P. Berthaud

Prospective Multicentric Randomized Phase III Study of Imatinib in Patients With Advanced Gastrointestinal Stromal Tumors Comparing Interruption Versus Continuation of Treatment Beyond 1 Year: The French Sarcoma Group

PURPOSE Imatinib is the standard treatment of advanced GI stromal tumors (GISTs). It is not known whether imatinib may be stopped in patients in whom disease is controlled. METHODS This prospective, randomized, multicentric phase III study was designed to compare continuous (CONT) compared with interrupted (INT) imatinib beyond 1 year of treatment in patients with advanced GIST. The primary end point was progression-free survival. Secondary end points included overall survival, response rate after reinitiation of imatinib, and quality of life. Early stopping rules in cases of rapid progression of disease were defined, with preplanned interim analyses. RESULTS Between May 2002 and April 2004, 182 patients with advanced GIST were enrolled. Between May 2003 and April 2004, 98 patients in response or stable disease under imatinib reached more than 1 year of follow-up. Forty were not eligible for randomization, and 58 patients were randomly assigned, 32 and 26 patients in the INT and CONT arms, respectively. As of October 15, 2005, eight of 26 patients in the CONT group and 26 of 32 patients in the INT group had documented disease progression (P < .0001). Twenty-four of 26 patients with documented progression in the INT arm responded to imatinib reintroduction. No differences in overall survival or imatinib resistance were observed between the two arms. Quality of life evaluated 6 months after random assignment using the 30-item Quality of Life Questionnaire was not significantly different between the two groups of randomly assigned patients. CONCLUSION Imatinib interruption results in rapid progression in most patients with advanced GIST, and cannot be recommended in routine practice unless patient experience significant toxicity

Pharmacokinetic-Pharmacodynamic Relationships of Imatinib and Its Main Metabolite in Patients with Advanced Gastrointestinal Stromal Tumors

Purpose: This study explored factors affecting the pharmacokinetic variability of imatinib and CGP 74588, and the pharmacokinetic-pharmacodynamic correlations in patients with advanced gastrointestinal stromal tumors. Experimental Design: Thirty-five patients with advanced gastrointestinal stromal tumors received 400 mg of imatinib daily. Six blood samples were drawn: before intake, during 1- to 3- and 6- to 9-hour intervals after intake on day 1, and before intake on days 2, 30, and 60. Plasma imatinib and CGP 74588 concentrations were quantified by reverse-phase high-performance liquid chromatography coupled with tandem mass spectrometry, and analyzed by the population pharmacokinetic method (NONMEM program). The influence of 17 covariates on imatinib clearance (CL) and CGP 74588 clearance (CLM/fm) was studied. These covariates included clinical and biological variables and occasion (OCC = 0 for pharmacokinetic data corresponding to the first administration, or OCC = 1 for the day 30 or 60 administrations). Results: The best regression formulas were: CL (L/h) = 7.97 (AAG/1.15)−0.52, and CLM/fm (L/h) = 58.6 (AAG/1.15)−0.60 × 0.55OCC, with the plasma α1-acid glycoprotein (AAG) levels indicating that both clearance values decreased at a higher AAG level. A significant time-dependent decrease in CLM/fm was evidenced with a mean (+SD) CGP 74588/imatinib area under the curve (AUC) ratio of 0.25 (±0.07) at steady state, compared with 0.14 (±0.03) on day 1. Hematologic toxicity was correlated with pharmacokinetic variables: the correlation observed with the estimated unbound imatinib AUC at steady-state (r = 0.56, P < 0.001) was larger than that of the total imatinib AUC (r = 0.32, NS). Conclusions: The plasma AAG levels influenced imatinib pharmacokinetics. A protein-binding phenomenon needs to be considered when exploring the correlations between pharmacokinetics and pharmacodynamics.

