Main Selection criteria (1)

TRUSTS / EORTC 62091/SARC021: A PHASE IIB/III STUDY OF TRABECTEDIN VS DOXORUBICIN AS FIRST LINE THERAPY FOR

LOCALLY ADVANCED/METASTATICSOFT TISSUE SARCOMASanalysis 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

• 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

Main Selection criteria (1)

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

• 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

Main Selection criteria (2)

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2 Steps Study Design

4

Phase IIb 120 pts Phase III 250 pts

R

Trabectedin 1.5 mg/m2 24h

Doxorubicin 75 mg/m2 Doxo 75 mg/m

T 3h or 24hSelect the best

PFS & safety

Trabectedin 1.3 mg/m2 3h

PFS?

Stratification factors: - age (<60 vs ≥ 60 yrs) - presence of liver metastases (yes vs no)

Secondary endpoints- OS, QoL, RR

- toxicity

R

• 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

Statistical considerations

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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.

Protocol decision after phase 2b

6

7

Follow-up

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)

(months)0 2 4 6 8 10 12 14 16 18

0

10

20

30

40

50

60

70

80

90

100

All patients

Follow-up

(months)0 2 4 6 8 10 12 14 16 18

0

10

20

30

40

50

60

70

80

90

100

Trab_3hrs Trab_24hrs Doxo

Follow-upBy treatment arm

Accrual from June 2011 to August 2012

8

Trab_3hrs

(N=47)Trab_24hrs

(N=43)Doxo

(N=43)Total

(N=133)

N (%) N (%) N (%) N (%)Eligible

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)

Eligibility

Patient id

Hospital number Treatment Reason

3 234 Trab_3hrs Grade 3 GGT10 234 Trab_3hrs Grade 3 GGT49 287 Trab_24hrs Grade 3 GGT51 8673 Doxo Grade 3 GGT54 229 Trab_3hrs Grade 3 GGT72 301 Trab_24hrs ineligible tumor type (well

differentiated adipocytic sarcoma)85 227 Trab_24hrs Grade 3 GGT

Baseline characteristics

9

Trab_3hrs(N=47)

Trab_24hrs(N=43)

Doxo(N=43)

Total(N=133)

N (%) N (%) N (%) N (%)Age at randomization

< 60yrs

23 (48.9)

21 (48.8)

20 (46.5)

64 (48.1)

≥ 60yrs

24 (51.1)

22 (51.2)

23 (53.5)

69 (51.9)

Median

60 60 60 60

Range

34 - 84 23 - 78 24 - 77 23 - 84

Presence of liver metastasis at randomization

No 38 (80.9) 35 (81.4) 37 (86.0) 110 (84.7)Yes 9 (19.1) 8 (18.6) 6 (14.0) 23 (17.3)

Sex Male

18 (38.3)

20 (46.5)

18 (41.9)

56 (42.1)

Female

29 (61.7)

23 (53.5)

25 (58.1)

77 (57.9)

WHO performance status

0

25 (53.2)

21 (48.8)

26 (60.5)

72 (54.1)

1

22 (46.8)

22 (51.2)

17 (39.5)

61 (45.9)

Tumor type ADI 6 (12.8)

10 (23.3)

13 (30.2)

29 (21.8)

(local path) LMS 18 (38.3)

8 (18.6)

14 (32.6)

40 (30.1)

SYN 2 (4.3)

3 (7.0)

3 (7.0)

8 (6.0)

OTH 21 (44.6) 22 (51.1) 13 (30.2) 56 (42.1)

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)

Relative dose intensity (at least 6 cycles)

10

Trab_3hrs

(N=46)Trab_24hrs

(N=41)Doxo(N=40)

Number of cycles

Median

3 4 6

Range

1 - 19 1 - 22 1 - 6

Still on treatment?

No

40 (87.0)

36 (87.8)

39 (97.5)

Yes

6 (13.0)

5 (12.2)

1 (2.5)





Protocol decision rules for IDMC

11

Trab_3hrs(N=46)

Trab_24hrs(N=41)

Doxo(N=40)

Total(N=127)

N (%) N (%) N (%) N (%)Still on protocol treatment 6 (13.0)

5 (12.2)

1 (2.5)

12 (9.4)

Off protocol treatment due to

Disease progression (+ death due to PD)

26 (56.5)

23 (56.1)

12 (30.0)

61 (48.0)

Symptomatic deterioration

3 (6.5)

1 (2.4)

2 (5.0)

6 (4.7)

Stop for Toxicity (+ toxic death)

