Gemcitabine With or Without Capecitabine and/or Radiation Therapy or Gemcitabine With or Without Erlotinib in Treating Patients With Locally Advanced Pancreatic Cancer That Cannot Be Removed by Surgery

Randomized Multicenter Phase III Study in Patients With Locally Advanced Adenocarcinoma of the Pancreas: Gemcitabine With or Without Chemoradiotherapy and With or Without Erlotinib. Intergroup Study

RATIONALE: Drugs used in chemotherapy, such as gemcitabine and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Erlotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high-energy x-rays to kill tumor cells. It is not yet known which regimen of chemotherapy with or without erlotinib and/or radiation therapy is most effective in treating pancreatic cancer.

PURPOSE: This randomized phase III trial is studying giving gemcitabine together with or without capecitabine and/or radiation therapy to see how well it works compared with giving gemcitabine together with or without erlotinib in treating patients with locally advanced pancreatic cancer that cannot be removed by surgery.

Study Overview

• Status: Completed
• Conditions: Pancreatic Cancer
• Intervention / Treatment: Radiation: radiation therapy; Other: laboratory biomarker analysis; Drug: gemcitabine hydrochloride; Drug: capecitabine; Drug: erlotinib hydrochloride

Detailed Description

OBJECTIVES:

Primary

• To assess whether administrating chemoradiotherapy in patients whose tumor is controlled after 4 months of induction chemotherapy (CT) increases survival compared with continuation of the same CT in patients with unresectable, locally advanced adenocarcinoma of the pancreas.

Secondary

• To assess whether erlotinib hydrochloride combined with gemcitabine hydrochloride and administered as maintenance treatment increases progression-free survival compared with gemcitabine hydrochloride alone and without maintenance treatment.
• To evaluate the response rate in the CT and chemoradiotherapy (CRT) arms.
• To evaluate tolerance to erlotinib hydrochloride as maintenance treatment after the end of CT or CRT.
• To study the predictive molecular factors (i.e., survivin, K-ras, EGFR, PTEN, or AKT) of survival.

OUTLINE: This is a multicenter study. Patients in the first randomization are stratified according to center and ECOG performance status (0-1 vs 2). Patients in the second randomization are stratified according to center and initial treatment arm (I vs II).

• First randomization: Patients are randomized to 1 of 2 treatment arms.

  • Arm I: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1, 8, 15, 22, 29, 36, and 43. Following the first evaluation, patients continue to receive gemcitabine hydrochloride on days 57, 64, 71, 85, 92, and 99 for a total of 4 months.
  • Arm II: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1, 8, 15, 22, 29, 36, and 43. Following the first evaluation, patients continue to receive gemcitabine hydrochloride on days 57, 64, 71, 85, 92, and 99. Patients also receive oral erlotinib hydrochloride once daily for 4 months.

After completion of treatment in the first randomization proceed to the second randomization.

• Second randomization: Patients are randomized to 1 of 4 treatment arms.

  • Arm I: Patients continue gemcitabine hydrochloride as in arm I in the first randomization on days 113, 120, and 127 and on days 141, 148, and 155 for 2 months in the absence of disease progression.
  • Arm II: Patients continue gemcitabine hydrochloride as in arm II in the first randomization on days 113, 120, and 127 and on days 141, 148, and 155 and oral erlotinib hydrochloride daily for 2 months followed by erlotinib hydrochloride alone as maintenance therapy in the absence of disease progression.
  • Arm III: Patients receive oral capecitabine twice daily and undergo radiotherapy beginning on day 127, 5 days a week, for 6 weeks, in the absence of disease progression.
  • Arm IV: Patients receive oral capecitabine twice daily and undergo radiotherapy beginning on day 127, 5 days a week, for 6 weeks. Beginning 15 days after completion of CRT, patients receive a reintroduction of oral erlotinib hydrochloride alone once daily in the absence of disease progression or unacceptable toxicity.

Tumor tissue will be analyzed for the relationship between biological markers and resistance to treatment.

After completion of study treatment, patients are followed every 2 months.

