Short Study Report for Health Authorities

Size: px

Start display at page:

Download "Short Study Report for Health Authorities"

Gerald West
5 years ago
Views:

the Active Title of the Study Randomised trial of single agent doxorubicin versus doxorubicin plus ifosfamide in the first line treatment of advanced or metastatic soft tissue sarcoma Investigators &

1 the Active Title of the Study Randomised trial of single agent doxorubicin versus doxorubicin plus ifosfamide in the first line treatment of advanced or metastatic soft tissue sarcoma Investigators & Study Centers Country City Number of pts Belgium Hopital Jules Bordet (BE) Brussels U.Z. Antwerpen (BE) Edegem U.Z. Gasthuisberg (BE) Leuven 28 Canada T Baker Cancer Centr (CA) Calgary MUHC (CA) Dr Bliss Murphy Ctre (CA) St. John'S, Newfoundland Juravinski Ctr (CA) Hamilton 1 Denmark Herlev Copenhag. (DK) Herlev Aarhus Univ.Hosp. (DK) Aarhus 4 France Centre Leon Berard (FR) Lyon 26 Germany Un.C.G.Carus Dresden (DE) Dresden Uni.Koeln (DE) Koeln Uni.Essen (DE) Essen Klinikum Grosshadern (DE) Muenchen Univ. Mannheim (DE) Mannheim Med.Hochsch.Hannover (DE) Hannover E.K.Uni.Tuebingen (DE) Tuebingen 33 Netherlands NKI / AVL (NL) Amsterdam 25 1 of 5

2 the Active 302.U.Z.Rotterdam (NL) Rotterdam RU Nijmegen (NL) Nijmegen Univ Med Ctr Leiden (NL) Leiden UMCG (NL) Groningen 8 Slovakia National Cancer Inst (SK) Bratislava 22 Spain Hosp Univ San Carlos (ES) Madrid Hosp. Vall D'Hebron (ES) Barcelona 2 Switzerland CHUV Lausanne (CH) Lausanne 2 United Kingdom St James's Hospital (GB) Leeds Freeman Hospital (GB) Newcastle upon Tyne Weston Park Hospital (GB) Sheffield Christie Manchester (GB) Manchester Royal Marsden Hosp. (GB) London Univ College hosp (GB) London UHB Queen Elisabeth hospital (GB) Birmingham Western Gen Hospital (GB) Edinburgh Western Inf Glasgow (GB) Glasgow Campus for Ageing and Vitality (GB) Newcastle-Upon-Tyne Gartnavel General Hospital (GB) Glasgow Nottingham City Hospital (GB) Nottingham 5 Grand Total of 5

3 the Active Publication (reference) The overall study data have not been published yet, however, publications about the results in abstract form were presented van der Graaf WTA, Judson I, Verweij J, et al. Results of a randomised phase III trial ( 62012) of single agent doxorubicin versus doxorubicin plus ifosfamide as first line chemotherapy for patients with advanced or metastatic soft tissue sarcoma a survival study by the Soft Tissue and Bone Sarcoma Group. Paper presented at 37th European Society for Medical Oncology Congress (ESMO); September 28-October 2, 2012; Vienna, Austria. Abstract LBA7 Judson I, Verweij J, et al. Results of a randomised phase III trial ( 62012) of single agent doxorubicin versus doxorubicin plus ifosfamide as first line chemotherapy for patients with advanced or metastatic soft tissue sarcoma a survival study by the Soft Tissue and Bone Sarcoma Group. To be presented at CTOS 2012 Objective(s) The objective of the trial was to determine whether intensive combination chemotherapy with ifosfamide and doxorubicin is superior to doxorubicin alone in terms of overall survival. Methodology This is a randomized, two-arm, open label, multicenter phase III comparison trial. Number of patients Number planned (Statistical design) Number analyzed A total of 450 patients were required to be randomized 11. The sample size for the final analysis comparing the two treatment arms for overall survival in the intent to treat population was determined based on a two-sided log rank test at alpha= stratified for the performance status, the age group (< 50 years vs >= 50 years), presence of liver metastases and histological grade (grade 2 vs. grade 3) and a global power of 80%. According to this design, 366 deaths were needed for the analysis, therefore it was planned to enter 450 patients. A total of 455 patients have been registered Diagnosis and main criteria for inclusion Histological evidence of high grade soft tissue sarcoma with advanced unresectable or metastatic disease. Main inclusion criteria Histological evidence of soft tissue sarcoma / High grade (grade2-3) No prior chemotherapy for advanced or metastatic disease WHO Performance status < 2, Age of 5

