| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with early breast cancer |
| Patienten mit primärem Brustkrebs |
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| E.1.1.1 | Medical condition in easily understood language |
| Patients with early breast cancer |
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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 | LLT |
| E.1.2 | Classification code | 10007050 |
| E.1.2 | Term | Cancer |
| E.1.2 | System Organ Class | 100000004864 |
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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 |
Co-Primary Objectives
• A: To compare the pathological complete response (pCR= ypT0 ypN0) rates of neoadjuvant treatment with or without denosumab in addition to backbone treatment consisting of nPac 125mg/m² weekly (Cb)EC or nPac 125mg/m² day 1,8 q22 (Cb)EC plus anti-HER2 treatment (i. e. trastuzumab/pertuzumab in case of positive HER2-status) in patients with early breast cancer.
• B: To compare the pathological complete response (pCR= ypT0 ypN0) rates of nPac 125mg/m² weekly(Cb)EC or nPac 125mg/m² day 1,8 q22 (Cb)EC plus anti-HER2 treatment (i. e. trastuzumab/pertuzumab in case of positive HER2-status) in patients with early breast cancer.
• To assess the pathological complete response (pCR= ypT0 ypN0) rate of neoadjuvant treatment with ABP 980 and pertuzumab in the overall HER2+ cohort and compare with the results obtained in GeparSepto study. |
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| E.2.2 | Secondary objectives of the trial |
•To test for interaction of denosumab treatment with RANK expression.
•To assess the pCR rates per arm for both randomizations separately for TNBC and HR-/HER2+.
•To assess the pCR rates per arm for patients with RANK high and RANK low.
•To determine the rates of ypT0/Tis ypN0; ypT0 ypN0/+; ypT0/Tis ypN0/+; ypT(any) ypN0 for both randomizations.
•To assess the toxicity and compliance, including time to onset of peripheral sensory neuropathy grade 2-4 and resolution of peripheral sensory neuropathy grade 2-4 to grade 1.
• To determine loco-regional invasive recurrence free survival (LRRFS), distant-disease-free survival (DDFS), invasive disease-free survival (IDFS), EFS (event free survival) and overall survival (OS) in both arms and according to stratified subpopulations.
• To compare RANK/L expression from baseline to surgery.
• To assess mammographic density–changes induced by denosumab.
• To assess quality of life with a focus on persisting peripheral sensory neuropathy. |
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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 |
• To assess, characterize, and correlate disseminated tumor cells with the treatment effect (DTC Substudy).
• To correlate Single Nucleotide Polymorphisms (SNPs) of genes with the associated toxicity and histologically assessed treatment effect (Pharmacogenetic substudy).
• Detection of microRNA and correlation with pCR (Substudy on urinary miRNA sampling (UMS)). |
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| 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 tumor isn’t measurable by sonography, then MRI or mammography is sufficient. In case of inflammatory disease, the extent of inflammation can be used as measurable lesion.
• 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% or
- cT1c and HER2-pos
• Patients must have stage cT1c - cT4a-d disease.
• In patients with multifocal or multicentric breast cancer, the largest lesion should be measured.
• Centrally confirmed ER-negative, and PR-negative and HER2-status. Central pathology includes also assessment of HER2, Ki-67, TIL and RANK/L 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. LPBC (lymphocyte predominant breast cancer) is defined as more than 50% stromal tumour infiltrating lymphocytes. 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 3 months prior to randomization. Results must be above the normal limit of the institution. For patients with HER2-positive tumors 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.
• Serum calcium or albumin-adjusted serum calcium ≥2.0 mmol/L (8.0 mg/dL) and ≤2.9 mmol/L (11.5 mg/dL). Hypocalcemia has to be corrected before study entry by supplementation of calcium and vitamin D.
• Negative serum pregnancy test within 14 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.
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| E.4 | Principal exclusion criteria |
Pure lobular carcinomas (lobular histology and G1/G2 and HR+/HER2-)
• Patients with stages cT1a, cT1b, or any M1.
• Prior chemotherapy for any malignancy.
• Prior radiation therapy for breast cancer.
• History of disease with influence on bone metabolism, such as osteoporosis, Paget’s disease of bone, primary hyperparathyroidism requiring treatment at the time of randomization or considered likely to become necessary within the subsequent six months.
• Use of bisphosphonates or denosumab within the past 1 year.
• Significant dental/oral disease, including prior history or current evidence of osteonecrosis/ osteomyelitis of the jaw, active dental or jaw condition which requires oral surgery, non-healed dental/oral surgery, planned invasive dental procedure for the course of the study.
• Last visit at dentist > 1½ year ago.
• 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 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 inclusive calcium and vitamin D. Known hereditary fructose intolerance.
• 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.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Pathological complete response of breast and lymph nodes (ypT0 ypN0; primary endpoint) |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary endpoint will be summarized as pathological complete response rate for each treatment group for both randomizations. |
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| E.5.2 | Secondary end point(s) |
Secondary short-time efficacy endpoints
ypT0/Tis ypN0 is defined as no microscopic evidence of residual invasive viable tumor cells in all resected specimens of the breast and axilla; in case of sentinel node biopsy prior to treatment start, the axillary lymph nodes will be evaluated as described for the primary endpoint.
ypT0 ypN0/+ is defined as no microscopic evidence of residual invasive or non-invasieve viable tumor cells in all resected specimens of the breast; ypT0/Tis 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
Clinical (c) and imaging (i) response will be assessed every 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, MRI or mammography will be considered with decreasing priority. The same imaging method should be considered for the measurement before, during and after treatment.
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.
Breast conservation is defined as tumorectomy, segmentectomy or quadrantectomy as a most radical surgery.
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. The clinical tumor response by palpation prior to surgery will also be presented, if applicable.
LRRFS, DDFS, IDFS; EFS and OS are defined as the time period between registration and first event and will be analyzed after the end of the study by referring to data from GBG patient’s registry. Progressions during neoadjuvant treatment are not considered as events.
Tolerability and Safety: Descriptive statistics for the 4 treatments (+/- anti-HER2-treatment) 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 are defined by the NCI-CTCAE version 4.0.
Correlative science research: Exploratory analyses will be performed to identify possible relationships between biomarkers and drug activity. The aim is to identify potential prognostic/predictive biomarkers of short and long term outcome parameters (pCR, EFS, and OS). Mammographic density of the pre-treatment and pre-surgical mammogram will be assessed centrally. 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 |
ypT0/Tis ypN0 is defined as no microscopic evidence of residual 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-invasieve viable tumor cells in all resected specimens of the breast.
Clinical (c) and imaging (i) response will be assessed every 2nd cycle and before surgery by physical examination and imaging tests.
LRRFS, DDFS, IDFS; EFS and OS are defined as the time period between registration and first event and will be analyzed after the end of the study by referring to data from GBG patient’s registry. Progressions during neoadjuvant treatment are not considered as events.
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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 | 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) | 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 | 4 |
| 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 | 50 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 0 |
| 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 the study is defined as up to 2 months after last patient had surgery (not considering patients in which no surgery is planned or possible). |
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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 | 8 |
| E.8.9.1 | In the Member State concerned days | |
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