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O.S. Nielsen, P. Reichardt, D. Pink, J. Lindegaard, S. Daugaard, C. Hermans, K. Stoichkov,

CTOS 11th Annual Meeting 2005 Boca Raton, Florida. 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,

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O.S. Nielsen, P. Reichardt, D. Pink, J. Lindegaard, S. Daugaard, C. Hermans, K. Stoichkov,

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  1. CTOS 11th Annual Meeting 2005 Boca Raton, Florida 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.

  2. BACKGROUND Caelyx (pegylated liposomal doxorubicin) 40 mg/m2 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. 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. Study design Max. 6 cycles

  4. ENDPOINTS Main endpoint: • Toxicity (CTC). Occurrence of DLT: ANC < 0.5 x 109 lasting ≥7 days or ≥3 days + fever at least 38.5 oC, 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. ACCRUAL 5 pts not evaluable for response (only 1 cycle of treatment)

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

  7. RESULTS: Dose Limiting Toxicities Recommended dose level = 4:(Caelyx 30 mg/m² + Ifosfamide 3 g/m² d 1-3)

  8. Hematological toxicitiesRecommended dose level 4

  9. Non-hematological toxicitiesRecommended dose level 4

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

  11. 100 90 80 70 60 50 40 30 20 10 0 (months) 0 3 6 9 12 15 18 21 24 27 30 O N Number of patients at risk : Failure 19 28 23 18 12 9 7 4 3 1 1 OS 24 28 18 10 4 2 2 1 1 0 0 PFS Overall and progression free survival • Median OS ~ 11 months • Median PFS ~ 6 months

  12. 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.

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