ABSTRACT
BACKGROUND: GIST patients often undergo GI-surgery. Previous studies have shown that imatinib and nilotinib exposures were decreased in GIST patients with prior major gastrectomy. We investigated whether major gastrectomy influences the exposure to sunitinib and its active metabolite SU12662. METHODS: Pharmacokinetic data from 305 GIST patients included in 4 phase I-III trials were analyzed. Patients were subdivided into 6 groups according to their prior GI-surgery. Apparent clearance (CL/F) and dose-corrected steady-state plasma exposures (AUC24,ss) of sunitinib and SU12662 were estimated using a population PK approach. ANCOVA was performed to test for differences in AUC24,ss and CL/F between each surgery subgroup and controls. RESULTS: Major gastrectomy did not influence sunitinib or SU12662 exposure. The geometric mean of sunitinib and SU12662 AUC24,ss was decreased by 21% and 28% in patients with both gastrectomy and small bowel resection (n = 8) compared to controls (n = 63) for sunitinib (931 ng hr/mL (95%-CI; 676-1283) versus 1177 ng hr/mL (95%-CI; 1097-1263); p < 0.05) and SU12662 (354 ng hr/mL (95%-CI; 174-720) versus 492 ng hr/mL (95%-CI; 435-555); p < 0.05). No significant differences in exposure were observed in each of the other subgroups versus controls. CONCLUSION: In contrast to previous results for imatinib and nilotinib, gastrectomy alone does not influence sunitinib or SU12662 exposure. This should be taken into account for the treatment of gastrectomized GIST patients with TKIs. In patients who had undergone both gastrectomy and small bowel resection, sunitinib and SU12662 exposures are significantly, although clinically not relevantly, decreased.
Subject(s)
Antineoplastic Agents/pharmacokinetics , Gastrointestinal Neoplasms/surgery , Gastrointestinal Stromal Tumors/surgery , Indoles/pharmacokinetics , Pyrroles/pharmacokinetics , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/administration & dosage , Clinical Trials as Topic , Female , Gastrectomy/adverse effects , Gastrointestinal Neoplasms/drug therapy , Gastrointestinal Stromal Tumors/drug therapy , Humans , Indoles/administration & dosage , Male , Middle Aged , Pyrroles/administration & dosage , Sunitinib , Young AdultABSTRACT
Phase II trials in oncology drug development are usually conducted to perform the initial assessment of treatment activity. The common designs in this setting, for example, Simon 2-stage designs, are often developed based on testing whether a parameter of interest, usually a proportion (e.g. response rate), is less than a certain level or not. These designs usually consider only one parameter. However, sometimes we may encounter situations where we need to consider not a single parameter, but multiple parameters. This paper presents a two-stage design in which both primary and secondary endpoints are utilized in the decision rules. The family-wise Type 1 error rate and statistical power of the proposed design are investigated under a variety of situations by means of Monte-Carlo simulations.
Subject(s)
Clinical Trials, Phase II as Topic/methods , Endpoint Determination , Research Design , Humans , Monte Carlo MethodABSTRACT
Fifteen patients with refractory AML were treated in a phase 1 study with SU11248, an oral kinase inhibitor of fms-like tyrosine kinase 3 (Flt3), Kit, vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) receptors. Separate cohorts of patients received SU11248 for 4-week cycles followed by either a 2- or a 1-week rest period. At the starting dose level of 50 mg (n = 13), no dose-limiting toxicities were observed. The most frequent grade 2 toxicities were edema, fatigue, and oral ulcerations. Two fatal bleedings possibly related to the disease, one from a concomitant lung cancer and one cerebral bleeding, were observed. At the 75 mg dose level (n = 2), one case each of grade 4 fatigue, hypertension, and cardiac failure was observed, and this dose level was abandoned. All patients with FLT3 mutations (n = 4) had morphologic or partial responses compared with 2 of 10 evaluable patients with wild-type FLT3. Responses, although longer in patients with mutated FLT3, were of short duration. Reductions of cellularity and numbers of Ki-67(+), phospho-Kit(+), phospho-kinase domain-containing receptor-positive (phospho-KDR(+)), phospho-signal transducer and activator of transcription 5-positive (phospho-STAT5(+)), and phospho-Akt(+) cells were detected in bone marrow histology analysis. In summary, monotherapy with SU11248 induced partial remissions of short duration in acute myeloid leukemia (AML) patients. Further evaluation of this compound, for example in combination with chemotherapy, is warranted.
