MEGA (Met or EGFR Inhibition in Gastroesophageal Adenocarcinoma): FOLFOX Alone or in Combination With AMG 102 or Panitumumab as First-line Treatment in Patients With Advanced Gastroesophageal Adenocarcinoma (MEGA)

MEGA (Met or EGFR Inhibition in Gastroesophageal Adenocarcinoma): FOLFOX Alone or in Combination With AMG 102 or Panitumumab as First-line Treatment in Patients With Advanced Gastroesophageal Adenocarcinoma FNCLCC-FFCD-AGEO PRODIGE 17-ACCORD 20 Randomized Phase II Trial

This multicentre, open-label, randomized phase II trial is ongoing in 30 centres in France. Main eligibility criteria include: histologically proven adenocarcinoma of the stomach, esophagus or gastroesophageal junction; locally advanced or metastatic disease; measurable disease (RECIST 1.1); no known HER2 overexpression; no prior palliative chemotherapy.

Study Overview

• Status: Completed
• Conditions: Malignant Neoplasm of Stomach; Malignant Neoplasm of Esophagus
• Intervention / Treatment: Drug: Oxaliplatin; Drug: Folinic Acid; Drug: 5-fluoro-uracil; Drug: panitumumab; Drug: AMG102

Detailed Description

Patients are randomised to modified FOLFOX6 (oxaliplatin 85 mg/m2, FA 400 mg/m², FU 400 mg/m² bolus then 2400 mg/m² over 46 hr) alone or combined to either panitumumab (6 mg/kg) or AMG 102 (10 mg/kg), every two weeks until unacceptable toxicity or disease progression. Judgment criteria include 4-month progression-free survival (PFS) rate (primary endpoint), OS, objective response rate, and safety. Ancillary studies aim to identify candidate predictive and prognostic biomarkers among functional of molecular alterations of the EGFR/RAS/RAF and HGF/c-Met pathways, and to monitor circulating tumour cells and circulating immune cells (myeloid derived suppressor cells, NK cells) in sequential blood samples taken at baseline and through the study treatment. A total of 165 pts will be enrolled (Fleming's one-step design)

• Study Type: Interventional
• Enrollment (Actual): 162
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Villejuif, France, 94805
    • Institut Gustave Roussy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically proven adenocarcinoma of the stomach, the esophagus or the cardia (with or without signet ring cells; intestinal, diffuse or mixed form).
• Locally advanced (non resectable) or metastatic disease.
• Measurable disease (at least one measurable tumor) according to the RECIST V1.1 criteria (the tumor should not be located in a previous field of radiation).
• Absence of previous palliative chemotherapy. Previous neo-adjuvant or adjuvant chemotherapies (alone or combinated with radiotherapy) are authorized, including biotherapy (except anti-EGFR or anti-c-Met / HGF), if it has been stopped at least 12 months before inclusion.
• Previous radiotherapy authorized if stopped at least 14 days before randomization and if at least one measurable target outside the radiation area is present.
• No major surgery ≤ 28 days, or minor surgery ≤ 14 days, prior to randomization
• Sites of disease evaluated within 28 days prior to randomization with thoracic-abdominal-pelvic CT scan (or abdominal-pelvic MRI plus Chest X-ray).
• Age ≥ 18 years.
• Patient general status : ECOG 0-1.
• Life expectancy ≥ 3 months.
• Hemoglobin > or = 9 g/L - (transfusion authorized if necessary), PNN ≥ 1,5.109/l, platelets ≥ 100.109/l.
• Hepatic transaminases ≤ 2.5 times upper limit of normal (ULN) (≤ 5 ULN in case of hepatic metastases), alkaline phosphatase ≤ 2.5 ULN (≤ 5 ULN in case of hepatic metastases), total bilirubinemia ≤ 1.5 ULN)
• Creatinine clearance (calculated or measured) ≥ 50 ml / min, serum creatinine > 1.5 ULN
• Prothrombin time (PT) ≥ 60 %, INR < 1,5 (except if anticoagulant therapy)
• Magnesemia and calcemia ≥ Lower Limit of Normal (LLN)
• Negative Pregnancy test for women of child-bearing age.
• Information given to the patient and signed informed consent.
• Public Health insurance coverage.
• Sample of tumour (primitive or metastatic) available.

