Phase I-II trial of imatinib mesylate (Gleevec; STI571) in treatment of recurrent oligodendroglioma and mixed oligoastrocytoma. North central cancer treatment group study N0272 (ALLIANCE/NCCTG)

Abstract

PURPOSE:To evaluate the pharmacokinetics and efficacy of imatinib in patients with recurrent oligodendroglial tumors. METHODS:Patients with progressive WHO grade II-III recurrent tumors after prior RT and chemotherapy were eligible. A phase I dose-escalation study was conducted for patients on enzyme-inducing anticonvulsants (EIAC). A phase II study for non-EIAC patients utilized a fixed dose of 600mg/D. Primary efficacy endpoint was 6-month progression-free survival (PFS6). A 2stage design was utilized, with 90% power to detect PFS6 increase from 25% to 45%. RESULTS:In the Phase I, maximum tolerated dose was not reached at 1200 mg/D. For phase II patients, overall PFS6 was 33% and median PFS 4.0 months (95% CI, 2.1, 5.7). Median overall survival (OS) was longer in imatinib-treated patients compared with controls (16.6 vs. 8.0 months; HR=0.64, 95% CI, 0.41,1.0, p=0.049), and longer in patients with 1p/19q-codeleted tumors (19.2 vs. 6.2 months, HR =0.43, 95% CI, 0.21,0.89, p=0.019). Confirmed response rate was 3.9% (PR=1; REGR=1), with stable disease observed in 52.9%. At 600 mg/D, mean steady-state imatinib plasma concentration was 2513 ng/ml (95% CI, 1831,3195). Grade 3-4 adverse events (hematologic, fatigue, GI, hypophosphatemia, or hemorrhage) occurred in 61%. CONCLUSIONS:Although adequate plasma levels were achieved, the observed PFS6 of 33% did not reach our pre-defined threshold for success. Although OS was longer in imatinib-treated

Molecular Mechanism and Prevention Strategy of Chemotherapy- and Radiotherapy-Induced Ovarian Damage

“…Imatinib, a tyrosine kinase inhibitor used in cancer treatment, selectively inhibits the ABL kinase domain of the bcr-abl oncogenic protein present in patients with chronic myelogenous leukemia [ 131 ]. It is also known to inhibit cKIT and platelet-derived growth factor receptor tyrosine kinases in gastrointestinal stromal tumors [ 132 , 133 ]. As PF depletion by apoptosis or activation mechanisms are mainly mediated by the ABL/TAp63 and KIT/PI3K pathways, respectively, it can be hypothesized that imatinib might be able to prevent ovarian dysfunction caused by these pathways [ 134 ].…”

“…The average number of pups and pregnancy rates were also higher in mice transplanted with ovarian tissue treated with combined cisplatin and imatinib [ 130 ]. However, in a similar mouse model study, the number of PFs and the average number of pups were not significantly higher in the group treated with imatinib in addition to cisplatin [ 133 ]. This conflicting result is thought to be due to the different types of cisplatin used in each study, and thus the toxicity to PFs at the same dose was different.…”

Clinical Management of Diffuse Low-Grade Gliomas

“…Regarding the other potential drugs for LGG at recurrence, the use of everolimus was associated with disease stability in a phase II trial [ 122 ], while the development of immunotherapies like vaccines [ 123 ] could open new opportunities for LGG patients. By contrast, sunitinib [ 124 ] or imatinib [ 125 , 126 , 127 ] were insufficiently active. Moreover, ivosidenib, an inhibitor of mutant IDH1 , showed interesting results in recurrent LGG with mutated IDH [ 128 ], and a randomized phase 3 study with the similar drug vorasidenib (AG-881) is currently ongoing.…”

Osteomalacia in Adults: A Practical Insight for Clinicians

“…Below, we will briefly review some of the processes that may be of greater clinical interest in adults. Table 4 describes a number of drugs that can cause hypophosphatemia and whose chronic use could lead to OM if phosphate levels are not monitored [ 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 ].…”