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EORTC Phase IIb/III Study: Trabectedin vs Doxorubicin for Advanced Soft Tissue Sarcomas

This study assesses the efficacy and safety of Trabectedin compared to Doxorubicin as first-line therapy for patients with locally advanced or metastatic soft tissue sarcomas. The Phase IIb component includes 120 patients, while the Phase III component aims for 250 patients. Key selection criteria include histologically confirmed sarcomas, no prior anthracycline treatment, and measurable disease per RECIST 1.1. The endpoints include progression-free survival, overall survival, quality of life, and toxicity levels. Findings will provide insights into optimal treatment approaches for these challenging malignancies.

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EORTC Phase IIb/III Study: Trabectedin vs Doxorubicin for Advanced Soft Tissue Sarcomas

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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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