4 the Active Treatment Test product, dose and mode of administration (batch number if applicable) Duration of treatment Doxorubicin 25 mg/m² day 1,2 and 3 / 2.5 g/ m² day 1,2,3 and 4 + Neulasta (6 mg s.c. on day 5 of each cycles ) every 3 weeks Treatment should be administered until documented disease progression, unacceptable toxicity or patient refusal, up to a max of 6 cycles of chemotherapy. Reference therapy, dose and mode of administration (batch number if applicable) Criteria for evaluation Efficacy Doxorubicin 75 mg/m² day 1 or as a 72 hour continuous i.v. infusion every 3 weeks Treatment should be administered until documented disease progression, unacceptable toxicity or patient refusal, up to a max of 6 cycles of chemotherapy. Primary Overall survival (OS) Secondary - Progression free survival (PFS) - Objective tumor response Safety Safety profile CTCAE v2.0 Statistical methods OS and PFS were compared between the two treatment arms using a two-sided log rank test at alpha= for OS and alpha = 0.05 for PFS, stratified for the performance status, the age group (< 50 years vs >= 50 years), presence of liver metastases and histological grade (grade 2 vs. grade 3). OS and PFS were summarized by the Kaplan- Meier technique. To adjust for confounding variables, the Cox proportional hazards model was used. Objective tumor response was compared using a trend test. 4 of 5

5 the Active Summary of Results Efficacy Results The final analysis comparing the two treatment arms (as randomized) for overall survival in the intent to treat population was performed using a two-sided log rank test at alpha=0.0451, stratified for the performance status, the age group (< 50 years vs >= 50 years), presence of liver metastases and histological grade (grade 2 vs. grade 3). A total of 372 events have been observed of which 188 occurred in the doxorubicin arm and 184 in the combination arm. Based on the adjusted alpha = , there is no significant difference between the two treatment arms (HR 0.83, 95.5% CI , stratified logrank test p = 0.076). A total of 425 progressions were reported, 215 in the doxorubicin arm and 210 in the combination arm. There was a significant difference between the two arms for PFS (HR 0.74, 95% CI , stratified logrank test p = 0.003). 20% of all patients responded (CR/PR) to treatment, of which 13.6% responded to doxorubicin alone and 26.5% to the combination. This trend is significantly different between the two treatment arms (Mantel-Haenszel test, p<0.0001). Safety Results Conclusions The most commonly reported high grade ( 3) events during treatment were neutropenia (37.2% in the docorubicin arm vs 41.5% in the combination arm), leucopenia (17.9% vs 43.3%), febrile neutropenia (13.5% vs 45.9%) and anemia (4.4% and 34.9%). Significant differences between the treatment arms were observed for leucopenia, thrombocytopenia, anemia, febrile neutropenia and other neurological toxicity (excl dizziness, motor or sensory neuropathy), with more high grade events occurring in the combination arm. The lack of a significant improvement in OS does not support the routine use of this intensive combination of doxorubicin and ifosfamide for soft tissue sarcoma in the palliative setting. The higher response rate suggests that the combination might be justified in selected pts age <60 if tumour shrinkage is critical, but it is significantly more toxic. Doxorubicin remains the gold standard for comparative studies of first line systemic treatment in STS. Date of Report 12/10/ of 5

SIOPEL 6. International Childhood Liver Tumour Strategy Group - SIOPEL. Eudract Number:

SIOPEL 6. International Childhood Liver Tumour Strategy Group - SIOPEL. Eudract Number: SIOPEL 6 A multi-centre open label randomised phase III trial of the efficacy of Sodium Thiosulphate in reducing ototoxicity in patients receiving cisplatin chemotherapy for STANDARD RISK HEPATOBLASTOMA