Transcript Diapositive 1

A MULTICENTRIC PHASE I STUDY OF SUNITINIB
WITH CONCOMITANT RADIATION THERAPY IN
INOPERABLE SARCOMAS (GIST EXCLUDED)
M.P. SUNYACH, D. PEROL, N. PENEL, P. CASSIER,
X. LIEM, S. DUSSART, C. CROPET, E. BLANC, G. KANTOR
Background
Local control with exclusive radiotherapy (RT) in sarcoma is
infrequent even with higher doses. Preclinical data suggest
potential synergy of RT when combined with an angiogenesis
inhibitor.
Based on these findings, a dose-finding, dose escalation study to
assess the safety and feasibility of continuous dosing of sunitinib
(S) with concomitant RT in inoperable non-GIST sarcomas
patients was thus initiated.
Methods
 A 3+3 dose escalation design of sunitinib combined with
constant dose of RT:
3 to 6 patients were sequentially enrolled in 2 steps to receive 1 of 3
escalated doses of sunitinib
 Extension cohort: 12 additional patients at maximal
tolerated dose (MTD)
Main objective
 Determination of the MTD
Assessed by the incidence rate of dose-limiting toxicity (DLT) defined as:
- Musculo-skeletal or cutaneous grade ≥ 3 toxicity in the radiation field:
o at dose < 30 Gy
o at dose 30 Gy without return to a grade ≤ 2 in ≤ 4 weeks,
- Any grade ≥ 4 toxicity.
and observed during 14 weeks from the start of S+RT.
Treatment
 Radiotherapy (RT)
 60 Gy in 30 fractions (2 Gy x 5 fractions per week)
 Sunitinib (S)
 Dose level 1 (DL1): 25 mg/day during the 6-week RT
 Dose level 2 (DL2): 37.5 mg/day during the 6-week RT
 Dose level 3 (DL3): 50 mg/day during the 6-week RT
Study population
 Main inclusion criteria
o
o
o
o
o
o
Inoperable locally advanced or recurrent tumor without previous RT
Age ≥ 18 years
PS ≤ 2
Number of metastatic sites ≤ 2
ALT and AST ≤ 2.5 x ULN
Serum creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 50 mL/min
 Exclusion criteria
o Prior sunitinib treatment
o Brain metastases
o Uncontrolled hypertension
Patients characteristics
 10 patients were enrolled between May 2011 and June 2013
Characteristics
Age (median/range)
Female
Type
Osteosarcoma
Pleomorphic undifferentiated
Spindle cell
Liposarcoma
Epithelioid
Chordoma
Irradiation field
Limb
Face
Pelvis
Pleura
N = 10
59 / 40-82
8
2
3
1
1
1
1
4
3
2
1
Patients characteristics
Characteristics
N = 10
Previous chemotherapy
5
Previous surgery
4
Previous targeted therapy
1
No previous treatment
4
Local relapse or progression
4
Metastases
2
DLT
 9# patients evaluable for DLT
Dose level
DL1
Sunitinib
25 mg
N
3
DLT
No DLT
DL2
37.5 mg
3
3
1 DLT: grade 4 thrombopenia*
No DLT
DL3
50 mg
Not tested
#
1 non-evaluable patient (early stop of sunitinib at DL1)
* with grade 3 dyspnea and lymphopenia resolved with antibiotic therapy.
Other toxicities
 No toxicities requiring discontinuation of RT were reported:
60 Gy were delivered to all patients (except for the patient
with DLT: 40 Gy).
 No toxicities requiring interruption of sunitinib (≥ 9 days,
consecutive or not) were reported.
 Interruption ≤ 8 days for 2 patients (1 at DL1 and 1 at DL2): grade 1
thrombopenia and grade 3 sunitinib cutaneous allergy outside the
irradiation field
 Permanent discontinuation of sunitinib for 1 patient at DL1 (grade 2
hypertension – non compliance with antihypertensive therapy) =
patient considered non-evaluable for DLT
Decision of independant Data Safety
Monitoring Board – Sept 2013
Based on:
 Occurrence of grade 3 events at DL2 (4/6 patients)
 DL3 (sunitinib 50 mg/day during 6 weeks) higher than standard
dose
 Stop of dose escalation / formal MTD not reached
 Extension cohort at DL2
Efficacy – Preliminary results
 Local progression within 12 months from inclusion: 3 patients
 2 to 8 months
 Local control at the end of follow-up (12 months): 6 patients
(5 at DL2)
 1 complete response (CR) after surgery (inoperable patient at
inclusion) – patient at DL1
 Partial response: 2 patients
 Stable disease: 2 patients
 Suspicion of relapse at 12 months after CR: 1 patient (relapse (10
mm) confirmed at 15 months).
 1 patient non evaluable for local control (early study
withdrawal).
Conclusions
 RT combined with
sunitinib at 37.5 mg/day given
continuously during 6-week radiotherapy appears safe and
feasible.
 Enrolment of 12 additional patients at DL2 is ongoing to
confirm these findings.
Acknowledgements
 All patients who participated
 Investigators
Lyon: M.P. Sunyach, J.Y. Blay, P. Cassier, P. Heudel
Lille: N. Penel, X. Liem, A. Cordoba Largo, E. Lartigau
Bordeaux: G. Kantor
Villejuif: C. Le Péchoux, J. Domont, A. Le Cesne, O. Mir
Marseille: F. Duffaud, D. Badinand, T. Duberge, T.K. Huynh,
L. Padovani, S. Salas
 French Ministry of Health (PHRC)
 Pfizer for drug supply