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Main Selection criteria (1)

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 .

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Main Selection criteria (1)

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  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

  2. 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

  3. 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

  4. 2 Steps Study Design Phase IIb 120 pts Phase III 250 pts Doxorubicin 75 mg/m2 Doxo 75 mg/m PFS? R Selectthebest PFS & safety Trabectedin 1.3 mg/m23h R T 3h or24h Trabectedin 1.5 mg/m224h • Stratification factors: • age (<60 vs ≥ 60 yrs) • presence of liver metastases (yes vs no) • Secondary endpoints • OS, QoL, RR • toxicity

  5. 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 Trab24h arm

  6. Protocol decision after phase 2b • 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. • The study is not futile (i.e. HR > 1) for PFS • The selected trabectedin arm should not be inferior (by more than 10% in terms of hazard ratio) to the other investigational arm. • 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.

  7. Follow-up AccrualfromJune 2011 to August 2012 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)

  8. Eligibility

  9. Baseline characteristics

  10. Relative dose intensity (at least 6 cycles)

  11. Protocol decision rules for IDMC • 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. • 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. • The study is not futile (i.e. HR > 1) for PFS

  12. Reasons for stopping treatment

  13. Causes of treatment discontinuations Treatment discontinuation undertrabectedin*: 15 • 1 treatmentrelateddeath: sepsis (T3h) • 8 hematologicaltoxicities • Leuco/neutropenia:3 (sepsis:1) • Thrombopenia:5 • 6 liverbiologicaltoxicities • Only cause of discontinuation in 3 patients • 1 General statusimpairment • 1 decrease of VEF>10% • 1 creatininincrease, 1CPK increase Treatment discontinuation under doxorubicin:1 • troponinincrease *causes of discontinuation couldbe multiple *discontinuation if no return to grade 1 or less 14 daysaftertheoretical date to resumetreatment

  14. Protocol decision rules for IDMC • 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. • The study is not futile (i.e. HR > 1) for PFS • 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.

  15. Progression free survival

  16. Progression free survival Doxorubicin Trabectedin 24hrs Trabectedin 3hrs

  17. Best overall response • Trend test (considering early death and not-assessable/not-evaluable as PD): • Trab 3hrs vsdoxo: 2-sided p-value 0.329 • Trab 24hrs vsdoxo: 2-sided p-value 0.159

  18. Doxorubicin Trabectedin 24 hrs Trabectedin 3 hrs

  19. Overall survival

  20. Doxorubicin Trabectedin 24 hrs Trabectedin 3 hrs

  21. Conclusions • Only 1 toxic death occurred, but more than 15% of patients stopped allocated treatment due to toxicity in the trabectedin arms. • Both trabectedin infusion arms compare to doxorubicin with an HR larger than the cut-off for futility, thus the trial meets futility criteria • The mean relative dose intensity was not different in the 3hr schedule than in the 24hr schedule. • With a HR = 1.30 the 3hr schedule is less active than the 24hr schedule. According to the decision rules, the study is stopped

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

  23. Safety

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