1. 12 th Annual CTOS Meeting 2006 SINGLE AGENT DOXORUBICIN VS DOSE INTENSIVE COMBINATION THERAPY WITH EPIRUBICIN / IFOSFAMIDE IN PREVIOUSLY UNTREATED ADULT PATIENTS WITH ADVANCED OR METASTATIC SOFT TISSUE SARCOMA: RESULTS FROM A RANDOMIZED PHASE II TRIAL M. Schuler 1, D. Pink 1, D. Schoeler 2, T. Lindner 1, JT Hartmann 3, S. Micheel 1, P. Reichardt 1, 2 1 Robert-Rössle-Klinik, HELIOS Klinikum Berlin-Buch, Charité Campus Buch, Berlin, Germany 2 Charité Campus Virchow-Klinikum, Berlin, Germany 3 Universitätsklinikum Tübingen, Germany

2. 12 th Annual CTOS Meeting 2006 Introduction Median survival for patients with metastatic soft tissue sarcoma is about 12 months So far, statistical superiority of combination chemotherapy over single agent therapy has not been proven for overall survival (first-line) However, combination regimens in randomized trials have been suboptimal (lack of growth factors)

3. 12 th Annual CTOS Meeting 2006

4. ASCO 2006

5. 12 th Annual CTOS Meeting 2006 Phase II – Trials: Anthracyclines + Ifosfamide

6. 12 th Annual CTOS Meeting 2006 Phase II – trial: Overall Survival Reichardt et al., J Clin Oncol 1998

7. 12 th Annual CTOS Meeting 2006 Randomized Phase II – trial Treatment Regimens

8. 12 th Annual CTOS Meeting 2006 Primary endpoints: –Response rate –Toxicity Secondary endpoints: –Progression-free survival –Overall survival 53 patients for arm B Second-line treatment with high-dose Ifosfamide recommended for Arm A Original Design

9. 12 th Annual CTOS Meeting 2006 Histologically proven metastatic or locally advanced soft tissue sarcoma with grading G2 or G3 At least one bidemensionally measurable target lesion ECOG-status < 2 Age 18 to 65 years Informed consent Inclusion Criteria (selected)

10. 12 th Annual CTOS Meeting 2006 Previous chemotherapy Grading G1 Gastrointestinal stromal tumor (GIST) Second malignancy Congestive heart failure Impaired renal, liver or bone marrow function Concommitant radiation Symptomatic brain metastases Exclusion Criteria (selected)

11. 12 th Annual CTOS Meeting 2006 Patients 39 patients were registered Stratification for center, PS 0 vs. 1 / 2, liver metastases 32 patients evaluable

12. 12 th Annual CTOS Meeting 2006 Patients Characteristics

13. 12 th Annual CTOS Meeting 2006 Best Response (WHO) Arm A N=13 n (%) Arm B N=19 n (%) Complete Response1 (8)1 (5) Partial Response2 (15)6 (32) Stable Disease3 (23)8 (25) Progression7 (54)3 (16) Not evaluable04 (21)

14. 12 th Annual CTOS Meeting 2006 Toxicity results

15. 12 th Annual CTOS Meeting 2006 Time to Progression median 2 months median 9 months

16. 12 th Annual CTOS Meeting 2006 Second-line Treatment 13 evaluable patients in arm A (single agent Doxorubicin) 11 patients received second-line high- dose Ifosfamide 14 g/m² Best response: –Stable disease 6 pts. –Progression 4 pts. –NE (tox.) 1 pt.

17. 12 th Annual CTOS Meeting 2006 Overall Survival median 15 months median 27 months

18. 12 th Annual CTOS Meeting 2006 Conclusions Combination chemotherapy seems to be more active than single agent treatment (trend for RR, TTP, OS) Combination chemotherapy associated with significant toxicity Trial was terminated early due to competitive trial by EORTC-STBSG Ambiguous results: Pro´s: „we always knew...“ Con´s: „no statistically significant difference, again!“