TRUSTS / EORTC 62091/SARC021:
A PHASE IIB/III STUDY OF TRABECTEDIN VS
DOXORUBICIN AS FIRST LINE THERAPY FOR
LOCALLY ADVANCED/METASTATIC
SOFT TISSUE SARCOMAS
analysis of phase IIb part
B. Bui-Nguyen, J. Butrynski, N. Penel, J-Y Blay, N. Isambert, M.
Milhem, J.M. Kerst, A.K.L. Reyners, S. Litière, S. Marreaud, A.P.
Dei Tos, WTA van der Graaf
November 2, CTOS 2013
Main Selection criteria (1)
• Histologically proven advanced and/or metastatic malignant soft
tissue sarcoma intermediate/high grade, except:
 Well-differentiated liposarcoma, Embryonal rhabdomyosarcoma,
Chondrosarcoma, Osteosarcoma (excluding extraskeletal osteosarcoma),
Ewing tumors / primitive neuroectodermal tumor (PNET), Gastro-intestinal
stromal tumors (GIST), Dermatofibrosarcoma protuberans

Measurable disease according to RECIST 1.1

Confirmed disease progression based on investigator’s judgment



No known history of CNS metastases or leptomeningeal tumor
spread
No prior anthracycline treatment
No prior anticancer therapy for advanced or metastatic malignant
soft tissue sarcoma
2
Main Selection criteria (2)
• No anti-cancer therapy (i.e systemic therapy, RT, surgery)
and no other investigational agent within 28 days prior to
treatment start and while on protocol treatment
•
•
•
•
> 18 years old
WHO PS 0 or 1
Normal bone marrow, hepatic, renal and cardiac function
No active or uncontrolled infections or serious illnesses or
medical conditions, including a history of chronic alcohol abuse,
hepatitis, HIV and/or cirrhosis.
• Contraception
• Written informed consent
3
2 Steps Study Design
Phase IIb 120 pts
Phase III 250 pts
Doxorubicin 75 mg/m2
Trabectedin 1.5 mg/m2 24h
Stratification factors:
- age (<60 vs ≥ 60 yrs)
- presence of liver metastases (yes vs no)
PFS?
Trabectedin 1.3 mg/m2 3h
Select the best
PFS & safety
R
R
Doxo 75 mg/m
T 3h or 24h
Secondary endpoints
- OS, QoL, RR
- toxicity
4
Statistical considerations
• Median PFS in control arm 6 months (max)
• Alpha = 0.025 (1-sided), power = 90%
• Target HR = 0.65 (i.e. 35% reduction in risk,
corresponding to PFS of ± 9 months)
• Interim analysis to be performed when both
 a total of 53 PFS events in doxo and Trab 3h arm
 a total of 53 PFS events in doxo and Trab 24h arm
5
Protocol decision after phase 2b
1.
If more than 5% of drug related deaths are observed, or
if more than 15% of patients have to withdraw for
toxicity, the safety profile of the trabectedin arms will be
considered as unacceptable.
2.
The study is not futile (i.e. HR > 1) for PFS
3.
The selected trabectedin arm should not be inferior (by
more than 10% in terms of hazard ratio) to the other
investigational arm.
4.
If the mean relative dose intensity in patients receiving
at least 6 cycles of therapy is 10% lower in the 3 hour
schedule (compared to the 24 hour schedule), the 3
hour treatment schedule will be considered as
unacceptable.
