Clinical trial NCT02676349: Neoadjuvant mFolfirinox With or Without Preoperative Concomitant Chemoradiotherapy in Patients With Borderline Resectable Pancreatic Carcinoma (PANDAS-PRODIGE 44)
Official title: Two Arm, Prospective, Multicenter Randomized Phase II Trial of Neoadjuvant Modified Folfirinox Regimen, With or Without Preoperative Concomitant Chemoradiotherapy in Patients With Borderline Resectable Pancreatic Carcinoma
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Pancreatic Carcinoma
Keywords: mFolfirinox
Chemoradiotherapy
Neoadjuvant treatment
Borderline
Lead sponsor: Institut de Cancérologie de Lorraine
Sponsor class: OTHER
First posted: 2016-02-08
Enrollment: 130
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a prospective, randomized phase II trial. The aim of this study is to assess the efficacy of two therapeutics strategies. Patients with borderline-resectable pancreatic cancer (BRPC) will be randomly in two arms : neoadjuvant mFolfirinox followed with or without preoperative chemoradiotherapy with capecitabine.

Detailed description: Surgery, especially if followed by adjuvant chemotherapy, offers the only chance of cure of pancreatic cancer. At first diagnosis, after careful assessment, only 10 to 15% of patients are considered to be candidates for surgical resection and about 7% have a potentially resectable disease. These potentially resectable tumors called "borderline resectable pancreatic cancer" (BRPC) are conceptualized as those that involve the mesenteric vasculature to a limited extent and those for which resection, while possible, would likely be compromised by positive surgical margins (R1) in the absence of neoadjuvant treatment. R0 resection is indeed considered as an independent prognostic factor for survival when the surgical procedures, histological examination and definition of microscopic invasion are standardized.

The objectives of neoadjuvant treatments of BRPC is to reduce tumor volume before surgery in order to improve the chances of radical (R0) resection and to reduce the rate of lymph node positivity and recurrences. The primary outcome in published studies is usually R0 resection rate, but these results also depend on the number of margins examined and the definition of microscopic margin involvement. Prospective studies with consistent selection criteria and standardized assessment criteria are needed.

Different neoadjuvant therapeutic strategies have been tested in pilot studies: preoperative chemoradiotherapy or neoadjuvant chemotherapy, followed or not by a preoperative (chemo)radiotherapy. Due to the lack of randomized studies, the best sequence of treatment administration has not been established.

The aim of this prospective, randomized, multicenter, trial is to evaluate the R0 resection rate with neoadjuvant Folfirinox, followed or not by radiochemotherapy for patients with borderline resectable pancreatic cancers.

Eligibility criteria: Inclusion Criteria:

* ECOG performance status 0 or 1
* Adult patients ≥ 18 years and ≤ 75 years of age
* Histologic or cytologic proven adenocarcinoma of the pancreas (histologic confirmation of diagnosis is preferred)
* Confirmation by independent multidisciplinary expert review of borderline resectable status, according to NCCN-Clinical Practice Guidelines in Oncology "pancreatic adenocarcinoma", version 1.2015.
* Adequate hematologic function, as follows:
* absolute neutrophil count (ANC) ≥ \> 2000/mm3
* platelet count ≥ 100 000/mm3
* haemoglobin ≥ 10 g/dL
* Adequate renal, hepatic and bone marrow function, defined as:

  * Calculated creatinine clearance ≥ 50 mL/min according to MDRD formula
  * Serum total bilirubin ≤ 1.5 times the institutional upper limit of normal. Patients with a biliary short metal stent due to cancer obstruction may be included provided that high-quality imaging is performed before stenting and bilirubin level after stent insertion decreased to ≤ 20 mg/L (≤ 34 µmol/l), and there is no cholangitis.
* Male and female subjects who agree to use highly effective methods of birth control (e.g., condoms, combined oral contraceptives, some intrauterine devices \[IUDs\], sexual abstinence, or sterilized partner)

  * for male subject: during the treatment and for up to 6 months after the last dose of oxaliplatin or up to 3 months after the last dose of irinotcan.
  * for female subject: during the treatment and for up to 4 months after the last dose of oxaliplatin or up to 3 months after the last dose of irinotcan.
* Ability to provide written informed consent before the start of any study specific procedures
* Patient's legal capacity to consent to study participation and to understand and comply with the requirements of the study.

