Transcript ETUDE DE PHASE III RANDOMISEE ET MULTICENTRIQUE …

RANDOMIZED PHASE II TRIAL COMPARING
FOLFIRINOX (5FU/LEUCOVORIN, IRINOTECAN
AND OXALIPLATIN) VS GEMCITABINE
AS 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
3. Institut Claudius Regaud, Toulouse
5. Centre Hospitalier R. Debré, Reims
7. Centre Oscar Lambret, Lille
2. Centre Léon Bérard, Lyon
4. Institut Gustave Roussy, Villejuif
6. Institut Bergonié, Bordeaux
8. Fédération Nationale des Centres de Lutte
Contre le Cancer- BECT, Paris
9. Centre Alexis Vautrin, Nancy, FRANCE
Abstract # 4516
RANDOMIZED PHASE II TRIAL COMPARING FOLFIRINOX
(5FU/LEUCOVORIN, IRINOTECAN
AND OXALIPLATIN) VS GEMCITABINE
AS 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
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
incurable disease with few good treatment options.
an
 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: FOLFIRINOX
Oxaliplatin 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
Bolus 5-FU 400 mg/m2
2h
L-OHP
85 mg/m2
2h
Leucovorin
400 mg/m2
CPT-11
180 mg/m2
1 h 30
Continuous 5-FU
2.400 mg/m2
46 h
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
Patients characteristics (1)
FOLFIRINOX (A)
n = 44
Sex ratio M / F
29/15
Median age
(years) [range]
58 [38-76]
PS (WHO)
0
1
19
25
Gemcitabine (B)
n = 44
26/18
56 [35-71]
15
19
RESULTS
Patients characteristics (2)
FOLFIRINOX (A)
n = 44
Gemcitabine (B)
n = 44
Tumor Location
Head
Other
13
31
17
27
Pancreatic Tumor Resected
6
2
Measurable Site
Liver
Pancreas
Nodes
Peritoneal
Lung
Other
38
15
7
5
1
4
38
15
4
3
4
2
RESULTS
Main grade 3-4 hematological toxicities
FOLFIRINOX (A)
n = 43
Number of patients (%)
Neutropenia
Gemcitabine (B)
n = 43
Number of patients (%)
38 (88%)
16 (37%)
1 (2%)
0
Thrombopenia
7 (16%)
0
Anemia
6 (14%)
2 (4%)
Febrile neutropenia
RESULTS
Main grade 3-4 non hematological toxicities
FOLFIRINOX (A)
n = 43
Number of patients
(%)
Vomiting
Gemcitabine (B)
n = 43
Number of patients
(%)
10 (23%)
2 (4%)
6 (14%)
6 (14%)
Diarrhea
1 (2%)
2 (4%)
Abdominal cramps
2 (4%)
3 (7%)
Neuropathy
10 (23%)
0 (0%)
Fatigue
15 (35%)
15 (35%)
Nausea
RESULTS – EFFICACY
Investigators Response Rate* (ITT Population)
FOLFIRINOX (A)
n = 44
Complete Response (CR)
Partial Response (PR)
[ 95 % IC ]
0
14 (31.8 %)
[18.6-47.6 %]
Gemcitabine (B)
n = 44
0
5 (11.4 %)
[3.8-24.6 %]
Stable Disease (SD)
12 (27.3 %)
9 (20.4 %)
Progressive Disease (PD)
15 (34.1 %)
27 (61.4 %)
3 (6.8 %)
3 (6.8 %)
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