6
Follow-up
Accrual from June 2011 to August 2012
Follow-up
Follow-up
By treatment arm
100
100
90
90
80
80
70
70
60
60
50
50
40
40
30
30
20
20
10
10
0
(months)
0
2
4
All patients
6
8
10
12
14
16
18
0
(months)
0
2
4
Trab_3hrs
6
8
Trab_24hrs
10
12
14
16
18
Doxo
Median follow-up of 7.9 months (IQR 5.9 – 11.1)
• doxorubicin: 7.8 months (IQR 5.4-10.3)
• trabectedin 3h infusion: 8.0 months (IQR 6.4 – 11.3)
• trabectedin 24 hr infusion: 7.9 months (IQR 5.7 – 11.3)
7
Eligibility
Trab_3hrs
(N=47)
Trab_24hrs
(N=43)
Doxo
(N=43)
Total
(N=133)
N (%)
N (%)
N (%)
N (%)
No
3 (6.4)
3 (7.0)
1 (2.3)
7 (5.3)
Yes
44 (93.6)
40 (93.0)
42 (97.7)
126 (94.7)
Eligible
Patient Hospital
id number
3
234
10
234
49
287
51
8673
54
229
72
301
85
227
Treatment
Trab_3hrs
Trab_3hrs
Trab_24hrs
Doxo
Trab_3hrs
Trab_24hrs
Trab_24hrs
Reason
Grade 3 GGT
Grade 3 GGT
Grade 3 GGT
Grade 3 GGT
Grade 3 GGT
ineligible tumor type (well
differentiated adipocytic sarcoma)
Grade 3 GGT
8
Baseline characteristics
Age at
randomization
Presence of liver
metastasis at
randomization
Sex
WHO performance
status
Tumor type
(local path)
< 60yrs
≥ 60yrs
Trab_3hrs
(N=47)
N (%)
23 (48.9)
24 (51.1)
Trab_24hrs
(N=43)
N (%)
21 (48.8)
22 (51.2)
Doxo
(N=43)
N (%)
20 (46.5)
23 (53.5)
Total
(N=133)
N (%)
64 (48.1)
69 (51.9)
Median
Range
No
Yes
60
34 - 84
38 (80.9)
9 (19.1)
60
23 - 78
35 (81.4)
8 (18.6)
60
24 - 77
37 (86.0)
6 (14.0)
60
23 - 84
110 (84.7)
23 (17.3)
Male
Female
0
1
18 (38.3)
29 (61.7)
25 (53.2)
22 (46.8)
20 (46.5)
23 (53.5)
21 (48.8)
22 (51.2)
18 (41.9)
25 (58.1)
26 (60.5)
17 (39.5)
56 (42.1)
77 (57.9)
72 (54.1)
61 (45.9)
ADI
LMS
SYN
OTH
6 (12.8)
18 (38.3)
2 (4.3)
21 (44.6)
10 (23.3)
8 (18.6)
3 (7.0)
22 (51.1)
13 (30.2)
14 (32.6)
3 (7.0)
13 (30.2)
29 (21.8)
40 (30.1)
8 (6.0)
56 (42.1)
9
Relative dose intensity (at least 6 cycles)
Number of cycles
Median
Range
Still on treatment?
No
Yes
Trab_3hrs
(N=46)
Trab_24hrs
(N=41)
Doxo
(N=40)
3
1 - 19
4
1 - 22
6
1-6
40 (87.0)
6 (13.0)
36 (87.8)
5 (12.2)
39 (97.5)
1 (2.5)
Treatment
Relative dose intensity (%)
Trab_3hrs
(N=15)
Trab_24hrs
(N=15)
Doxo
(N=23)
Median
72.8
72.4
92.5
Range
47.4 - 99.6
49.4 - 102.7
74.7 - 102.6
Mean (SD)
75.8 (17.5)
73.0 (15.6)
91.3 (7.4)
10
Protocol decision rules for IDMC
1. If more than 5% of drug related deaths are
observed, or if more than 15% of patients have to
withdraw for toxicity, the safety profile of the
trabectedin arms will be considered as
unacceptable.
2. If the mean relative dose intensity in patients
receiving at least 6 cycles of therapy is 10% lower
in the 3 hour schedule (compared to the 24 hour
schedule), the 3 hour treatment schedule will be
considered as unacceptable.
3. The selected trabectedin arm should not be inferior
(by more than 10% in terms of hazard ratio) to the
other investigational arm.
