Bevacizumab, Everolimus (RAD001), and Lapatinib as Neoadjuvant Chemotherapy Regimes for Primary Breast Cancer

NCT00567554 | Completed Phase 3 DMC

• 2 other identifiers: GBG 442006-005834-19
• Study Type: interventional
• Target: 2,600
• Locations: 1 country
• Sites: 1

Brief Summary

Anthracycline-taxane based chemotherapy regimens are recommended mainly by current guidelines for neoadjuvant application of systemic treatment. The addition of other cytotoxic agents, e.g. antimetabolites, vincaalkaloids, or platinum salts resulted in marginal increase in efficacy, but was associated also with an increase in toxicity. Recently, only the addition of the Her-2 antibody trastuzumab has significantly improved pathologic response rate. Therefore, two major strategies are followed in current research projects:

• To improve the selection of patients according to their tumors' sensitivity to chemotherapy.
• To implement small molecules with specific mechanism of action. Within the GeparQuinto trial, the first strategy is followed by:
• The PREDICT substudy. A gene signature specific for the response to anthracyclines and taxanes will be prospectively evaluated for its ability to identify patients with chance higher than 50% for a pCR. The results may leed to a better risk-benefit ratio for the use of conventional chemotherapy.
• Adapting further chemotherapy to the response of the tumor to the first couple of chemotherapy cycles. Based on the previous experience made by the GeparTrio study, patients not responding early have a low chance to respond with a pCR irrespective of the type of chemotherapy. So, if further chemotherapy is planned, therapy should be selected according to a favorable toxicity profile. The second strategy is followed by investigating in three parallel group comparisons the efficiency of three distinct small molecules which appear to be generally active in breast cancer:
• Bevacizumab, an inhibitor of the VEGF pathway targeting tumor neo-angiogenesis.
• Lapatinib, an inhibitor of the Her-1 and Her-2 receptor tyrosine kinase.
• RAD001 (Everolimus), an inhibitor of the mTOR molecule, a central controller of tumor cell growth and angiogenesis and chemosensitizer. Treatment for patients participating in the GeparQuinto study will be allocated according to the Her-2 status of the tumor as well as according to the sonographic response after the first 4 cycles of treatment. Experimental therapy with bevacizumab, lapatinib, and everolimus (RAD001) will be randomly added in distinct settings.

Conditions

Breast Cancer

Keywords

breast cancer; primary systemic therapy; pCR Rates; Bevacizumab; Trastuzumab; Lapatinib; Everolimus

Outcome Measures

Primary Outcomes (1)

• To compare the pCR rates of neoadjuvant treatment in all 3 Settings

  2009

Secondary Outcomes (5)

• To assess the toxicity of and compliance to all six treatments.

  2009

• To determine the breast conservation rate after each treatment.

  2009

• 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.

  2012

• To assess treatment efficacies in subgroups defined according to tumor stage (T2-3 vs T4) receptor status (ER and/or PR pos. vs ER and PR neg.) and response by best appropriate imaging method to the first 4 cycles of treatment (complete vs partial vs no)

  2009

• To examine and compare prespecified molecular markers on core biopsy before and after end of chemotherapy

  2012

Study Arms (6)

1

EXPERIMENTAL

EC-T

Drug: epirubicin - cyclophosphamide / docetaxel

2

EXPERIMENTAL

EC-T +/- B

Drug: epirubicin - cyclophosphamide / docetaxel + bevacizumab

3

EXPERIMENTAL

Pw

Drug: paclitaxel

4

EXPERIMENTAL

Pw + RAD001

Drug: paclitaxel + everolimus (RAD001)