• Study Type: Interventional
• Enrollment (Anticipated): 820
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Agen, France, 47000
    • Centre Radiotherapie Oncologie Moyenne Garonne
  • Aix en Provence, France, 13616
    • Centre Hospitalier d'Aix en Provence
  • Angers, France, 49036
    • Centre Paul Papin
  • Auxerre, France, 89011
    • Centre Hospitalier d'Auxerre
  • Auxerre, France, 89000
    • Polyclinique Sainte marguerite
  • Avignon, France, 84000
    • Institut Sainte Catherine
  • Avignon, France, 84902
    • Hopital Duffaut
  • Bayonne, France, 64100
    • Centre Hospitalier de la Cote Basque
  • Beauvais, France, 72037
    • Centre Hospitalier de Beauvais
  • Besancon, France, 25030
    • Centre Hospitalier Regional de Besancon - Hopital Jean Minjoz
  • Beziers, France, 34525
    • Hopital de Beziers
  • Bordeaux, France, 33076
    • Institut Bergonie
  • Bordeaux, France, 33075
    • Hopital Saint André
  • Bordeaux, France, 33300
    • Polyclinique Bordeaux Nord Aquitaine
  • Bordeaux, France, F-33000
    • Clinique Tivoli
  • Boulogne-Billancourt, France, F-92104
    • Hôpital Ambroise Paré
  • Bourgoin-Jallieu, France, 38300
    • Centre Hospitalier Pierre Oudot
  • Caen, France, 14033
    • CHU de Caen
  • Caen, France, 14052
    • Polyclinique du Parc
  • Clichy, France, 92110
    • Hôpital Beaujon
  • Colmar, France, 68024
    • Hopital Louis Pasteur
  • Compiegne, France, 60321
    • Centre Hospitalier Compiegne
  • Creteil, France, 94000
    • Centre Hospitalier Universitaire Henri Mondor
  • Dax, France, 40100
    • Centre Hospitalier de Dax
  • Digne Cedex, France, 04003
    • Centre Hospitalier de Digne les Bains
  • Dijon, France, 21034
    • Hôpital du Bocage
  • Dijon, France, 21079
    • Centre de Lutte Contre le Cancer Georges-Francois Leclerc
  • Draguignan, France, 83300
    • Centre Hospitalier Draguignan
  • Grenoble, France, 38043
    • CHU de Grenoble - Hopital de la Tronche
  • La Roche Sur Yon, France, F-85025
    • Centre Hospitalier Departemental
  • Lagny Sur Marne, France, 77405
    • Centre Hospitalier de Lagny
  • Le Coudray, France, 28630
    • Hopital Louis Pasteur - Le Coudray
  • Le Kremlin Bicetre, France, 94275
    • Centre Hospitalier Universitaire de Bicêtre
  • Le Mans, France, F-72000
    • Clinique Victor Hugo
  • Libourne, France, 33500
    • Hôpital Robert Boulin
  • Lille, France, 59000
    • Polyclinique Du Bois
  • Lormont, France, 33310
    • Polyclinique des Quatre Pavillons
  • Lyon, France, 69437
    • Hopital Edouard Herriot - Lyon
  • Lyon, France, 69373
    • Centre Léon Bérard
  • Lyon, France, 69317
    • Hopital de la croix rousse
  • Lyon, France, 69008
    • Hôpital Privé Jean Mermoz
  • Lyon, France, 69007
    • Centre Hospitalier St. Joseph St. Luc
  • Macon, France, 71018
    • Centre Hospitalier Chanaux
  • Marseille, France, 13385
    • CHU de la Timone
  • Marseille, France, 13273
    • Marseille Institute of Cancer - Institut J. Paoli and I. Calmettes
  • Maubeuge, France, 59600
    • Centre Gray
  • Meaux, France, 77104
    • Centre Hospitalier de Meaux
  • Mont-de-Marsan, France, 40000
    • Centre Hospitalier General de Mont de Marsan
  • Montelimar, France, 26200
    • Centre Hospitalier de Montelimar
  • Nimes, France, 30029
    • C.H.U. de Nimes - Groupe Hospitals-Universitaire Caremeau
  • Nimes, France, 30900
    • Clinique De Valdegour
  • Orleans, France, 45067
    • CHR D'Orleans - Hopital de la Source
  • Paris, France, 75015
    • Hopital Europeen Georges Pompidou
  • Paris, France, 75018
    • Hôpital Bichat - Claude Bernard
  • Paris, France, 75970
    • Hopital Tenon
  • Paris, France, 75571
    • Hôpital Saint Antoine
  • Paris, France, 75013
    • Hopital Pitie-Salpetriere
  • Paris, France, 75475
    • Hôpital Saint-Louis
  • Paris, France, 75674
    • Hopital Saint Joseph
  • Perpignan, France, 66000
    • Centre Catalan d'Oncologie
  • Pessac, France, 33604
    • Hopital Haut Leveque
  • Pierre Benite, France, 69495
    • Centre Hospitalier Lyon Sud
  • Poitiers, France, 86021
    • CHU Poitiers
  • Pontoise, France, 95300
    • Hôpital René Dubos
  • Reims, France, 51092
    • CHU - Robert Debre
  • Rouen, France, 76031
    • Hopital Charles Nicolle
  • Saint-Omer, France, 62505
    • Centre Hospitalier
  • Tarbes, France, 65013
    • Centre hospitalier de Tarbes
  • Thionville, France, 57126
    • Centre Hospitalier Regional Metz Thionville
  • Tours, France, 37000
    • CHRU de Tours - Hopital Trousseau
  • Valence, France, 26000
    • Nouvelle Clinique Generale
  • Vannes, France, 56016
    • Centre hospitalier Bretagne Atlantique

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the pancreas meeting the following criteria:

  • De novo locally advanced disease
  • Unresectable disease

  • Stage III according to the UICC classification

    • No distant metastases
    • No localized stage IA-IIB or metastatic stage IV disease according to UICC classification
  • Not considered for curative resection after pluridisciplinary discussion

