English Summary- GeparQuinto
A phase III trials program exploring the integration of Bevacizumab, Everolimus (RAD001), and Lapatinib into current neoadjuvant chemotherapy regimes for primary breast cancer
Trial design
Prospective, randomised, open label, mulitcenter phase III
Current Status: Open to accrual
Treatment
Her-2 negative disease (Setting I):
Bevacizumab: 15 mg/kg i.v., day 1q day 21 for 8 cycles. Bevacizumab treatment will be stopped in patients without a sonographic response to 4x EC. Breast surgery should not be performed within 28 days after the last dose of bevacizumab.
Her-2 negative patients without response after 4 cycles of EC +/-B treatment (Setting II):
RAD001 (Everolimus): 5 mg orally daily.
Treatment with RAD001 should start 21 to 35 days after the last application of EC with a dose escalation of Day 1: 2.5 mg; Day 2: skipped; Day 3: 2.5 mg; Day 4: skipped; Day 5: 2.5 mg; Day 6: 2.5 mg; Day 7: 2.5 mg; Day 8: 2.5 mg; Day 9: 5 mg; Day 10: 2.5 mg; Day 11: 5 mg; Day 12: 2.5 mg, Day 13 and thereafter every day: 5 mg. Treatment with paclitaxel should start within 7-14 days after the start of RAD001.
Her-2 positive disease (Setting III):
Trastuzumab: Loading dose: 8 mg/kg, maintenance dose: 6 mg/kg, day 1 q day 21 for 8 cycles.
Lapatinib: 1000 mg (4 tablets) orally once daily continuously for 24 weeks starting on day 1 of the 1st cycle of EC until day 21 of the 4th cycle of T. Supportive therapy during TL cycles 1-4: pegfilgrastim (day 2).
Chemotherapy:
4 cycles of EC Epirubicin: 90 mg/m², day 1 q day 21 for 4 cycles followed by
Cyclophosphamide: 600 mg/m², day 1 q day 21 for 4 cycles. 4 cycles of T (as part of setting I or III)
Docetaxel: 100 mg/m², day 1 q day 21 for 4 cycles. 4 cycles of Pw (as part of setting II) Paclitaxel: 80 mg/m² i.v. given weekly on day 1 q day 8 for 12 weeks. Her-2 positive disease: post-surgical treatment with trastuzumab should be applied according to the current guidelines of the AGO (www.ago-online.org). A total treatment duration of 1 year with trastuzumab has to be achieved.
Patient population
Inclusion criteria
- Written informed consent for all study procedures including an additional core biopsy after the first four cycles of EC +/-B must be obtained and documented 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 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. In case of inflammatory disease, the extent of inflammation can be used as measurable lesion
- Patients should be in a stage of disease in which adjuvant chemotherapy would be considered. Therefore the following tumor stages are eligible * :
- locally advanced tumors with cT3 or cT4
- Estrogen (ER) and progesterone (PgR) receptor negative tumors or
- ER or PgR positive tumors which are cN+ (for cT2) or pNSLN+ (for cT1).*
During the Run-In Phase only patients with cT4 or cT3 cN+ disease are eligible. In patients with multifocal or multicentric breast cancer, the largest lesion should be measured
- Known HER-2/neu status detected on core biopsy. HER-2/neu positive is defined as HercepTest IHC 3+ or central FISH+.
- Age ≥18 years
- Karnofsky Performance status index ≥80%
- 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 and 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 < 1x UNL and
- ASAT (SGOT) and ALAT (SGPT) ≤ 2.5 x UNL and
- Alkaline phosphatase ≤ 5x UNL. Patients with ASAT and/or ALAT > 1.5x UNL and associated with alkaline phosphatase > 2.5x UNL are not eligible for the study.
- Renal function
Creatinine ≤ 175 µmol/L (2 mg/dL) < 1.5x UNL (or the calculated creatinine clearance should be ≤60 mL/min). - Proteinuria
Urine dipstick for proteinuria < 2+. Patients discovered to have ≥ 2+ proteinuria on dipstick urinalysis should undergo a 24-hour urine collection and must demonstrate ≤ 1g of protein in 24 hours.
- Hematology
- Paraffin tumor tissue block and two serum samples centrally made available (except when the patient does not agree to central biomaterial collection)
- 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 treatment and follow-up. Patients registered on this trial must be treated and followed up at the participating or at a cooperating center
Primary Objectives
- To compare the pCR rates of neoadjuvant treatment of epirubicin / cyclophosphamide followed by docetaxel (EC-T) with or without bevacizumab (EC-T vs. ECB-TB) in patients with Her-2 negative primary breast cancer (Setting I).
- To compare the pCR rates of neoadjuvant treatment with weekly paclitaxel with or without Everolimus (RAD001) (Pw vs. PwR) in patients with Her-2 negative primary breast cancer showing no sonographic response to 4 cycles of EC +/-B (Setting II).
- To compare the pCR rates of neoadjuvant treatment with epirubicin / cyclophosphamide followed by docetaxel with either trastuzumab or lapatinib (ECH-TH vs. ECL-TL) in patients with Her-2 positive primary breast cancer (Setting III).
Secondary Objectives
- To assess the toxicity of and compliance to all six treatments.
- To determine the response rates of the breast tumor and axillary nodes by physical examination and imaging tests (sonography, mammography, or MRI) after treatment in all arms.
- To determine the rates of pCR breast, pCR invasive, pCR invasive and nodes.
- To determine the breast conservation rate after each treatment.
- To determine the (loco-regional and distant) disease-free and overall survival after each treatment. In Her-2 positive disease, the cerebral disease-free survival will be determined separately.
- To assess treatment efficacies in subgroups defined according to tumor stage (T2-3 vs. T4), receptor status (ER and / or PgR positive vs. ER and PgR negative) and response by best appropriate imaging method to the first four cycles of treatment (complete vs. partial vs. no change).
- To examine and compare pre-specified molecular markers such as Ki-67, phospho-mTOR, YB-1, COX-2, HuR, phospho-p70 S6K, p65 NF kappa B, PTEN, PI3-K, Akt, and a marker for stem cell like breast cancers(SOX-10) on core biopsy before and after end of chemotherapy
Primary Endpoint
Pathological complete response of breast and lymph nodes (pCR breast and nodes; primary endpoint)