5

EXPERIMENTAL

EC-T + H

Drug: epirubicin - cyclophosphamide / docetaxel + trastuzumab

6

EXPERIMENTAL

EC-T + L

Drug: epirubicin - cyclophosphamide / docetaxel + lapatinib

Interventions

epirubicin - cyclophosphamide / docetaxel DRUG

1

epirubicin - cyclophosphamide / docetaxel + bevacizumab DRUG

2

paclitaxel DRUG

3

paclitaxel + everolimus (RAD001) DRUG

4

epirubicin - cyclophosphamide / docetaxel + trastuzumab DRUG

5

epirubicin - cyclophosphamide / docetaxel + lapatinib DRUG

6

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent
• Complete baseline documentation 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.
• Tumor lesion in the breast with a palpable size of ≥ 2 cm or a sonographically size of at least 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 have stages of disease in which adjuvant chemotherapy would be considered.
• Locally advanced tumors with cT4 or cT3 or
• 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-Safety phase only patients with cT4 or cT3 cN+ disease are eligible.
• Known HER-2/neu status detected on core biopsy. HER-2/neu positive is defined as HercepTest IHC 3+ or FISH+;
• Age older than 18 years;
• Karnofsky Performance status index at least 80%;
• Normal cardiac function must be confirmed by ECG and cardiac ultrasound (LVEF or shortening fraction) within 1 month prior to registration.
• Laboratory requirements:
• Hematology: Absolute neutrophil count (ANC) ≥ 2.0 x 10e9/L platelets ≥ 100 x 10e9/L, Hemoglobin ≥ 10 g/dL (≥ 6.2 mmol/L) Hepatic function: Total bilirubin \< 1 x UNL ASAT (SGOT) and ALAT (SGPT)≤ 2.5 x UNL Alkaline phosphatase ≤ 5 UNL. Patients with ASAT and / or ALAT \> 1.5 x UNL associated with alkaline phosphatase \> 2.5 x UNL are not eligible for the study; Renal function: Creatinine ≤ 175 µmol/L (2 mg/dL) \< 1,25 UNL (or the calculated creatinine clearance ≥ 60 mL/min) Urine dipstick for proteinuria \< 2+. Patients discovered to have ≥2+ proteinuria on dipstick urinalysis should undergo a 24 hour urine collection and must demonstrate ≤1 g of protein in 24 hours
• Paraffin tumor tissue block and two serum samples centrally made available

You may not qualify if:

• Patients with low or moderate risk, which are only doubtful candidates for adjuvant chemotherapy
• Evidence of distant metastasis;
• Prior chemotherapy for any malignancy;
• Prior radiation therapy for breast cancer;
• Pregnant or lactating patients.
• Inadequate general condition
• Previous malignant disease
• 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, un- or poorly controlled arterial hypertension, rhythm abnormalities requiring permanent treatment, clinically significant valvular heart disease
• Previous thromboembolic event
• Known hemorrhagic diathesis or increased bleeding risk
• History of significant neurological or psychiatric disorders that would prohibit the understanding and giving of informed consent;
• Pre-existing motor or sensory neuropathy of a severity more than grade 2 by NCI criteria
• Currently active infection;incomplete wound healing
• Active peptic ulcer
• Disease significantly affecting gastrointestinal function

Sponsors & Collaborators

• GBG Forschungs GmbH: lead
• AGO Study Group: collaborator

Study Sites (1)

Universitätsfrauenklinik Frankfurt / Main

Frankfurt am Main, Germany

Location

Related Publications (5)

• Fasching PA, Loibl S, Hu C, Hart SN, Shimelis H, Moore R, Schem C, Tesch H, Untch M, Hilfrich J, Rezai M, Gerber B, Costa SD, Blohmer JU, Fehm T, Huober J, Liedtke C, Weinshilboum RM, Wang L, Ingle JN, Muller V, Nekljudova V, Weber KE, Rack B, Rubner M, von Minckwitz G, Couch FJ. BRCA1/2 Mutations and Bevacizumab in the Neoadjuvant Treatment of Breast Cancer: Response and Prognosis Results in Patients With Triple-Negative Breast Cancer From the GeparQuinto Study. J Clin Oncol. 2018 Aug 1;36(22):2281-2287. doi: 10.1200/JCO.2017.77.2285. Epub 2018 May 23.

  PMID: 29791287 DERIVED

• Untch M, von Minckwitz G, Gerber B, Schem C, Rezai M, Fasching PA, Tesch H, Eggemann H, Hanusch C, Huober J, Solbach C, Jackisch C, Kunz G, Blohmer JU, Hauschild M, Fehm T, Nekljudova V, Loibl S; GBG and the AGO-B Study Group. Survival Analysis After Neoadjuvant Chemotherapy With Trastuzumab or Lapatinib in Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer in the GeparQuinto (G5) Study (GBG 44). J Clin Oncol. 2018 May 1;36(13):1308-1316. doi: 10.1200/JCO.2017.75.9175. Epub 2018 Mar 15.

