Epirubicin Hydrochloride, Cisplatin, and Fluorouracil or Capecitabine With or Without Lapatinib Ditosylate as First-Line Therapy in Treating Patients With Stomach Cancer or Gastroesophageal Junction Cancer

Effectiveness of First Line Treatment With Lapatinib and ECF/X in Histologically Proven Adenocarcinoma of the Stomach or the Esophagogastric Junction, Metastatic or Not Amenable to Curative Surgery According to HER2 and EGFR Status: a Randomized Phase II Trial

RATIONALE: Drugs used in chemotherapy, such as epirubicin hydrochloride, cisplatin, fluorouracil, and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Lapatinib ditosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether giving combination chemotherapy together with or without lapatinib ditosylate is more effective in treating patients with cancer of the stomach or gastroesophageal junction.

PURPOSE: This randomized phase II trial is studying how well epirubicin hydrochloride, cisplatin, and fluorouracil or capecitabine works when given together with or without lapatinib ditosylate as first-line therapy in treating patients with stomach cancer or gastroesophageal junction cancer.

Study Overview

• Status: Terminated
• Conditions: Gastric Cancer; Adenocarcinoma of the Gastroesophageal Junction
• Intervention / Treatment: Drug: fluorouracil; Drug: cisplatin; Drug: capecitabine; Drug: epirubicin hydrochloride; Drug: lapatinib ditosylate

Detailed Description

OBJECTIVES:

Primary

• To determine the activity of first-line treatment comprising epirubicin hydrochloride, cisplatin, and fluorouracil or capecitabine with or without lapatinib ditosylate in patients with adenocarcinoma of the stomach or esophagogastric junction that is metastatic or not amenable to curative surgery according to HER2 and EGFR status.

Secondary

• To explore the activity of this regimen in patients who are HER2 negative by FISH, but HER2 positive by IHC (2+ and 3+) as well as patients who are HER2 positive or negative by FISH and negative by IHC (0 or 1+), but EGFR positive by FISH or by IHC (2+ and 3+).
• To assess the concordance of HER2 determination by FISH and IHC.

OUTLINE: This is a multicenter study. Patients are stratified according to institution and the combination of EGFR/HER2 status as determined by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) assays (HER2 positive by FISH/HER2 positive by IHC 2/3+ vs HER2 negative by FISH/HER2 positive by IHC 2/3+ vs HER2 negative by IHC 0/1+/EGFR positive by FISH or by IHC 2/3+). Patients are randomized to 1 of 2 treatment arms.

• Arm I (experimental): Patients receive epirubicin hydrochloride IV and cisplatin IV on day 1; fluorouracil IV continuously on days 1-21 or oral capecitabine twice daily on days 1-21; and oral lapatinib ditosylate once daily on days 1-21. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
• Arm II (control): Patients receive epirubicin hydrochloride, cisplatin, and fluorouracil or capecitabine as in arm I. Patients also receive oral placebo once daily on days 1-21. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed at 8 weeks, every 3 months for 2 years, and then every 6 months thereafter.

• Study Type: Interventional
• Enrollment (Actual): 29
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium
    • Institut Jules Bordet
  • Leuven, Belgium
    • U.Z. Gasthuisberg
• Germany
  • Mainz, Germany
    • Johannes Gutenberg Universitaetskliniken
• Portugal
  • Lisboa, Portugal
    • I.P.O. Francisco Gentil - Centro De Lisboa

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the stomach or the esophagogastric junction

  • Metastatic disease OR not amenable to curative surgery
• Tissue material for HER2 and EGFR assessment must be available
• Positive HER2 status by immunohistochemistry (IHC) OR positive EGFR by either fluorescence in situ hybridization (FISH) or IHC at time of randomization
• No clinical signs of CNS involvement

PATIENT CHARACTERISTICS:

