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

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) 3

2 Steps Study Design 4 Phase IIb 120 pts Phase III 250 pts R R Trabectedin 1.5 mg/m 2 24h Doxorubicin 75 mg/m 2 Doxo 75 mg/m T 3h or 24h Select the best PFS & safety Trabectedin 1.3 mg/m 2 3h PFS? Stratification factors: -age (<60 vs ≥ 60 yrs) -presence of liver metastases (yes vs no) Secondary endpoints -OS, QoL, RR -toxicity R R

Median PFS in control arm 6 months (max) Alpha = (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 5

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 ) trabectedin 3h infusion: 8.0 months (IQR 6.4 – 11.3) trabectedin 24 hr infusion: 7.9 months (IQR 5.7 – 11.3) Accrual from June 2011 to August 2012

8 Trab_3hrs (N=47) Trab_24hrs (N=43) Doxo (N=43) Total (N=133) 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 numberTreatmentReason 3234Trab_3hrsGrade 3 GGT 10234Trab_3hrsGrade 3 GGT 49287Trab_24hrsGrade 3 GGT DoxoGrade 3 GGT 54229Trab_3hrsGrade 3 GGT 72301Trab_24hrsineligible tumor type (well differentiated adipocytic sarcoma) 85227Trab_24hrsGrade 3 GGT

Baseline characteristics 9 Trab_3hrs (N=47) Trab_24hrs (N=43) Doxo (N=43) Total (N=133) 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) Median60 Range Presence of liver metastasis at randomization No38 (80.9)35 (81.4)37 (86.0)110 (84.7) Yes9 (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 typeADI 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) 8 (6.0) OTH21 (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 Range 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 Median346 Range Still on treatment? No 40 (87.0) 36 (87.8) 39 (97.5) Yes 6 (13.0) 5 (12.2) 1 (2.5)

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 Protocol decision rules for IDMC 11

Trab_3hrs (N=46) Trab_24hrs (N=41) Doxo (N=40) Total (N=127) 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 12

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 Causes of treatment discontinuations 13

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. 3.The selected trabectedin arm should not be inferior (by more than 10% in terms of hazard ratio) to the other investigational arm. Protocol decision rules for IDMC 14

Progression free survival 15 Treatment Patients (N) Observed Events (O) Hazard Ratio (95% CI) 1-sided P-Value Median (95% CI) (Months) Doxo (3.12, 7.23) Trab_24hrs (0.67, 1.90) (1.91, 7.82) Trab_3hrs (0.91, 2.48) (1.45, 5.52) Treatment Patients (N) Observed Events (O) Hazard Ratio (95% CI) Trab_24hrs Trab_3hrs (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 (%) Complete response 1 (2.1) 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 Trab 24hrs vs doxo: 2-sided p-value 0.159

18 Doxorubicin Trabectedin 24 hrs Trabectedin 3 hrs

Overall survival 19 Treatment Patients (N) Observed Events (O) Hazard Ratio (95% CI) 1-sided P-Value Median (95% CI) (Months) Doxo Not reached Trab_24hrs (0.39, 2.25)0.441Not reached Trab_3hrs (0.58, 2.90) (8.2, 17.3) Trab_3hrs (N=47) Trab_24hrs (N=43) Doxo (N=43) N (%) Cause of death: Progression of disease (PD) 12 (25.5) 9 (20.9) 8 (18.6) Toxicity 1 (2.1) 0 (0.0) Other (not due to toxicity or PD) 2 (4.3) 1 (2.3) Unknown 1 (2.1) 0 (0.0) 1 (2.3)

20 Doxorubicin Trabectedin 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 21

Thanks to The patients All the EORTC and SARC investigators EORTC and SARC staff pharmaMar Acknowledgements 22

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IDSiteTreatment More details on toxicity 5228Trab_3hrsneutropenia, catheter infection treatment delayed and not possibility to restart treatment as per protocol 8228Trab_3hrsseptic choc (toxic death) Trab_3hrsAfter 3rd attempt Platelet count did not recover to required value. 97 K/MM Trab_3hrsTreatment delayed of more than 3 weeks due to Platelet count decreased 47906Trab_3hrsincrease of liver enzymes, decrease of platelets Trab_3hrsHepatopathy Trab_3hrstoxicity: thrombopenia, ALAT elevation, GGT elevation 19228Trab_24hrsgeneral status impairment, creatinine increased 28228Trab_24hrsliver toxicity Trab_24hrs3 weeks after last dose, pt still has Gr 2 decreased lymphocyte 690 (norm is ). CPK on 23/08/2012 is still elevated Grade 795 (norm ) 60228Trab_24hrshepatic toxicity 72301Trab_24hrsEjection fraction decrease below LLN (10% drop compared to baseline) 92228Trab_24hrsliver toxicity 96234Trab_24hrsplatelet count decreased Trab_24hrspancytopenia 76371DoxoTroponin increased due to cardiotoxicity for anthracycline 24

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Safety 29