4. The study is not futile (i.e. HR > 1) for PFS
11
Reasons for stopping treatment
Still on protocol treatment
Off protocol treatment due to
Disease progression (+ death due to PD)
Symptomatic deterioration
Stop for Toxicity (+ toxic death)
Death not due to malignant disease or
toxicity
Investigator decision (best interest)
Patient decision (not related to toxicity)
Other
Trab_3hrs
(N=46)
N (%)
6 (13.0)
Trab_24hrs
(N=41)
N (%)
5 (12.2)
Doxo
(N=40)
N (%)
1 (2.5)
Total
(N=127)
N (%)
12 (9.4)
26 (56.5)
3 (6.5)
7 (15.2)
2 (4.3)
23 (56.1)
1 (2.4)
8 (19.5)
1 (2.4)
12 (30.0)
2 (5.0)
1 (2.5)
1 (2.5)
61 (48.0)
6 (4.7)
16 (12.6)
4 (3.1)
0 (0.0)
1 (2.2)
1 (2.2)
1 (2.4)
2 (4.9)
0 (0.0)
1 (2.5)
1 (2.5)
1 (2.5)
2 (1.6)
4 (3.1)
2 (1.6)
12
Causes of treatment discontinuations
Treatment discontinuation under trabectedin*: 15
• 1 treatment related death: sepsis (T3h)
• 8 hematological toxicities
 Leuco/neutropenia:3 (sepsis:1)
 Thrombopenia:5
• 6 liver biological toxicities
 Only cause of discontinuation in 3 patients
• 1 General status impairment
• 1 decrease of VEF>10%
• 1 creatinin increase, 1CPK increase
Treatment discontinuation under doxorubicin:1

troponin increase
*causes of discontinuation could be multiple
*discontinuation if no return to grade 1 or less 14 days after theoretical date to
resume treatment
13
Protocol decision rules for IDMC
1.
If more than 5% of drug related deaths are observed, or
if more than 15% of patients have to withdraw for
toxicity, the safety profile of the trabectedin arms will be
considered as unacceptable.
1.
The study is not futile (i.e. HR > 1) for PFS
2.
If the mean relative dose intensity in patients receiving
at least 6 cycles of therapy is 10% lower in the 3 hour
schedule (compared to the 24 hour schedule), the 3
hour treatment schedule will be considered as
unacceptable.
The selected trabectedin arm should not be inferior (by
more than 10% in terms of hazard ratio) to the other
investigational arm.
3.
14
Progression free survival
Treatment
Observed
Patients Events
(N)
(O)
Hazard Ratio
(95% CI)
1-sided
P-Value
Doxo
43
26
Trab_24hrs
43
31 1.13 (0.67, 1.90)
0.675
3.09 (1.91, 7.82)
Trab_3hrs
47
37 1.50 (0.91, 2.48)
0.944
2.76 (1.45, 5.52)
Treatment
Trab_24hrs
Trab_3hrs
Patients
(N)
43
47
1.00
Median (95% CI)
(Months)
Observed
Events
(O)
31
5.52 (3.12, 7.23)
Hazard Ratio
(95% CI)
1.00
37 1.30 (0.81, 2.10)
15
Progression free survival
Doxorubicin
Trabectedin 24hrs
Trabectedin 3hrs
16
Best overall response
Complete response
Partial response
Trab_3hrs
(N=47)
N (%)
1 (2.1)
Trab_24hrs
(N=43)
N (%)
0 (0.0)
Doxo
(N=43)
N (%)
0 (0.0)
6 (12.8)
2 (4.7)
11 (25.6)
Stable disease
19 (40.4)
25 (58.1)
16 (37.2)
Progressive disease
15 (31.9)
15 (34.9)
9 (20.9)
Early death
5 (10.6)
0 (0.0)
2 (4.7)
Not assessable/not evaluable
1 (2.1)
1 (2.3)
5 (11.6)
Trend test (considering early death and not-assessable/not-evaluable as PD):
- Trab 3hrs vs doxo: 2-sided p-value 0.329
- Trab 24hrs vs doxo: 2-sided p-value 0.159
17
Stable disease duration
100
Doxorubicin
90
80
Trabectedin 24 hrs
70
60
50
Trabectedin 3 hrs
40
30
20
10
0
O
13
15
16
(months)
0
2
4
6
N
27
27
26
Number of patients at risk :
27
19
11
24
17
13
24
15
10
8
6
10
5
10
5
4
4
12
2
3
0
14
0
1
0
16
Treatment
Doxo
Trab_24hrs
Trab_3hrs
18
Overall survival
Treatment
Observed
Patients Events
(N)
(O)
Hazard Ratio
(95% CI)
1-sided
P-Value
1.00
Median (95% CI)
(Months)
Doxo
43
10
Trab_24hrs
43
10 0.94 (0.39, 2.25)
0.441
Not reached
Trab_3hrs
47
16 1.30 (0.58, 2.90)
0.741
17.3 (8.2, 17.3)
Trab_3hrs
(N=47)
N (%)
Cause of death:
Progression of disease (PD)
Toxicity
Other (not due to toxicity or PD)
Unknown
12 (25.5)
1 (2.1)
2 (4.3)
1 (2.1)
Not reached
Trab_24hrs
(N=43)
N (%)
9 (20.9)
0 (0.0)
1 (2.3)
0 (0.0)
Doxo
(N=43)
N (%)
8 (18.6)
0 (0.0)
1 (2.3)
1 (2.3)
19
Doxorubicin
Trabectedin 24 hrs
Trabectedin 3 hrs
20
Conclusions
1.
