Phase I/II Study of Neoadjuvant Lapatinib in Breast Cancer

NCT00450892 | Completed Phase 1 DMC

• 3 other identifiers: EORTC-10054GSK-EORTC-100542006-000864-94
• Study Type: interventional
• Target: 129
• Locations: 5 countries
• Sites: 15

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as docetaxel, fluorouracil, epirubicin, and cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Lapatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving these treatments before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving trastuzumab after surgery may kill any tumor cells that remain after surgery. PURPOSE: This randomized phase I/II trial is studying the side effects and best dose of docetaxel and lapatinib when given with or without combination chemotherapy and to see how well they work in treating women with locally advanced, inflammatory, or resectable breast cancer.

Conditions

Breast Cancer

Keywords

inflammatory breast cancer; stage II breast cancer; stage IIIA breast cancer; stage IIIB breast cancer; stage IIIC breast cancer

Outcome Measures

Primary Outcomes (2)

• Phase I part: Dose limiting toxicity during cycle 1

  during study

• Phase II: Pathological complete response rate

  end of study

Secondary Outcomes (2)

• Phase I: Changes in apoptosis and proliferation markers.

  end of Phase I

• Phase II: Tolerability, clinical/radiological response rates, breast conserving surgery, pharmacodynamics data

  end of study

Study Arms (3)

arm 1

OTHER

Drug: docetaxel+lapatinib

arm 2

OTHER

Drug: docetaxel + trastuzumab

arm 3

EXPERIMENTAL

Drug: docetaxel + trastuzumab + lapatinib

Interventions

docetaxel+lapatinib DRUG

3 cycles of docetaxel (100 mg/m²) + lapatinib (1000 mg/d) followed by 3 cycles of FEC

arm 1

docetaxel + trastuzumab DRUG

3 cycles of docetaxel (100 mg/m²) + trastuzumab weekly schedule followed by 3 cycles of FEC 100

arm 2

docetaxel + trastuzumab + lapatinib DRUG

3 cycles of docetaxel (100 mg/m²) + trastuzumab weekly schedule +lapatinib (1000 mg/d) followed by 3 cycles of FEC 100

arm 3

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

DISEASE CHARACTERISTICS: * Histologically confirmed invasive breast cancer meeting the following criteria: * Phase I * Locally advanced or inflammatory disease, or specified subgroup of large operable disease for whom neoadjuvant chemotherapy is appropriate, defined as any 1 of the following: * Clinical stage T4a-d, any N (inflammatory breast carcinoma: tumor mass, breast enlargement, oedema and warmth of the skin are often present but not mandatory for the diagnosis) * Any clinical T, N2 or N3 (ipsilateral supraclavicular nodes) * cT3cN0,1 any estrogen receptor (ER) * cT2cN1 any ER * cT2cN0 ER negative * Presence of bilateral breast cancer is allowed * No bone, liver, or other extensive metastases * Minimal lung, skin, or nodal metastases may be allowed at the discretion of the investigator (phase I only) * Phase II * Locally advanced or inflammatory breast cancer, defined as any 1 of the following: * Clinical T4a-d, any N (inflammatory breast carcinoma: tumor mass, breast enlargement, oedema and warmth of the skin are often present but not mandatory for the diagnosis) * Any clinical T, N2 or N3 (ipsilateral supraclavicular nodes) * And M0 * Bilateral breast cancer is allowed provided only 1 side is HER2-positive * Any large resectable T2 or T3 breast cancers, M0 * HER2-positive disease by immunohistochemistry, fluorescent in situ hybridization, and/or chromogenic in situ hybridization * No CNS involvement * Two frozen trucuts for every core biopsy indicated by the translational research study * Hormone receptor status: * Estrogen receptor- and/or progesterone receptor-positive or negative tumor PATIENT CHARACTERISTICS: * Female * WHO performance status 0-2 * Hemoglobin \> 10.0 g/dL * Absolute neutrophil count \> 1,500/mm\^3 * Platelet count \> 100,000/mm\^3 * Bilirubin \< 1.5 times upper limit of normal (ULN) * AST and ALT \< 3 times ULN * Creatinine \< 1.5 times ULN * No other malignancies within the past 3 years except basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix (phase II) * LVEF normal by MUGA or ECHO * ECG normal * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception 2 weeks prior to, during, and for 1 month after completion of study treatment * No current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, or stable chronic liver disease not requiring therapy as per investigator assessment) * No serious cardiac illness or medical condition within the past 6 months including, but not limited to, any of the following: * History of documented congestive heart failure * High-risk uncontrolled arrhythmias * Angina pectoris requiring antianginal medication * Clinically significant valvular heart disease * Evidence of transmural infarction on ECG * Poorly controlled hypertension, defined as systolic blood pressure (BP) \> 180 mm Hg or diastolic BP \> 100 mm Hg * Able to swallow and retain oral medication * Accessible for repeat dosing and follow up * No concurrent grapefruit juice * No active or uncontrolled infection * No other serious illness * No malabsorption syndrome * No other medical condition (i.e., history of chronic alcohol abuse, hepatitis, HIV, and/or cirrhosis) * No psychological, familial, sociological, or geographical condition that would preclude study participation PRIOR CONCURRENT THERAPY: * No prior therapy for any cancer, including chemotherapy, radiotherapy, or hormonal therapy for breast cancer (phase I) * No prior epidermal growth factor receptor- or HER2-targeted therapy or antibody therapy (phase I) * More than 10 days since prior and no concurrent CYP3A4 inducers or inhibitors * More than 14 days since prior and no concurrent herbal infusions or dietary supplements * No antacids 1 hour before or after lapatinib ditosylate administration * No other concurrent investigational therapy or anticancer therapy * No concurrent prophylactic antibiotics

