1. EORTC OSN/CTOS11 Safety of Caelyx combined with ifosfamide in previously untreated adult patients with advanced or metastatic soft tissue sarcomas. Final data of an EORTC phase I study. O.S. Nielsen, P. Reichardt, D. Pink, J. Lindegaard, S. Daugaard, C. Hermans, K. Stoichkov, M. van Glabbeke, I. Judson. CTOS 11th Annual Meeting 2005 Boca Raton, Florida

2. EORTC OSN/CTOS11 BACKGROUND Caelyx (pegylated liposomal doxorubicin) 40 mg/m 2 q 4 weeks seems to have the same efficacy in adult soft tissue sarcomas (STS) as doxorubicin with an improved toxicity profile (EORTC and others). It could thus be an alternative to doxorubicin and may well be easier to combine with agents such as Ifosfamide.

3. EORTC OSN/CTOS11 Study design Main eligibility criteria: Progression within 6 weeks, no previous chemotherapy, PFS < 2, 18-70 years and adequate cardiac, liver, renal and haematological function. Treatment: Caelyx as a 1 hr i.v. infusion d1 and Ifosfamide+mesna as a 4-hr i.v. infusion d1-3 every 3 weeks: Dose level I: Caelyx 30 mg/m² + Ifosfamide 1.7 g/m² d 1-3 Dose level 2: Caelyx 30 mg/m² + Ifosfamide 2 g/m² d 1-3 Dose level 3: Caelyx 30 mg/m² + Ifosfamide 2.5 g/m² d 1-3 Dose level 4: Caelyx 30 mg/m² + Ifosfamide 3 g/m² d 1-3 Dose level 5: Caelyx 40 mg/m² + Ifosfamide 3 g/m² d 1-3 Cohorts of 3 pts/dose level. DLT 1/3 pts a new cohort added. Evaluation after 2 treatment cycles. Non-evaluable pts replaced. Max. 6 cycles

4. EORTC OSN/CTOS11 ENDPOINTS Main endpoint: Toxicity (CTC). Occurrence of DLT: ANC < 0.5 x 10 9 lasting ≥ 7 days or ≥ 3 days + fever at least 38.5 o C, grade 4 thrombocytopenia, any grade 3-4 toxicity except nausea, vomiting and alopecia, and any toxicity requiring a 2 week treatment delay. Secondary endpoint: Objective response in patients with measurable disease (RECIST).

5. EORTC OSN/CTOS11 ACCRUAL 5 pts not evaluable for response (only 1 cycle of treatment)

6. EORTC OSN/CTOS11 Baseline characteristics Male/female:12/16 Median age: 60 years (29-69) PS: 75% PS 1 Leiomyos: 10 pts

7. EORTC OSN/CTOS11 RESULTS: Dose Limiting Toxicities Dose levelToxicityType DLT 5 Dyspnea + allergic reactionClinical 5 Thrombocytopenia + renal insufficiencyCombination 5 Febrile neutropeniaCombination 5 Febrile neutropenia Combination 5 Febrile Neutropenia Combination 5 Thrombocytopenia Combination Recommended dose level = 4: ( Caelyx 30 mg/m² + Ifosfamide 3 g/m² d 1-3)

8. EORTC OSN/CTOS11 Hematological toxicities Recommended dose level 4 Grade01234Total Leucopenia 21126 Granulocytopenia 21126 Thrombocytopenia 516 Anaemia 156

9. EORTC OSN/CTOS11 Non-hematological toxicities Recommended dose level 4 Grade01234Total Oedema 2226 Fatigue 426 PPE 66 Other skin tox 4116

10. EORTC OSN/CTOS11 Efficacy evaluation Currently, 4 pts alive + progression free, 5 pts alive + PD. All deaths were due to progression.

11. EORTC OSN/CTOS11 Overall and progression free survival (months) 036912151821242730 0 10 20 30 40 50 60 70 80 90 100 ONNumber of patients at risk :Failure 1928231812974311 242818104221100 OS PFS Median OS~ 11 months Median PFS~ 6 months

12. EORTC OSN/CTOS11 CONCLUSIONS 6 DLTs were observed amongst the 7 pts treated at dose level 5. No DLT was reported at any other dose level. Therefore, dose level 4 is the recommended dose for further trial, i.e. Caelyx 30 mg/m² + Ifosfamide 3 g/m² d 1-3. 2 PR were observed; the estimated median PFS was ~ 6 months (equivalent to 1st line doxorubicin based therapy), and the estimated median survival approximately 11 months. Combined Caelyx and Ifosfamide seems to be feasible in patients with advanced soft tissue sarcomas and this combination may allow to give Ifosfamide at a dosage similar to that used when given alone. BUT …… PR at dose level 5 (not level 4)! Caelyx is expensive! Hematopoietic growth factors? Further data needed – if possible.