randomized phase ii trial comparing folfirinox (5fu/leucovorin, irinotecan and oxaliplatin) vs...
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RANDOMIZED PHASE II TRIAL COMPARING FOLFIRINOX (5FU/LEUCOVORIN, IRINOTECAN
AND OXALIPLATIN) VS GEMCITABINEAS FIRST-LINE TREATMENT FOR METASTATIC
PANCREATIC ADENOCARCINOMA
FIRST RESULTS OF THE ACCORD 11/0402 TRIAL
M. Ychou1, F. Desseigne2, R. Guimbaud3, M. Ducreux4, O. Bouché5, Y. Bécouarn6, A. Adenis7, C. Montoto-Grillot8, E. Luporsi9, T. Conroy9
1. Centre Val d'Aurelle, Montpellier 2. Centre Léon Bérard, Lyon3. Institut Claudius Regaud, Toulouse 4. Institut Gustave Roussy, Villejuif5. Centre Hospitalier R. Debré, Reims 6. Institut Bergonié, Bordeaux7. Centre Oscar Lambret, Lille 8. Fédération Nationale des Centres de Lutte
Contre le Cancer- BECT, Paris9. Centre Alexis Vautrin, Nancy, FRANCE
Abstract # 4516
RANDOMIZED PHASE II TRIAL COMPARING FOLFIRINOX (5FU/LEUCOVORIN, IRINOTECAN
AND OXALIPLATIN) VS GEMCITABINEAS FIRST-LINE TREATMENT FOR METASTATIC PANCREATIC
ADENOCARCINOMAFIRST RESULTS OF THE ACCORD 11/0402 TRIAL
M. Ychou1, F. Desseigne2, R. Guimbaud3, M. Ducreux4, O. Bouché5, Y. Bécouarn6, A. Adenis7, C. Montoto-Grillot8, E. Luporsi9, T. Conroy9
Background:
In a phase II trial of Folfirinox (F) in 35 MPA patients (pts), we reported a 26% response rate and median survival of 9.5 months (mo) with quality of life improvement (Conroy, JCO 2005). The aim of this phase II trial was to compare the response rate and safety of F vs G in patients with MPA.
Methods:
Chemotherapy-naïve patients aged 18-75 years with histologically or cytologically confirmed measurable MPA were randomized to receive G (1000 mg/m2 IV weekly x 7 for 8 weeks [wks] then weekly x 3 out of 4 wks) or F (O 85mg/m2 d1 + I 180mg/m2 d1 + LV 400mg/m2 d1 followed by 5FU 400mg/m2 bolus d1 and 2400 mg/m2 46h continuous infusion biweekly). Patients were stratified by centre, performance status (ECOG 0 versus 1), and primary tumor location (head vs other). Primary endpoint was response rate.
Results: From 01/05 to 11/06, all planned 88 pts (44 per arm) were enrolled. Median age was 56 yrs [35-76]. Currently, safety data for 81 pts (41F/40G) and efficacy data for 65 pts (31F/34G) are available (17 too early). One pt was ineligible in arm F. Two pts, one in each arm, did not receive protocol therapy. Median number of wks on treatment was 18 (F) and 7 (G). No toxic death occurred. Main grade 3-4 toxicities (arm F vs G) were G3 neutropenia (32%/17.5), G4 neutropenia (19.5%/0), G3-4 thrombocytopenia (12%/0), G3 vomiting (17%/2.5), G3 transaminases (0%/15) and G3-4 fatigue (27%/15).Confirmed partial responses (PR) rates (F/G) were 38.7% (12/31) and 11.7 % (4/34) according to the investigators and median duration of response was 6,3 and 4,6 mo. PR and stable disease (SD) were documented for 21/31 evaluable pts in arm F and expert review confirmed 13 PR (41.9 %) and 6 SD (19.3%).
Conclusions: Folfirinox induces a response rate > 30% with manageable toxicity in ECOG 0-1 pts with MPA. According to these interim results, this trial will continue as a phase III study. Updated results will be presented at the meeting. Supported by a PHRC 2004 grant from the French Ministry of Health.
Background
Advanced pancreatic adenocarcinoma remains an incurable disease with few good treatment options.
Weekly gemcitabine has been widely adopted as the standard of care, with median survival of 4.6 to 7.3 months in phase III randomized studies.
Background
Folfirinox regimen (oxaliplatin, irinotecan, bolus and continuous infusion 5-FU plus leucovorin) was assessed in a phase II study and seems promising in good performance status patients (Conroy T et al. J Clin Oncol 2005;23:1228-36).
A confirmed response rate of 25.7 % and a median overall survival of 9.5 months was described in 35 patients with metastatic disease. Quality of life (assessed with EORTC QLQ-C30) was improved.
Background
Therefore, we launched a phase II-III randomized study comparing Folfirinox regimen to gemcitabine alone.
We report here the first results of the randomized phase II step.
Objectives
Primary objective (for the phase II step) :
to assess the response rate in both arms
Secondary objective
to assess the toxicity profile of each arm using NCI-CTC version 3.0, especially grade 3-4 toxicities
Study design
Multicenter (n=17) randomized phase II trial
Randomization between the 2 arms with stratification according to : center performance status : 0 versus 1 location of the tumor : head versus other location
of pancreatic tumors
Treatments
Arm A: FOLFIRINOXOxaliplatin 85 mg/m2 in 2 hours infusion,Folinic acid 400 mg/m2 in 2 hours infusion,Irinotecan 180 mg/m2 in 90mn infusion,
Bolus 5-FU 400 mg/m2, Continuous infusion 5-FU 2.4 g/m2 on 46 hours.