Only 1 toxic death occurred, but more than 15% of patients
stopped allocated treatment due to toxicity in the trabectedin
arms.
2.
Both trabectedin infusion arms compare to doxorubicin with
an HR larger than the cut-off for futility, thus the trial meets
futility criteria
3.
The mean relative dose intensity was not different in the 3hr
schedule than in the 24hr schedule.
4.
With a HR = 1.30 the 3hr schedule is less active than the 24hr
schedule.
According to the decision rules, the study is stopped
21
Acknowledgements
•
•
•
•
•
Thanks to
The patients
All the EORTC and SARC investigators
EORTC and SARC staff
pharmaMar
22
23
ID
Site
Treatment More details on toxicity
5
228
8
25
228
8673
34
527
47
104
116
19
28
30
906
527
227
228
228
8673
60
72
228
301
92
96
110
76
228
234
227
371
Trab_3hrs neutropenia, catheter infection treatment delayed and not
possibility to restart treatment as per protocol
Trab_3hrs septic choc (toxic death)
Trab_3hrs After 3rd attempt Platelet count did not recover to required value.
97 K/MM3
Trab_3hrs Treatment delayed of more than 3 weeks due to Platelet count
decreased
Trab_3hrs increase of liver enzymes, decrease of platelets
Trab_3hrs Hepatopathy
Trab_3hrs toxicity: thrombopenia, ALAT elevation, GGT elevation
Trab_24hrs general status impairment, creatinine increased
Trab_24hrs liver toxicity
Trab_24hrs 3 weeks after last dose, pt still has Gr 2 decreased lymphocyte
count @ 690 (norm is 875-3300).
CPK on 23/08/2012 is still elevated Grade 2 @ 795 (norm 40-200)
Trab_24hrs hepatic toxicity
Trab_24hrs Ejection fraction decrease below LLN (10% drop compared to
baseline)
Trab_24hrs liver toxicity
Trab_24hrs platelet count decreased
Trab_24hrs pancytopenia
Doxo Troponin increased due to cardiotoxicity for anthracycline
24
25
26
Progression free survival
Performance status 0
100
90
80
70
60
50
40
Progression free survival
30
Performance status 1
20
100
10
90
0
O
15
14
17
(months)
80
0
2
4
6
N
26
21
25
Number of patients at risk :
21
14
7
15
10
8
17
8
5
8
10
4
6
3
4
4
2
12
14
60 1
0
1
0
70
50 2
40
0
16
Treatment
Doxo
Trab_24hrs
Trab_3hrs
30
20
10
0
O
11
17
20
(months)
0
2
4
6
N
17
22
22
Number of patients at risk :
9
6
3
12
8
5
9
8
6
8
10
12
14
2
4
3
1
1
2
0
1
0
Treatment
Doxo
Trab_24hrs
Trab_3hrs
27
Stable disease duration
100
90
80
70
60
50
40
30
20
10
0
O
13
15
16
(months)
0
2
4
6
N
27
27
26
Number of patients at risk :
27
19
11
24
17
13
24
15
10
8
6
10
5
10
5
4
4
12
2
3
0
14
0
1
0
16
Treatment
Doxo
Trab_24hrs
Trab_3hrs
28
Safety
29