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• European Organisation for Research and Treatment of Cancer - EORTC: lead
• GlaxoSmithKline: collaborator

Study Sites (15)

C.H.U. Sart-Tilman

Liège, Belgium

Location

Clinique Sainte Elisabeth

Namur, Belgium

Location

Institut Bergonie

Bordeaux, France

Location

Institut Bergonié

Bordeaux, France

Location

CHRU de Limoges

Limoges, France

Location

Centre Leon Berard

Lyon, France

Location

CRLC Val D'Aurelle

Montpellier, France

Location

Centre Henri Becquerel

Rouen, France

Location

Hopital Rene Huguenin - Institut Curie

Saint-Cloud, France

Location

Centre Paul Strauss

Strasbourg, France

Location

Institut Gustave Roussy

Villejuif, France

Location

The Institute Of Oncology

Ljubljana, Slovenia

Location

Hôpitaux universitaires de Genève - HUG - site de Cluse-Roseraie

Geneva, Switzerland

Location

Centre Hospitalier Universitaire Vaudois

Lausanne, Switzerland

Location

Western General Hospital

Edinburgh, United Kingdom

Location

Related Publications (2)

• Bonnefoi H, Jacot W, Saghatchian M, Moldovan C, Venat-Bouvet L, Zaman K, Matos E, Petit T, Bodmer A, Quenel-Tueux N, Chakiba C, Vuylsteke P, Jerusalem G, Brain E, Tredan O, Messina CG, Slaets L, Cameron D. Neoadjuvant treatment with docetaxel plus lapatinib, trastuzumab, or both followed by an anthracycline-based chemotherapy in HER2-positive breast cancer: results of the randomised phase II EORTC 10054 study. Ann Oncol. 2015 Feb;26(2):325-32. doi: 10.1093/annonc/mdu551. Epub 2014 Dec 1.

  PMID: 25467016 RESULT

• Bonnefoi H, Zaman K, Debled M, Fiche M, Fournier M, Nobahar M, Pierga JY, Koch KM, Bartlett J, Zimmer A, Marreaud S, Bogaerts J, Cameron D. An European Organisation for Research and Treatment of Cancer phase I study of lapatinib and docetaxel as neoadjuvant treatment for human epidermal growth factor receptor 2 (HER2) positive locally-advanced/inflammatory or large operable breast cancer. Eur J Cancer. 2013 Jan;49(2):281-9. doi: 10.1016/j.ejca.2012.08.006. Epub 2012 Sep 18.

  PMID: 22999386 RESULT

MeSH Terms

Conditions

Breast Neoplasms; Inflammatory Breast Neoplasms

Interventions

Docetaxel; 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; Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• David Cameron, MD

  Edinburgh Cancer Centre at Western General Hospital

  STUDY CHAIR

• Herve Bonnefoi, MD

  Institut Bergonié

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 20, 2007
• First Posted: March 22, 2007
• Study Start: February 1, 2007
• Primary Completion: July 1, 2013
• Study Completion: July 1, 2013
• Last Updated: July 7, 2016

Record last verified: 2016-07

Locations

BE (2); FR (9); SL (1); GB (1); CH (2)