Exclusion Criteria:

• Known brain or leptomeningeal metastases.
• Positive HER2 Status (IHC 3+ or IHC2+/FISH or CISH+) .
• contraindication, allergy or hypersensitivity to ANY OF the study treatments.
• Prior Treatment with EGFR inhibitor or HGF / c-Met inhibitor.
• Patient already included in another clinical trial testing an experimental drug.
• Peripheral edema > grade 2.
• Proteinuria > 1 g/24h
• Clinically significant cardiovascular disease (such as unstable angina pectoris, severe congestive heart failure, uncontrolled severe cardiac arrhythmia) within 12 months prior to randomization.
• Thrombosis or ischemic vascular event during the last 12 months (deep venous thrombosis, pulmonary embolism, STROKE or established cerebral infarction, myocardial infarction).
• Medical history or signs of interstitial pneumopathy or pulmonary fibrosis.
• Peripheral neuropathy > grade 1.
• Clinically significant hemorrhage of the upper gastrointestinal tract (requiring blood transfusion or hemostatic interventional procedure.
• Actively evolutive inflammatory bowel disease or any other intestinal disease causing chronic diarrhea (≥ grade 2).
• Any uncontrolled concomitant disease (e.g., uncontrolled diabetes) or medical history (e.g., organ transplantation) which, according to the opinion of the investigator, may interfere with the interpretation of the study results.
• Any comorbidity or situation which, according to the opinion of the investigator, could increase the risk of toxicity (e.g., Dihydropyrimidine dehydrogenase deficiency).
• Chronic or active HIV, HBV or HCV infections.
• Severe and\or not healed wound.
• Any active infection requiring systemic treatment, or any uncontrolled infection within 14 days before randomization.
• Other concomitant malignancy or history of cancer (except carcinoma in situ of the cervix, or non melanoma skin cancer, with curative intent treatment), except when considered in complete remission for at least 5 years before randomization.
• Pregnant women or women who might become pregnant during the study (or who plan to become pregnant within 6 months after the last administration of a study drug) or lactating women.
• Men or women who have the age of procreation and who do not abide with the use of a highly efficient contraceptive means (according to the current institutional standards) or, alternatively, the use of abstinence during the study treatment and until 6 months after last administration of the study drugs.
• Patient unwilling to comply with the medical follow-up required by the trial because of geographic social or psychological reasons.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Arm A : simplified Folfox 4; Every 2 weeks : Oxaliplatin : 85 mg/m2 over 120 mn (2h) IV on D1; Folinic acid : 400 mg/m² (racemic form) (or 200 mg/m² if L-folinic acid) over 2 h IV on D1 followed by :; 5-fluoro-uracil : 400 mg/m² in IV bolus on D1 followed by :; 5-fluoro-uracil : 2400 mg/m² in IV infusion over 46 h	Drug: Oxaliplatin; 85mg/m² over 120 mn every 2 weeks up to progression or toxicity; Other Names: Eloxatine; Drug: Folinic Acid; 400mg/m² over 120 mn every 2 weeks up to progression or toxicity; Drug: 5-fluoro-uracil; 400mg/m² in bolus, then 2400mg/m² over 46 h every 2 weeks up to progression or toxicity
