Patients with early breast cancer MedDRA version: 20.0 Level: LLT Classification code 10007050 Term: Cancer System Organ Class: 100000004864
Conditions
Interventions
Trade Name: XGEVA
Pharmaceutical Form:
INN or Proposed INN: Denosumab
CAS Number: 615258-40-7
Other descriptive name: DENOSUMAB
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: e
Sponsors
German Breast Group
Eligibility
Sex/Gender
All
Inclusion criteria
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. Are the trial subjects under
Exclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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.;Secondary Objective: •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.;Primary end point(s): Pathological complete response of breast and lymph nodes (ypT0 ypN0; primary endpoi | — |
Secondary
| Measure | Time frame |
|---|---|
| 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 | — |
Countries
Germany
Outcome results
None listed