Clinical trial NCT00634725: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pancreatic Cancer
Keywords: adenocarcinoma of the pancreas
stage III pancreatic cancer
Lead sponsor: GERCOR - Multidisciplinary Oncology Cooperative Group
Sponsor class: OTHER
First posted: 2008-03-13
Enrollment: 820
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Overall survival
timeFrame: 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 outcomes:
measure: Progression-free survival
timeFrame: 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.
measure: Relationship between biological markers and survival
timeFrame: From baseline to death, assessed up to 8 years after the beginning of the study
measure: tolerance to erlotinib
timeFrame: from start of treatment until the event has resolved or stabilized or until death
Other outcomes:
Locations:
city: Agen
country: France
facility: Centre Radiotherapie Oncologie Moyenne Garonne
city: Aix en Provence
country: France
facility: Centre Hospitalier d'Aix en Provence
city: Angers
country: France
facility: Centre Paul Papin
city: Auxerre
country: France
facility: Polyclinique Sainte Marguerite
city: Auxerre
country: France
facility: Centre Hospitalier d'Auxerre
city: Avignon
country: France
facility: Institut Sainte Catherine
city: Avignon
country: France
facility: Hopital Duffaut
city: Bayonne
country: France
facility: Centre Hospitalier de la Cote Basque
city: Beauvais
country: France
facility: Centre Hospitalier de Beauvais
city: Besancon
country: France
facility: Centre Hospitalier Regional de Besancon - Hopital Jean Minjoz
city: Beziers
country: France
facility: Hopital de Beziers
city: Bordeaux
country: France
facility: Hopital Saint Andre
city: Bordeaux
country: France
facility: Institut Bergonie
city: Bordeaux
country: France
facility: Polyclinique Bordeaux Nord Aquitaine
city: Bordeaux
country: France
facility: Clinique Tivoli
city: Boulogne-Billancourt
country: France
facility: Hopital Ambroise Pare
city: Bourgoin-Jallieu
country: France
facility: Centre Hospitalier Pierre Oudot
city: Caen
country: France
facility: CHU de Caen
city: Caen
country: France
facility: Polyclinique Du Parc
city: Clichy
country: France
facility: Hopital Beaujon
city: Colmar
country: France
facility: Hopital Louis Pasteur
city: Compiegne
country: France
facility: Centre Hospitalier Compiegne
city: Creteil
country: France
facility: Centre Hospitalier Universitaire Henri Mondor
city: Dax
country: France
facility: Centre Hospitalier de Dax
city: Digne Cedex
country: France
facility: Centre Hospitalier de Digne les Bains
city: Dijon
country: France
facility: Hopital Du Bocage
city: Dijon
country: France
facility: Centre de Lutte Contre le Cancer Georges-Francois Leclerc
city: Draguignan
country: France
facility: Centre Hospitalier Draguignan
city: Grenoble
country: France
facility: CHU de Grenoble - Hopital de la Tronche
city: La Roche Sur Yon
country: France
facility: Centre Hospitalier Departemental
city: Lagny Sur Marne
country: France
facility: Centre Hospitalier de Lagny
city: Le Coudray
country: France
facility: Hopital Louis Pasteur - Le Coudray
city: Le Kremlin Bicetre
country: France
facility: Centre Hospitalier Universitaire de Bicetre
city: Le Mans
country: France
facility: Clinique Victor Hugo
city: Libourne
country: France
facility: Hopital Robert Boulin
city: Lille
country: France
facility: Polyclinique Du Bois
city: Lormont
country: France
facility: Polyclinique des Quatre Pavillons
city: Lyon
country: France
facility: Centre Hospitalier St. Joseph St. Luc
city: Lyon
country: France
facility: Hopital Prive Jean Mermoz
city: Lyon
country: France
facility: Hopital de la Croix Rousse
city: Lyon
country: France
facility: Centre Leon Berard
city: Lyon
country: France
facility: Hopital Edouard Herriot - Lyon
city: Macon
country: France
facility: Centre Hospitalier Chanaux
city: Marseille
country: France
facility: Marseille Institute of Cancer - Institut J. Paoli and I. Calmettes
city: Marseille
country: France
facility: CHU de la Timone
city: Maubeuge
country: France
facility: Centre Gray
city: Meaux
country: France
facility: Centre Hospitalier de Meaux
city: Mont-de-Marsan
country: France
facility: Centre Hospitalier General de Mont de Marsan
city: Montelimar
country: France
facility: Centre Hospitalier de Montelimar
city: Nimes
country: France
facility: C.H.U. de Nimes - Groupe Hospitals-Universitaire Caremeau
city: Nimes
country: France
facility: Clinique De Valdegour
city: Orleans
country: France
facility: CHR D'Orleans - Hopital de la Source
city: Paris
country: France
facility: Hopital Pitie-Salpetriere
city: Paris
country: France
facility: Hopital Europeen Georges Pompidou
city: Paris
country: France
facility: Hopital Bichat - Claude Bernard
city: Paris
country: France
facility: Hopital Saint-Louis
city: Paris
country: France
facility: Hopital Saint Antoine
city: Paris
country: France
facility: Hopital Saint Joseph
city: Paris
country: France
facility: Hopital Tenon
city: Perpignan
country: France
facility: Centre Catalan d'Oncologie
city: Pessac
country: France
facility: Hopital Haut Leveque
city: Pierre Benite
country: France
facility: Centre Hospitalier Lyon Sud
city: Poitiers
country: France
facility: CHU Poitiers
city: Pontoise
country: France
facility: Hopital Rene Dubos
city: Reims
country: France
facility: CHU - Robert Debre
city: Rouen
country: France
facility: Hopital Charles Nicolle
city: Saint-Omer
country: France
facility: Centre Hospitalier
city: Tarbes
country: France
facility: Centre Hospitalier de Tarbes
city: Thionville
country: France
facility: Centre Hospitalier Regional Metz Thionville
city: Tours
country: France
facility: CHRU de Tours - Hopital Trousseau
city: Valence
country: France
facility: Nouvelle Clinique Generale
city: Vannes
country: France
facility: Centre Hospitalier Bretagne Atlantique
Study officials:
affiliation: Hopital Beaujon
name: Pascal Hammel, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.