EXPERIMENTAL: Arm B : simplified FOLFOX 4 + panitumumab; Every 2 weeks : Oxaliplatin : 85 mg/m2 over 120 mn IV on D1; Folinic acid : 400 mg/m² (racemic form) (or 200 mg/m² with L-folinic acid) over 2 h IV on D1 (in Y to oxaliplatin) followed by :; 5-fluoro-uracil : 400 mg/m², IV bolus on D1, followed by :; 5-fluoro-uracil : 2400 mg/m², IV infusion IV over 46 h; Panitumumab : 6 mg/kg de 60 à 90 mn ± 15 mn IV every 14 days, just before chemotherapy administration (oxaliplatin and folinic acid), on Day 1 of each cycle. If the 1st infusion of panitumumab is well tolerated, the next infusions can be administered over 30 ± 10 mn.	Drug: Oxaliplatin; 85mg/m² over 120 mn every 2 weeks up to progression or toxicity; Other Names: Eloxatine; Drug: Folinic Acid; 400mg/m² over 120 mn every 2 weeks up to progression or toxicity; Drug: 5-fluoro-uracil; 400mg/m² in bolus, then 2400mg/m² over 46 h every 2 weeks up to progression or toxicity; Drug: panitumumab; 6mg/kg over 60-90 mn every 2 weeks up to progression or toxicity; Other Names: Vectibix
EXPERIMENTAL: Arm C : simplified FOLFOX 4 + AMG 102; Every 2 weeks : Oxaliplatin : 85 mg/m2 over 120 mn IV on D1; Folinic Acid : 400 mg/m² (racemic) (or 200 mg/m² with L-folinic acid) over 2 h IV on D1 (in Y/concomitant with oxaliplatin) followed by :; 5-fluoro-uracil : 400 mg/m² IV bolus on D1 followed by :; 5-fluoro-uracil : 2400 mg/m² in IV perfusion over 46 h; AMG 102 : 10 mg/kg over 60 ± 15 mn IV every 14 days, just before chemotherapy administration (oxaliplatin and folinic acid), on Day 1 of each cycle. If the first infusion is well tolerated (without severe infusion-related reactions), the following infusions can be administered over 30 ± 10 mn.	Drug: Oxaliplatin; 85mg/m² over 120 mn every 2 weeks up to progression or toxicity; Other Names: Eloxatine; Drug: Folinic Acid; 400mg/m² over 120 mn every 2 weeks up to progression or toxicity; Drug: 5-fluoro-uracil; 400mg/m² in bolus, then 2400mg/m² over 46 h every 2 weeks up to progression or toxicity; Drug: AMG102; 10mg/kg over 60 mn every 2 weeks up to progression or toxicity; Other Names: Rilotumumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival at 4 months	based on the proportion of success in each patient group (patient without progression at 4 months)	4 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival	Progression-free survival is defined as the time from randomization to progression (RECIST v1.1 criteria) or death. Patients alive without progression will be censored at the last tumoral evaluation and 5 years maximum.	until progression or death
Overall survival	Overall survival is defined as the time from randomization to death any cause or last follow-up news (censored data).	until death
Time to progression	Time to progression is defined as the time from randomization to progression (RECIST v1.1 criteria). Patients alive without progression will be censored at the last tumoral evaluation. Patients died without progression will be censored at the death date any cause.	4 months
Objective tumor response rate (OR) (= complete responses [CR] + partial responses [PR]) according to RECIST V1.1	The objective tumor response will be evaluated by the investigator with RECIST v1.1 criteria every 8 (± 1) weeks up to disease progression. Patients with symptoms suggestive of disease progression will have a tumoral evaluation when symptoms will occur.	until progression
Objective response duration	The Objective response duration is defined as time from first Complete Response or Partial Response to progression. Patients died without progression will be censored at death date.	until progression
Disease control rate (Complete Response + Partial Response + stable disease [SD])	The tumor control rate is rate of objective responses (complete responses and partial responses) and stable disease responses.	4 months
Tolerance of the treatment	Tolerability of the treatment will be based on toxicities of evaluated products by clinical and biological measurements (NCIC/CTC (CTCAE V4) criteria, except for peripheral neuropathy toxicity (Lévi scale)).	24 months