• WHO performance status 0-1
• WBC > 3 x 10^9/L
• Absolute neutrophil count > 1.5 x 10^9/L
• Platelet count > 100 x 10^9/L
• Hemoglobin > 9 g/dL
• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• AST/ALT ≤ 3 times ULN (≤ 5 times ULN in case of liver metastases)
• Serum creatinine ≤ 2.0 mg/dL
• Creatinine clearance ≥ 60 mL/min
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 1 month after completion of study therapy
• LVEF normal by MUGA scan or ECHO
• No serious cardiac illness within the past 6 months
• No previous or concurrent malignancies except for adequately treated cone-biopsied carcinoma in situ of the cervix or basal cell carcinoma of the skin
• Able to swallow and retain oral medication
• No history or evidence of interstitial pneumonitis or pulmonary fibrosis
• No uncontrolled infections or serious illnesses, malabsorption syndrome, or medical conditions including chronic alcohol abuse, hepatitis, HIV, and/or cirrhosis
• No psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol or follow-up schedule

PRIOR CONCURRENT THERAPY:

• At least 12 months since prior neoadjuvant or adjuvant chemotherapy
• No other investigational drugs from 28 days prior to the first dose of study treatment until 30 days after the last dose of study treatment
• At least 30 days since prior and no concurrent drugs or herbal constituents known to be inducers or inhibitors of CYP3A4
• No prior palliative systemic chemotherapy
• No prior EGFR pathway-targeting therapy (e.g., antibodies or tyrosine kinase inhibitors)
• No concurrent traditional Chinese medicines
• No concurrent non-drug therapies such as radiotherapy (other than for pain relief) or surgery
• No other concurrent anticancer therapy or investigational agents
• No concurrent grapefruit or its juice

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lapatinib; Chemotherapy + lapatinib	Drug: fluorouracil; Drug: cisplatin; Drug: capecitabine; Drug: epirubicin hydrochloride; Drug: lapatinib ditosylate
Placebo Comparator: Placebo; Chemotherapy + placebo	Drug: fluorouracil; Drug: cisplatin; Drug: capecitabine; Drug: epirubicin hydrochloride

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Progression-free survival

Secondary Outcome Measures

Outcome Measure
Toxicity
Response rate
Overall survival
Concordance of diagnostic tests

Collaborators and Investigators

• Sponsor: European Organisation for Research and Treatment of Cancer - EORTC
• Investigators: Study Chair: Arnaud Roth, Hôpital Cantonal Universitaire de Genève

Publications and helpful links

General Publications

• Roth A, Moehler MH, Mauer M, et al.: Lapatinib in combination with ECF/x in EGFR1 or HER2-overexpressing first-line metastatic gastric cancer (GC): A phase II randomized placebo controlled trial (EORTC 40071). [Abstract] J Clin Oncol 28 (Suppl 15): A-TPS205, 2010.

Study record dates

Study Major Dates

• Study Start: December 1, 2010
• Primary Completion (Actual): August 1, 2013
• Study Completion (Actual): September 1, 2014

Study Registration Dates

• First Submitted: May 13, 2010
• First Submitted That Met QC Criteria: May 13, 2010
• First Posted (Estimate): May 14, 2010

Study Record Updates

• Last Update Posted (Estimate): October 12, 2016
• Last Update Submitted That Met QC Criteria: October 11, 2016
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Keywords: stage IV gastric cancer; adenocarcinoma of the stomach; adenocarcinoma of the gastroesophageal junction; stage IIIA gastric cancer; stage IIIB gastric cancer; stage IIIC gastric cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Stomach Diseases; Head and Neck Neoplasms; Esophageal Diseases; Stomach Neoplasms; Adenocarcinoma; Esophageal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Protein Kinase Inhibitors; Antibiotics, Antineoplastic; Cisplatin; Fluorouracil; Capecitabine; Epirubicin; Lapatinib
• Other Study ID Numbers: EORTC-40071; EU-21036; 2009-011580-36 (EudraCT Number)