SafetyofCaelyxcombinedwithifosfamideinpreviously

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level Target of 400 patients to detect of 15% (50-65) in PFS at 3 years (166 events),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,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.,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/m + Ifosfamide 1.7 g/m d 1-3,Dose level 2: Caelyx 30 mg/m + Ifosfamide 2 g/m d 1-3,Dose level 3: Caelyx 30 mg/m + Ifosfamide 2.5 g/m d 1-3,Dose level 4: Caelyx 30 mg/m + Ifosfamide 3 g/m d 1-3,Dose level 5: Caelyx 40 mg/m + Ifosfamide 3 g/m 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,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).,ACCRUAL,5 pts not evaluable for response (only 1 cycle of treatment),Baseline characteristics,Male/female:12/16,Median age: 60 years (29-69),PS: 75% PS 1,Leiomyos: 10 pts,RESULTS: Dose Limiting Toxicities,Dose level,Toxicity,Type DLT,5,Dyspnea + allergic reaction,Clinical,5,Thrombocytopenia + renal insufficiency,Combination,5,Febrile neutropenia,Combination,5,Febrile neutropenia,Combination,5,Febrile Neutropenia,Combination,5,Thrombocytopenia,Combination,Recommended dose level = 4:,(,Caelyx 30 mg/m + Ifosfamide 3 g/m d 1-3),Hematological toxicities,Recommended dose level 4,Non-hematological toxicities,Recommended dose level 4,Efficacy evaluation,Currently, 4 pts alive + progression free, 5 pts alive + PD.,All deaths were due to progression.,Overall and progression free survival,(months),0,3,6,9,12,15,18,21,24,27,30,0,10,20,30,40,50,60,70,80,90,100,O,N,Number of patients at risk :,Failure,19,28,23,18,12,9,7,4,3,1,1,24,28,18,10,4,2,2,1,1,0,0,OS,PFS,Median OS,11 months,Median PFS, 6 months,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/m + Ifosfamide 3 g/m 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.,