Nilotinib 800 Mg And Imatinib 800 Mg For The Treatment Of Patients With Gastrointestinal Stromal Tumors (Gist) Refractory To Imatinib 400 Mg (MACS0375)
The study will investigate the comparative efficacy and safety of two oral inhibitors of Kit and PDGFR: nilotinib 400 mg bid, a novel agent, and imatinib 400 mg bid, an approved agent with an established efficacy.
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Randomized Phase III Trial Comparing Nilotinib 800mg to Imatinib 800 mg for the Treatment of Patients With Advanced and/or Metastatic Gastrointestinal Stromal Tumors Refractory to Imatinib 400 mg|
- Progression-free survival (PFS) [ Time Frame: every 6 weeks in the first 6 months and every 8 weeks thereafter ] [ Designated as safety issue: No ]Progression-free survival (PFS) is the time from date of randomization to the date of first documented progression or death due to any cause. If a participant has not had an event, progression-free survival is censored at the time of last adequate tumor assessment. Progression is defined according to modified RECIST criteria as at least a 20% increase in the sum of the longest diameter of target lesions, worsening of the non-target lesions or the appearance of one or more new lesions.
- To compare the efficacy of nilotinib 400 mg bid to imatinib 400 mg bid with regard to the following endpoints: DCR, OS, TTF, and TTP (key secondary endpoints) [ Time Frame: every 2 months ] [ Designated as safety issue: Yes ]The DCR rates for each treatment arm will be computed using the exact Clopper-Pearson interval estimation methodology. OS is defined as the time from the date of randomization to the date of death due to any cause or the date of last contact prior to or on the date of data cutoff. The median time to overall survival and its associated 95 % CI will be derived, for each treatment arm, using the time to event analysis based on Kaplan-Meier methodology. TTF, defined as the time from date of randomization to the earliest of date of the first objective tumor progression, date of death due to any cause, or date of discontinuation due to reasons other than 'Protocol deviation' or 'Administrative problems'.
- To compare the safety and tolerability of 400 mg bid nilotinib and 400 mg bid imatinib; [ Time Frame: all visits ] [ Designated as safety issue: Yes ]All concentration data of nilotinib/imatinib obtained by day and time point. Inter- and intra-patient variability in the trough (and potentially peak) concentrations of nilotinib and imatinib will be summarized based on (1) actual trough or peak concentrations associated with no dose modifications. (2) dose-normalized trough or peak concentrations regardless of dose modifications. If there are sufficient samples, the potential covariates contributing to the inter-patient variability in nilotinib/imatinib concentrations (actual or dose-normalized), such as patient demographics, clinical factors, KIT and PDGFR mutation status, might be explored by linear regression analysis. The potential relationship between the trough or peak concentrations of nilotinib/imatinib versus clinical responses might also be explored graphically and/or by appropriate correlation analyses
- To evaluate the mutational status of tumors with regard to Kit and PDGFR, correlating specific mutations with efficacy endpoints [ Time Frame: when available ] [ Designated as safety issue: Yes ]
Mutational status of the KIT and PDGFRA gene in tumor tissue prior to imatinib or nilotinib therapy will be summarized and correlated with drug response and clinical outcome.
Frequency of overall KIT and PDGFRA mutations and individual genotypes will be calculated. The locations of mutations within the gene and their impact on response profiles will also be evaluated. Association of mutations with response, for the imatinib and nilotinib arms, will be investigated.
|Study Start Date:||June 2009|
|Study Completion Date:||August 2012|
|Primary Completion Date:||August 2012 (Final data collection date for primary outcome measure)|
800mg per day throughout the study
Other Name: Tasigna
|Active Comparator: Imatinib||
800mg per day throughout the study
This is an international, randomized, open-label, double-arm, phase III trial that will be conducted in centers in Latin America, Asia, Europe and Canada. The study will be sponsored by Novartis Pharmaceuticals Corporation. Patient enrollment will be competitive and will have a duration of up to 30 months. An interim analysis is planned to occur when approximately 60% of the PFS events occurs. A total of 150 patients per arm will be enrolled in the study. Eligible patients will have advanced/metastatic, inoperable GIST of any anatomical location or recurrent GIST while on or post imatinib adjuvant therapy, with documented disease progression on therapy with imatinib 400 mg q.d.
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|Study Director:||Novartis Pharmaceuticals||Novartis Pharmaceuticals|