prior to beginning specific protocol procedures.
• Complete baseline documentation must be submitted via MEdCODES to GBG Forschungs GmbH.
• Unilateral or bilateral primary carcinoma of the breast, confirmed histologically by core biopsy. Fine-needle aspiration from the breast lesion alone is not sufficient. Incisional biopsy or axillary clearance 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. In case of inflammatory disease, the extent of inflammation can be used as measurable lesion.
• Patients must have stage cT1c - cT4a-d disease. Patients with HER2-positive or TNBC are eligible irrespective of nodal status (cN0-cN3). Patients with luminal B-like tumors (defined here as ER and/or PgR >1% stained cells, HER2 negative, Ki-67 >20%) only with histologically (sentinel-node biopsy, core- or fine-needle biopsy) involved lymph nodes (pN1-3).
• In patients with multifocal or multicentric breast cancer, the largest lesion should be measured.
• Centrally confirmed ER, PR and HER2 status. Central pathology includes also assessment of Ki-67 and LPBC status on core biopsy. ER/PR negative is defined as <=1% stained cells and HER2-positive is defined as IHC 3+ or in-situ hybridization (ISH) and according to ASCO-CAP guidelines as of 2013). Formalin-fixed, paraffin-embedded (FFPE) breast tissue from core biopsy has therefore to be sent to the GBG central pathology laboratory prior to randomization.
• Age 18 years.
• Karnofsky Performance status index 90%.
• Confirmed normal cardiac function by ECG and cardiac ultrasound (LVEF or shortening fraction) within 4 weeks prior to randomization. LVEF must be above 55%.
• 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.
• Negative serum pregnancy test within 7 days prior to randomization for all women of childbearing potential with the result available before dosing.
• 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 in case of high risk for primary metastasis. In case of a positive bone scan, bone X-ray or CT scan is mandatory. Other tests may be performed as clinically indicated.
• Patients must agree with central pathology testing of core biopsy specimen and final pathology specimen and be available and compliant for treatment and follow-up.
• In addition for patients to be randomized to the two supportive anemia treatment arms:
- Hemoglobin level <10g/dl
- Body weight ≥ 40 kg
- No need for immediate red blood cell transfusion
- Transferrin saturation (TSAT) ≤20% and serum ferritin
<600ng/ml.*
* Serum ferritin levels of the first 100 patients with hemoglobin drop below 10g/dl will be reviewed. In case less than 25 of these patients have levels <300 ng/ml, the Protocol Board will decide to
• either increase the threshold of serum ferritin to reach an incidence of 40% of patients eligible for randomization to the supportive anemia treatments or
• to close the randomization if it will be non-realistic to recruit a sufficient number of patients or
• to modify and amend the current statistical design to a lower target sample size that can be reached with the expected number of eligible patients.
|
|
| E.4 | Principal exclusion criteria |
• Patients with ER- and/or PR-positive, HER2-negative breast cancer and Ki-67 <= 20% (any luminal A-like subtype) or luminal B-like (Ki67>20%) subtype without nodal involvement.
• Patients with stages cT1a, cT1b, or any M1.
• Patients with pure lobular invasive breast cancer.
• Prior chemotherapy for any malignancy.
• Prior radiation therapy for breast cancer.
• Pregnant or lactating patients. Patients of childbearing potential must agree to use one highly effective or two effective forms of non-hormonal contraceptive measures during study treatment and 7 months following the last dose of mAbs.
• Inadequate general condition (not fit for dose-dense, dose-intensified anthracycline-taxane-targeted agents-based chemotherapy).
• Previous malignant disease 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.
• Pre-existing motor or sensory neuropathy of a severity grade 2 by NCI-CTC criteria v 4.0.
• Currently active infection.
• Incomplete wound healing.
• Definite contraindications for the use of corticosteroids.
• Known hypersensitivity reaction to one of the compounds or incorporated substances used in this protocol.
• 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.
• Participation in another clinical trial with any investigational, not marketed drug within 30 days prior to study entry.
• Male patients.
In addition for patients to be randomized to the two supportive anemia treatment arms:
• Iron substitution (oral or IV) or blood transfusions or treatment with r-HuEPO with the last 4 weeks prior to study start.
• Known hypersensibility or contraindication against ferric carboxymaltose.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary efficacy endpoint:
Pathological complete response of breast and lymph nodes (ypT0/is ypN0; primary endpoint)
|
|
| 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. |
|
| E.5.2 | Secondary end point(s) |
1. Secondary short-time efficacy endpoints (ypT0 ypN0; ypT0 ypN0/+; ypT0/is ypN0/+; ypT(any) ypN0, the residual cancer burden (RCB) score, response by physical examination, imaging response, breast conservation)
2. loco-regional invasive recurrence free survival (LRRFS), regional recurrence free survival (RRFS), distant-disease-free survival (DDFS), invasive disease-free survival (IDFS), and overall survival (OS) are defined as the time period between registration and first event.
3. Tolerability and Safety: Descriptive statistics for the 5 treatments (ETC +/- anti-HER2-treatment, PM +/- anti-HER2-treatment, PMCb) will be given on the number of patients whose treatment had to be reduced, delayed or permanently stopped.
4. Correlative science research: Exploratory analyses will be performed to identify possible relationships between biomarkers and drug activity. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Clinical (c) and imaging (i) response will be assessed every 2nd cycle
and before surgery by physical examination and imaging tests.
2. LRRFS, RRFS, LRFS, DDFS, IDFS and OS are defined as the time period
between registration and first event.
3. Throughout the up to 18 weeks treatment period and the 30 day safety follow up.
4. With core examination and surgery. In addition and optional after 6 weeks of chemotherapy, before and after surgery. |
|
| 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 | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | 100 |
| 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
|
The end of the study is defined as 1 month after last patient had
surgery (not considering patients in which no surgery is planned or
possible. |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
Print