1 cycle = 14 days
1 h 30
2 h
2 h
46 h
L-OHP85 mg/m2
CPT-11180 mg/m2
Leucovorin400 mg/m2
Continuous 5-FU 2.400 mg/m2
Bolus 5-FU 400 mg/m2
Treatments
Arm B: Gemcitabine
Gemcitabine 1000 mg/m2 over 30 minutes
given weekly X 7/8 and then weekly X 3/4
1 cycle = 28 days
A 6 months duration of chemotherapy was advised for both arms
Statistical considerations
The sample size calculation was calculated to reject a 10% response rate in favor of a target response rate of 24% for the experimental arm, with a significance level of 0.05 and a power of 92% by using Fleming's method:
- In the initial stage, a total of 20 evaluable patients were to be entered and evaluated for response. If there was less than 3 responses, accrual was to be terminated.
- If more than 3 responses were observed in the first stage, then 10 additional patients were to be entered in the second stage to
achieve a target sample size of 30 evaluable patients.
- Further accrual of 10 patients was planned if more than 4 responses were observed in the first 30 patients in the Folfirinox arm.
A sample size of 80 patients (40 patients per study arm) was needed. Taking into consideration the estimate of approximately 5% of patients which will not be evaluable, a total number of 88 patients had to be randomized.
Inclusion criteria
Histologically or cytologically proven adenocarcinoma of the pancreas
ECOG performance status of 0 or 1
Measurable metastases (outside a radiotherapy field)
No prior cytotoxic chemotherapy
No prior abdominal radiotherapy
Age 18-75 years
Adequate hematopoietic, hepatic and renal function
No unstable angina or myocardial infarction within 12 months before the study
Written informed consent
Non inclusion criteria
Other pancreatic tumor (endocrine, acinar cell…)
Central nervous system metastases
Chronic diarrhea
Previous or concomitant other malignant disease
Locally advanced pancreatic cancer without distant metastases (stage III)
Efficacy assessment
Tumor Response investigator assessment every 8 weeks according RECIST criteria independent blinded review of Objective Response (OR)
and Stable Disease (SD)
Quality of life assessment with EORTC QLQ-C30 (results not shown)
RESULTS Inclusion period from January 2005 to October 2006
1519
1925
PS (WHO) 0 1
56 [35-71]58 [38-76]Median age (years) [range]
26/1829/15 Sex ratio M / F
Gemcitabine (B)n = 44
FOLFIRINOX (A)n = 44
Patients characteristics (1)
RESULTS
3815 4 3 4 2
3815 7 5 1 4
Measurable Site Liver Pancreas Nodes Peritoneal Lung Other
26Pancreatic Tumor Resected
1727
1331
Tumor Location Head Other
Gemcitabine (B)n = 44
FOLFIRINOX (A)n = 44
Patients characteristics (2)
RESULTS
0
2 (4%)
7 (16%)
6 (14%)Anemia
0 1 (2%)Febrile neutropenia
16 (37%)38 (88%)Neutropenia
Gemcitabine (B)n = 43
Number of patients (%)
FOLFIRINOX (A)n = 43
Number of patients (%)
Main grade 3-4 hematological toxicities
Thrombopenia
RESULTS
2 (4%)
6 (14%)
2 (4%)
3 (7%)
0 (0%)
15 (35%)
10 (23%)
6 (14%)
1 (2%)
2 (4%)
10 (23%)
15 (35%)
Vomiting
Gemcitabine (B)n = 43
Number of patients (%)
FOLFIRINOX (A)n = 43
Number of patients (%)
Main grade 3-4 non hematological toxicities
Nausea
Diarrhea
Abdominal cramps
Neuropathy
Fatigue
RESULTS – EFFICACY
9 (20.4 %)
27 (61.4 %)
3 (6.8 %)
12 (27.3 %)
15 (34.1 %)
3 (6.8 %)
Stable Disease (SD)
5 (11.4 %) [3.8-24.6 %]
14 (31.8 %)[18.6-47.6 %]
Partial Response (PR)[ 95 % IC ]
00 Complete Response (CR)
Gemcitabine (B)n = 44
FOLFIRINOX (A)n = 44
Investigators Response Rate* (ITT Population)
Progressive Disease (PD)
Non Evaluable (NE)**
* Panel confirmed 15 PR in arm A and 4 in arm B** 2 non treated and 4 ineligible
Conclusions
Folfirinox induces a response rate > 30% with manageable toxicity in ECOG 0-1 pts with metastatic pancreatic adenocarcinoma.
According to these interim results, this trial will continue as a phase III study to demonstrate an improvement in overall survival.
Acknowledgments
Patients Co-investigators Sponsor : J. Genève, M. Torres, F. Do Nascimento, AC.
Le Gall (FNCLCC, BECT, Paris)
Data center : C. Kadouci (Centre Alexis Vautrin, Nancy)
Supported by a Clinical Research Hospital Program grant (PHRC 2004) grant from the French Ministry of Health
Grants from Pfizer and sanofi-aventis