PATIENT CHARACTERISTICS:

Inclusion criteria:

• ECOG performance status 0-2
• Life expectancy ≥ 12 weeks
• Polynuclear neutrophils ≥ 1.5 x 10^9/L
• Platelets ≥ 100 x 10^9/L
• Hemoglobin ≥ 9 g/dL

• Total bilirubin ≤ 1.5 times upper limit of normal (ULN)

  • For patients who have had a recent biliary drain and whose bilirubin is descending, a value of ≤ 3 times ULN is acceptable
• Creatinine ≤ 2 mg/dL
• AST and ALT ≤ 2.5 times ULN
• Alkaline phosphatase ≤ 5 times ULN
• Albumin ≥ 25 g/L
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 3 months after completion of therapy

Exclusion criteria:

• Diarrhea ≥ grade 2 and/or uncontrolled diarrhea
• Affiliated with a social security regime
• Unable to follow instructions for psychological, familial, or geographical reasons
• Allergic to one of the ingredients in erlotinib hydrochloride
• Cancer within the past 5 years, except for in situ cancer of the neck of the uterus or basal cell skin cancer
• Severe infection
• Ophthalmic disease (i.e., inflammation, keratopathy, or infection)
• Symptomatic coronary or cardiac insufficiency, myocardial infarction, or stroke within the last 6 months
• Unable to take oral treatments
• Gastrointestinal disorders that could be associated with absorption disorders
• Untreated gastric or duodenal ulcer

PRIOR CONCURRENT THERAPY:

• No prior radiotherapy (including abdominal radiotherapy) or chemotherapy for any reason
• No prior anti-epidermal growth factor-receptor therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm 1 (A1) - Gemcitabine; Gemcitabine 2 months, then stop until progression	Other: laboratory biomarker analysis; Drug: gemcitabine hydrochloride
Experimental: Arm 2 (B1) Gemcitabine + Erlotinib; B1 Gemcitabine + Erlotinib (100mg/d) 2 months, then erlotinib maintenance (150 mg/d)until progression	Other: laboratory biomarker analysis; Drug: gemcitabine hydrochloride; Drug: erlotinib hydrochloride
Experimental: Arm 3 (A2) CRT; A2 CRT then stop until progression	Radiation: radiation therapy; Other: laboratory biomarker analysis; Drug: capecitabine
Experimental: Arm 4 (B2) CRT then erlotinib; B2 CRT then erlotinib maintenance (150mg/d) until progression	Radiation: radiation therapy; Other: laboratory biomarker analysis; Drug: capecitabine; Drug: erlotinib hydrochloride

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	an interim analysis is planned when 196 deaths will be observed	from the date of the first randomization to the date of patient death,due to any cause, or to the last date the patient was known to be alive, assessed up to 8 years after the beginning of the study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival		time from the date of the first randomization to the date of progressive disease or death, assessed up to 8 years after the beginning of the study.
Relationship between biological markers and survival	1 biopsy/patient of the pancreas before treatment	From baseline to death, assessed up to 8 years after the beginning of the study
tolerance to erlotinib	To evaluate tolerance to erlotinib as maintenance treatment after the end of CT or CRT. During each visit, any adverse events will be noted and graded according to version 3 of the NCI-CTCAE. Any adverse events that persist at the end of the CTI will be followed up until they disappear.	from start of treatment until the event has resolved or stabilized or until death

Collaborators and Investigators

• Sponsor: GERCOR - Multidisciplinary Oncology Cooperative Group
• Investigators: Principal Investigator: Pascal Hammel, MD, PhD, Hôpital Beaujon

Publications and helpful links

General Publications

• Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, Borbath I, Bouche O, Shannon J, Andre T, Mineur L, Chibaudel B, Bonnetain F, Louvet C; LAP07 Trial Group. Effect of Chemoradiotherapy vs Chemotherapy on Survival in Patients With Locally Advanced Pancreatic Cancer Controlled After 4 Months of Gemcitabine With or Without Erlotinib: The LAP07 Randomized Clinical Trial. JAMA. 2016 May 3;315(17):1844-53. doi: 10.1001/jama.2016.4324.

Study record dates

Study Major Dates

• Study Start: February 1, 2008
• Primary Completion (Actual): February 1, 2013
• Study Completion (Actual): September 1, 2014

Study Registration Dates

• First Submitted: March 12, 2008
• First Submitted That Met QC Criteria: March 12, 2008
• First Posted (Estimate): March 13, 2008

Study Record Updates

• Last Update Posted (Estimate): December 11, 2015
• Last Update Submitted That Met QC Criteria: December 10, 2015
• Last Verified: November 1, 2012

More Information

Terms related to this study

• Keywords: adenocarcinoma of the pancreas; stage III pancreatic cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Pancreatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protein Kinase Inhibitors; Gemcitabine; Erlotinib Hydrochloride; Capecitabine
• Other Study ID Numbers: CDR0000589283; GERCOR-LAP-07-D07-1; EU=20827; ROCHE-GERCOR-LAP-07-D07-1; EudraCT- 2007-001174-81