Continuous vs intermittent imatinib treatment in advanced GIST after one year: A prospective randomized phase III trial of the French Sarcoma Group

9006 Background: Imatinib (Im) is usually given in advanced GIST until progression or intolerance. Secondary resistance to Im is often related to the clonal expansion of clones with Im insensitive KIT mutations. Whether intermittent administration of Im may prevent the long term emergence of resistant clones is unknown. METHODS BFR14, a prospective multicentric phase III study of continuous vs interrupted imatinib treatment in advanced GIST, was initiated in June 2002. Inclusion criterias were: advanced GIST, expressing KIT or PDGFRa mutation. After 1 year of treatment with Im, patients are randomized between 1) continuous (CONT) or 2 ) interruption (STOP) of Im until progression and restart. Patients declining randomization were followed. Primary endpoint was progression free survival. Early stopping rule in case of high rates of re-progression at 3 months were scheduled after the randomisation of 14 patients (n>5) and 29 pts (n>10). RESULTS As of December 2003, 159 pts were included: 61% were males, 39% emales (39%), with gastric 27%, small bowel (32%), large bowel (12%), mesenteric (20%), or other primaries (9%). Metastatic sites were: liver (55%), peritoneum (35%), nodes (6%), others (19%). 13% pts experienced immediate progression. At 6 months, CR was achieved in 10%, PR in 42%, SD in 36%, PD in 6%, NE in 6% . 41 SAE were observed in 29 pts. Surgery was perfomed in 6 (4%) pts during the 1st year. As of Dec 15, 46 of the 74 (62%) candidate pts were randomized, 23 in both arms: 0 and 5 (21%) pts have a documented reprogression at 3 months in the CONT and STOP arms respectively; Im reintroduction enabled tumor control in all pts with sufficient follow-up so far. CONCLUSIONS Although the early stopping rule on progression at 3 months was not met in the first 14 pts randomized in the STOP arm of the BFR14 trial, advanced GIST pts stopping Gleevec® experience frequent re-progression at 3 months. Supported by Grants from the Centre L.Bérard, Cancéropole Rhone Alpes and Novartis. [Table: see text].

Intensive induction chemotherapy (API-AI regimen) followed by conservative surgery in adult patients with locally advanced soft tissue sarcoma (STS): Survival is predicted by the histological response

9036 Background: to determine predictive parameters of response and survival after intensive induction chemotherapy (CT) in patients (pts) with locally advanced high grade STS (LASTS). METHODS from 1996 to 2003, 60 pts (37 m, 23 f) received a CT regimen consisting in 2 cycles of doxorubicin (A) (60 mg/m2 d1 and d15), cisplatinum (100 mg/m2 d1) and ifosfamide (I) 5 g/m2 (d2 and d15). GCSF was added after each course (c) for 6 days, cycle repeated every 4 wks. The median age was 43 yrs (18-68) and the median tumor size was 10 cm (4-25). MRI assessments were performed before CT and surgery (planned at day 65) Results: 222 c of CT were administered (median 4 c/pt). The median DI of AI was 87%. Toxicity (T) was mainly haematological with febrile neutropenia, gde 3/4 neutropenia and thrombocytopenia observed in 46%, 76% and 36% of pts respectively. Two pts had a renale failure and 1 toxic death was observed. Clinical benefit was observed in 56% of pts while 10% of pts progressed clinically during CT. MRI responses (59 evaluable pts) were: 3%CR, 29%PR, 7%MR, 52%SD and 8%PD. All but 2 pts underwent surgery (s): 6 amputations and 52 conservative s (90%). A surgical downstaging was achieved in 13 pts (22%). A good histological response (≥95% necrosis) (GR) was observed in 31% of pts. No correlation was found between histological and clinical response. All but 7 pts (88%) received adjuvant RT. Median follow-up was 39 months (range 2-84). The median time to relapse (5 local and 19 distant relapses) was 19,5 months (0,46-83,5). The 5-yr DFS and OS were 43% [26-59] and 64% [46-81] respectively. GR is the only prognostic predictive factor for DFS (p=0.03) and OS (p=0.04). The 5-yr DFS were 80 % [55-100] and 33 % [14-53] for pts achieving a GR vs poor response respectively. CONCLUSIONS despite haematological T, this induction intensive CT in pts with LASTS allows surgical downstaging and long-term limb salvage. The histological response is a more accurate indicator of chemosensitivity than clinical response and predicts survival in LASTS. No significant financial relationships to disclose.