7 (15.2)

8 (19.5)

1 (2.5)

16 (12.6)

Death not due to malignant disease or toxicity

2 (4.3)

1 (2.4)

1 (2.5)

4 (3.1)

Investigator decision (best interest)

0 (0.0)

1 (2.4)

1 (2.5)

2 (1.6)

Patient decision (not related to toxicity)

1 (2.2)

2 (4.9)

1 (2.5)

4 (3.1)

Other 1 (2.2)

0 (0.0)

1 (2.5)

2 (1.6)

Reasons for stopping treatment

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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 increaseTreatment 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

Causes of treatment discontinuations

13





Protocol decision rules for IDMC

14

Progression free survival

15

TreatmentPatients(N)

ObservedEvents(O)

Hazard Ratio(95% CI)

1-sided P-Value

Median (95% CI)(Months)

Doxo 43 26 1.00 5.52 (3.12, 7.23) 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)


ObservedEvents(O)


Trab_24hrs

43 31 1.00

Trab_3hrs

47 37 1.30 (0.81, 2.10)

Progression free survival

16

Doxorubicin

Trabectedin 24hrs

Trabectedin 3hrs

Trab_3hrs(N=47)

Trab_24hrs(N=43)

Doxo(N=43)

N (%) N (%) N (%)Complete response 1 (2.1)

0 (0.0)

0 (0.0)

Partial response 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)

Best overall response

17

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

18

(months)0 2 4 6 8 10 12 14 16

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Treatment13 27 27 19 11 6 5 2 015 27 24 17 13 10 4 3 116 26 24 15 10 5 4 0 0

DoxoTrab_24hrsTrab_3hrs

Stable disease duration

Doxorubicin

Trabectedin 24 hrs

Trabectedin 3 hrs

Overall survival

19


ObservedEvents(O)


1-sided P-Value

Median (95% CI)(Months)

Doxo 43 10 1.00 Not reachedTrab_24hrs 43 10 0.94 (0.39, 2.25) 0.441 Not reachedTrab_3hrs 47 16 1.30 (0.58, 2.90) 0.741 17.3 (8.2, 17.3)

Trab_3hrs(N=47)

Trab_24hrs(N=43)

Doxo(N=43)

N (%) N (%) N (%)Cause of death:

Progression of disease (PD)

12 (25.5)

9 (20.9)

8 (18.6)

Toxicity 1 (2.1)

0 (0.0)

0 (0.0)

Other (not due to toxicity or PD)

2 (4.3)

1 (2.3)

1 (2.3)

Unknown 1 (2.1)

0 (0.0)

1 (2.3)

20

DoxorubicinTrabectedin 24 hrs

Trabectedin 3 hrs

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

Conclusions

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• Thanks to• The patients• All the EORTC and SARC investigators• EORTC and SARC staff• pharmaMar

Acknowledgements

22

23

ID Site Treatment More details on toxicity5 228 Trab_3hrs neutropenia, catheter infection treatment delayed and not

possibility to restart treatment as per protocol8 228 Trab_3hrs septic choc (toxic death)25 8673 Trab_3hrs After 3rd attempt Platelet count did not recover to required value.

97 K/MM334 527 Trab_3hrs Treatment delayed of more than 3 weeks due to Platelet count

decreased47 906 Trab_3hrs increase of liver enzymes, decrease of platelets104 527 Trab_3hrs Hepatopathy116 227 Trab_3hrs toxicity: thrombopenia, ALAT elevation, GGT elevation19 228 Trab_24hrs general status impairment, creatinine increased28 228 Trab_24hrs liver toxicity30 8673 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)

60 228 Trab_24hrs hepatic toxicity72 301 Trab_24hrs Ejection fraction decrease below LLN (10% drop compared to

baseline)92 228 Trab_24hrs liver toxicity96 234 Trab_24hrs platelet count decreased110 227 Trab_24hrs pancytopenia76 371 Doxo Troponin increased due to cardiotoxicity for anthracycline

24

25

26

27

(months)0 2 4 6 8 10 12 14 16

0

10

20

30

40

50

60

70

80

90

100



Progression free survivalPerformance status 0

(months)0 2 4 6 8 10 12 14

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Treatment11 17 9 6 3 2 1 017 22 12 8 5 4 1 120 22 9 8 6 3 2 0


Progression free survivalPerformance status 1

28

(months)0 2 4 6 8 10 12 14 16

0

10

20

30

40

50

60

70

80

90

100



Stable disease duration

Safety

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Documents

Main Selection criteria (1)