  PMID: 29543566 DERIVED

• von Minckwitz G, Loibl S, Untch M, Eidtmann H, Rezai M, Fasching PA, Tesch H, Eggemann H, Schrader I, Kittel K, Hanusch C, Huober J, Solbach C, Jackisch C, Kunz G, Blohmer JU, Hauschild M, Fehm T, Nekljudova V, Gerber B; GBG/AGO-B study groups; Gnauert K, Heinrich B, Pratz T, Groh U, Tanzer H, Villena C, Tulusan A, Liedtke B, Blohmer JU, Kittel K, Mau C, Potenberg J, Schilling J, Just M, Weiss E, Buckner U, Wolfgarten M, Lorenz R, Doering G, Feidicker S, Krabisch P, Deichert U, Augustin D, Kunz G, Kast K, von Minckwitz G, Nestle-Kramling C, Rezai M, Hoss C, Terhaag J, Fasching P, Staib P, Aktas B, Kuhn T, Khandan F, Mobus V, Solbach C, Tesch H, Stickeler E, Heinrich G, Wagner H, Abdallah A, Dewitz T, Emons G, Belau A, Rethwisch V, Lantzsch T, Thomssen C, Mattner U, Nugent A, Muller V, Noesselt T, Holms F, Muller T, Deuker JU, Schrader I, Strumberg D, Uleer C, Solomayer E, Runnebaum I, Link H, Tome O, Ulmer HU, Conrad B, Feisel-Schwickardi G, Eidtmann H, Schumacher C, Steinmetz T, Bauerfeind I, Kremers S, Langanke D, Kullmer U, Ober A, Fischer D, Kohls A, Weikel W, Bischoff J, Freese K, Schmidt M, Wiest W, Sutterlin M, Dietrich M, Griesshammer M, Burgmann DM, Hanusch C, Rack B, Salat C, Sattler D, Tio J, von Abel E, Christensen B, Burkamp U, Kohne CH, Meinerz W, Grasshoff ST, Decker T, Overkamp F, Thalmann I, Sallmann A, Beck T, Reimer T, Bartzke G, Deryal M, Weigel M, Huober J, Weder P, Steffens CC, Lemster S, Stefek A, Ruhland F, Hofmann M, Schuster J, Simon W, Kronawitter U, Clemens M, Fehm T, Janni W, Latos K, Bauer W, Rossmann A, Bauer L, Lampe D, Heyl V, Hoffmann G, Lorenz-Salehi F, Hackmann J, Schlag R. Survival after neoadjuvant chemotherapy with or without bevacizumab or everolimus for HER2-negative primary breast cancer (GBG 44-GeparQuinto)dagger. Ann Oncol. 2014 Dec;25(12):2363-2372. doi: 10.1093/annonc/mdu455. Epub 2014 Sep 15.

  PMID: 25223482 DERIVED

• von Minckwitz G, Eidtmann H, Rezai M, Fasching PA, Tesch H, Eggemann H, Schrader I, Kittel K, Hanusch C, Kreienberg R, Solbach C, Gerber B, Jackisch C, Kunz G, Blohmer JU, Huober J, Hauschild M, Fehm T, Muller BM, Denkert C, Loibl S, Nekljudova V, Untch M; German Breast Group; Arbeitsgemeinschaft Gynakologische Onkologie-Breast Study Groups. Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. N Engl J Med. 2012 Jan 26;366(4):299-309. doi: 10.1056/NEJMoa1111065.

  PMID: 22276820 DERIVED

• Untch M, Loibl S, Bischoff J, Eidtmann H, Kaufmann M, Blohmer JU, Hilfrich J, Strumberg D, Fasching PA, Kreienberg R, Tesch H, Hanusch C, Gerber B, Rezai M, Jackisch C, Huober J, Kuhn T, Nekljudova V, von Minckwitz G; German Breast Group (GBG); Arbeitsgemeinschaft Gynakologische Onkologie-Breast (AGO-B) Study Group. Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial. Lancet Oncol. 2012 Feb;13(2):135-44. doi: 10.1016/S1470-2045(11)70397-7. Epub 2012 Jan 17.

  PMID: 22257523 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

EC regimen; Docetaxel; Bevacizumab; Paclitaxel; Everolimus; Trastuzumab; Lapatinib

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Sirolimus; Macrolides; Lactones; Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Gunter von Minckwitz, MD, Prof.

  GBG Forschungs GmbH

  PRINCIPAL INVESTIGATOR

• Michael Untch, MD, Prof.

  AGO Study Group

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 4, 2007
• First Posted: December 5, 2007
• Study Start: October 1, 2007
• Primary Completion: August 1, 2011
• Study Completion: October 1, 2015
• Last Updated: February 10, 2016

Record last verified: 2016-02

Locations

DE (1)