Collaborators and Investigators

• Sponsor: UNICANCER
• Investigators: Principal Investigator: Bruno BUECHER, Dr, Institut Curie Paris; Principal Investigator: Christophe BORG, Pr, Hôpital Andre Boulloche-MONTBELIARD; Principal Investigator: Emmanuelle SAMALIN, Dr, Centre Val d'Aurelle Paul Lamarque-MONTPELLIER; Principal Investigator: You Heng LAM, Dr, Centre Paul Papin-ANGERS; Principal Investigator: François GHIRINGHELLI, Dr, Centre Georges Francois Leclerc-DIJON; Principal Investigator: Driffa MOUSSATA, Dr, Centre hospitalier Lyon Sud-PIERRE BENITE; Principal Investigator: Marie-Pierre GALAIS, Dr, Centre François Baclesse-CAEN; Principal Investigator: Frédérique CVITKOVIC, Dr, Centre René Huguenin-SAINT-CLOUD; Principal Investigator: Marie-Claire KAMINSKY, Dr, Centre Alexis Vautrin-VANDOEUVRE LES NANCY; Principal Investigator: Olivier BOUCHE, Pr, Hôpital Robert Debré - REIMS; Principal Investigator: Julien TAIEB, Pr, Hôpital Européen Georges Pompidou-PARIS (HEGP); Principal Investigator: Yves BECOUARN, Dr, Institut Bergonié Bordeaux; Principal Investigator: Barbara DAUVOIS, Dr, Centre Hospitalier La Source-ORLEANS; Principal Investigator: Julien FORESTIER, Dr, Hôpital Edouard Herriot-LYON; Principal Investigator: Christelle DE LA FOUCHARDIERE, Dr, Centre Léon Bérard; Principal Investigator: Christophe BORG, Pr, Centre Hospitalier Jean Minjoz; Principal Investigator: Jean Baptiste BACHET, Dr, Centre hospitalier La Pitié Salpetriere; Principal Investigator: Jean Luc RAOUL, Dr, Institut Paoli-Calmettes; Principal Investigator: Leila BENGRINE LEFEVRE, Dr, Hopital Saint Antoine; Principal Investigator: Laurent MIGLIANICO, Dr, CHP Saint Grégoire; Principal Investigator: Laetitia DAHAN, Dr, Centre Hospitalier La Timone; Principal Investigator: Thomas APARICIO, Pr, Hopital Avicenne; Principal Investigator: Hervé PERRIER, Dr, Hôpital Saint Joseph; Principal Investigator: Jean Philippe METGES, Dr, CHU Morvan; Principal Investigator: Eric TERREBONNE, Dr, Hopital Haut Leveque; Principal Investigator: Pascal ARTRU, Dr, Hopital Prive Jean Mermoz; Principal Investigator: Gaël DEPLANQUE, Dr, Groupe Hospitalier Saint Joseph; Principal Investigator: Emmanuel MAILLARD, Dr, CHR Annecy; Principal Investigator: Antoine ADENIS, Pr, Centre Oscar Lambret

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 1, 2011
• Primary Completion (ACTUAL): March 1, 2014
• Study Completion (ACTUAL): September 1, 2018

Study Registration Dates

• First Submitted: August 11, 2011
• First Submitted That Met QC Criteria: September 28, 2011
• First Posted (ESTIMATE): September 29, 2011

Study Record Updates

• Last Update Posted (ACTUAL): November 17, 2020
• Last Update Submitted That Met QC Criteria: November 13, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: Adenocarcinoma; First line treatment; Locally advanced (non operable) or metastatic
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Stomach Diseases; Head and Neck Neoplasms; Esophageal Diseases; Neoplasms; Stomach Neoplasms; Adenocarcinoma; Esophageal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Antineoplastic Agents, Immunological; Micronutrients; Vitamins; Antidotes; Vitamin B Complex; Hematinics; Fluorouracil; Oxaliplatin; Leucovorin; Levoleucovorin; Folic Acid; Panitumumab; Rilotumumab
• Other Study ID Numbers: PRODIGE 17 / ACCORD 20/0904; 2009-012797-12 (EUDRACT_NUMBER)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No