Exclusion Criteria:

* Any previous treatment of the pancreatic cancer except biliary short metal stenting (chemotherapy, targeted tumor therapy, local ablative therapy, previous irradiation within the actual fields of planned radiotherapy)
* Evidence of distant metastases including ascites
* Evidence of extent of pancreatic cancer beyond that defined as "borderline resectable" : suspicious lymphadenopathy outside of the standard field of resection (i.e., aortocaval nodes, distant abdominal nodes)
* Contraindication for pancreas resection
* Pregnant or breast feeding females
* Patients with known Gilbert's Syndrome or homozygosity for UGT1A1\*28 polymorphism
* Uracilemia ≥ 16ng/mL either a partial or complete deficiency in dihydropyrimidine dehydrogenase (DPD)
* Participation in any other clinical trial or treatment with any experimental drug within 28 days before enrolment to the study or during study participation until the end of treatment visit that can be interfering with the objectives of the study
* Previous or concurrent malignant tumor disease other than underlying tumor disease (with the exception of cervical cancer in situ, adequately treated non-melanoma skin cancers, superficial bladder tumors (Ta, Tis, and T1) or any curatively treated without chemotherapy and favourable prognosis tumors without evidence of disease for \> 3 years prior to enrolment)
* Any severe and/or uncontrolled medical conditions including but not limited to:

  * Clinically significant cardiovascular or vascular disease : angina pectoris (even controlled), previous myocardial infarction, serious uncontrolled cardiac arrhythmia, chronic heart failure, acute or chronic infectious disease requiring general treatment)
  * Acute and chronic, active infectious disorders that requires systemic treatment
  * Peripheral polyneuropathy \> grade 1
  * Any previous inflammatory disease of colon or rectum
  * Any other severe concomitant disease or disorder, which could influence patient's ability to participate in the study and his/her safety during the study e.g. severe hepatic, renal, pulmonary, metabolic, or psychiatric disorders
* Uncorrected disturbed electrolyte balance, in particular hypokalemia or hypocalcemia
* Hypersensitivity against any of the study drugs (gemcitabine, oxaliplatin, irinotecan, 5-fluorouracil, folinic acid), or the ingredients of these drugs (e.g. fructose).

Primary outcomes:
measure: To assess the efficacy of two neoadjuvant therapies in patients with borderline resectable pancreatic carcinoma evaluated on histological R0 resection margin rate
timeFrame: up to 7.5 months
Secondary outcomes:
measure: Evaluate the toxicities associated with chemotherapy and chemoradiotherapy
timeFrame: up to 7 years
measure: Evaluate the proportion of resected patients
timeFrame: up to 7.5 months
measure: Evaluate the response rate to chemotherapy and chemoradiotherapy
timeFrame: up to 7.5 months
measure: Evaluate the histological complete response rate in resected patients.
timeFrame: up to 7.5 months
measure: Evaluate the perioperative mortality rate
timeFrame: up to 8.5 months
measure: Evaluate the perioperative morbidity rate
timeFrame: up to 8.5 months
measure: Evaluate the overall survival
timeFrame: up to 7 years
measure: Evaluate the quality of life
timeFrame: up to 7.5 months
measure: Evaluate the loco-regional relapse-free survival
timeFrame: 7 years
measure: Evaluate the metastatic Progression Free Survival
timeFrame: 7 years
measure: Evaluate the progression-free survival
timeFrame: 7 years
Other outcomes:
Locations:
city: Bordeaux
country: France
facility: Institut Bergonié
city: Bordeaux
country: France
facility: Polyclinique Bordeaux Nord
city: Clichy
country: France
facility: Hôpital Beaujon
city: Colmar
country: France
facility: Chu Colmar
city: Creteil
country: France
facility: Hôpital Henri Mondor (APHP)
city: Lille
country: France
facility: Centre Oscar Lambret
city: Lille
country: France
facility: Chru Lille
city: Lyon
country: France
facility: Infirmerie Protestante de Lyon
city: Marseille
country: France
facility: Hôpital Européen Marseille
city: Marseille
country: France
facility: Hôpital La Timone
city: Marseille
country: France
facility: Institut Paoli CALMETTES
city: Montpellier
country: France
facility: Institut du Cancer de Montpellier
city: Nantes
country: France
facility: Chu Nantes
city: Paris
country: France
facility: Hôpital Cochin (APHP)
city: Paris
country: France
facility: Institut Mutualiste Montsouris
city: Paris
country: France
facility: Pitié Salpêtrière (APHP)
city: Pessac
country: France
facility: Hôpital Haut-Lévêque
city: Reims
country: France
facility: CHU Reims
city: Rennes
country: France
facility: Centre Eugène Marquis
city: Rouen
country: France
facility: Chu Rouen
city: Saint Grégoire
country: France
facility: CHP Saint Grégoire
city: Saint-Herblain
country: France
facility: Institut de Cancérologie de l'Ouest
city: Tours
country: France
facility: Chru Tours
city: Vandoeuvre-les-nancy
country: France
facility: Chru Nancy
city: Vandoeuvre-les-nancy
country: France
facility: Institut de Cancérologie de Lorraine
city: Villejuif
country: France
facility: Hôpital Paul Brousse
Study officials:
affiliation: Institut de Cancérologie de Lorraine
name: Thierry CONROY, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: Groupe Hospitalier Pitié-Salpêtrière
name: Jean-Baptiste BACHET, Pr
role: STUDY_CHAIR
affiliation: Hôpital Paul Brousse - Hôpitaux de Paris (AP-HP)
name: Pascal HAMMEL, Pr
role: STUDY_CHAIR
References: