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Phase I and pharmacokinetic study of irinotecan in combination with R115777, a farnesyl protein transferase inhibitor.

ABSTRACT: The aims of this study were to determine the maximum-tolerated dose (MTD), toxicity profile, and pharmacokinetics of irinotecan given with oral R115777 (tipifarnib), a farnesyl protein transferase inhibitor. Patients were treated with escalating doses of irinotecan with interval-modulated dosing of R115777 (continuously or on days 1-14, and repeated every 21 days). In total, 35 patients were entered onto the trial for a median duration of treatment of 43 days (range, 5-224 days). Neutropenia and thrombocytopenia were the dose-limiting toxicities; other side effects were mostly mild. The MTD was established at R115777 300 mg b.i.d. for 14 consecutive days with irinotecan 350 mg x m(-2) given every 3 weeks starting on day 1. Three patients had a partial response and 14 had stable disease. In the continuous schedule, the area under the curves of irinotecan and its active metabolite SN-38 were 20.0% (P=0.004) and 38.0% (P<0.001) increased by R115777, respectively. Intermittent dosing of R115777 at a dose of 300 mg b.i.d. for 14 days every 3 weeks is the recommended dose of R115777 in combination with the recommended single-agent irinotecan dose of 350 mg x m(-2).

SUBMITTER: Sparreboom A

PROVIDER: S-EPMC2409716 | biostudies-other | 2004 Apr

REPOSITORIES: biostudies-other

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Phase 1 trial and pharmacokinetic study of the farnesyl transferase inhibitor tipifarnib in children and adolescents with refractory leukemias: a report from the Children's Oncology Group.

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Project description:Farnesyl transferase (FT) inhibitors (FTI) are anticancer agents developed to target oncogenic Ras proteins by inhibiting Ras farnesylation. FTIs potently synergize with paclitaxel and other microtubule-stabilizing drugs; however, the mechanistic basis underlying this synergistic interaction remains elusive. Here we show that the FTI lonafarnib affects the microtubule cytoskeleton resulting in microtubule bundle formation, increased microtubule stabilization and acetylation, and suppression of microtubule dynamics. Notably, treatment with the combination of low doses of lonafarnib with paclitaxel markedly enhanced tubulin acetylation (a marker of microtubule stability) as compared with either drug alone. This synergistic effect correlated with FT inhibition and was accompanied by a synergistic increase in mitotic arrest and cell death. Mechanistically, we show that the combination of lonafarnib and paclitaxel inhibits the in vitro deacetylating activity of the only known tubulin deacetylase, histone deacetylase 6 (HDAC6). In addition, the lonafarnib/taxane combination is synergistic only in cells lines expressing the wild-type HDAC6, but not a catalytic-mutant HDAC6, revealing that functional HDAC6 is required for the synergy of lonafarnib with taxanes. Furthermore, tubacin, a specific HDAC6 inhibitor, synergistically enhanced tubulin acetylation in combination with paclitaxel, similar to the combination of lonafarnib and paclitaxel. Taken together, these data suggest a relationship between FT inhibition, HDAC6 function, and cell death, providing insight into the putative molecular basis of the lonafarnib/taxane synergistic antiproliferative combination.

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Aborted autophagy and nonapoptotic death induced by farnesyl transferase inhibitor and lovastatin.

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The effect of the farnesyl protein transferase inhibitor SCH66336 on isoprenylation and signalling by the prostacyclin receptor.

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Phase I pharmacokinetic and pharmacodynamic study of cetuximab, irinotecan and sorafenib in advanced colorectal cancer.

Project description:Background This phase Ib study was designed to determine the maximum tolerated doses (MTD) and dose limiting toxicities (DLTs) of irinotecan and cetuximab with sorafenib. Secondary objectives included characterizing the pharmacokinetics and pharmacodynamics and evaluating preliminary antitumor activity in patients with advanced colorectal cancer (CRC). Methods Patients with metastatic, pretreated CRC were treated at five dose levels. Results Eighteen patients were recruited with median age 56.5 years. In the first five patients treated, 2 irinotecan related DLTs were observed. With reduced dose intensity irinotecan, there were no further DLTs. The most common toxicities were diarrhea, nausea/vomiting, fatigue, anorexia and rash. DLTs included neutropenia and thrombocytopenia. Two patients had partial responses (one with a KRAS mutation) and 8 had stable disease (8-36 weeks). The median progression free survival (PFS) and overall survival (OS) were 2.5 and 4.7 months respectively. Pharmacokinetic analyses suggest sorafenib and metabolite exposure correlate with OS and DLTs. Conclusions The recommended phase II dose (RP2D) is irinotecan 100 mg/m(2) i.v. days 1, 8; cetuximab 400 mg/m(2) i.v. days 1 and 250 mg/m(2) i.v. weekly; and sorafenib 400 mg orally twice daily in advanced, pretreated CRC. The combination resulted in a modest response rate.

| S-EPMC3674958 | biostudies-literature

Dual Farnesyl and Geranylgeranyl Transferase Inhibitor Thwarts Mutant KRAS-Driven Patient-Derived Pancreatic Tumors.

Project description:PURPOSE:Mutant KRAS is a major driver of pancreatic oncogenesis and therapy resistance, yet KRAS inhibitors are lacking in the clinic. KRAS requires farnesylation for membrane localization and cancer-causing activity prompting the development of farnesyltransferase inhibitors (FTIs) as anticancer agents. However, KRAS becomes geranylgeranylated and active when cancer cells are treated with FTIs. To overcome this geranylgeranylation-dependent resistance to FTIs, we designed FGTI-2734, a RAS C-terminal mimetic dual FT and geranylgeranyltransferase-1 inhibitor (GGTI). EXPERIMENTAL DESIGN:Immunofluorescence, cellular fractionation, and gel shift assays were used to assess RAS membrane association, Western blotting to evaluate FGTI-2734 effects on signaling, and mouse models to demonstrate its antitumor activity. RESULTS:FGTI-2734, but not the selective FTI-2148 and GGTI-2418, inhibited membrane localization of KRAS in pancreatic, lung, and colon human cancer cells. FGTI-2734 induced apoptosis and inhibited the growth in mice of mutant KRAS-dependent but not mutant KRAS-independent human tumors. Importantly, FGTI-2734 inhibited the growth of xenografts derived from four patients with pancreatic cancer with mutant KRAS (2 G12D and 2 G12V) tumors. FGTI-2734 was also highly effective at inhibiting, in three-dimensional cocultures with resistance promoting pancreatic stellate cells, the viability of primary and metastatic mutant KRAS tumor cells derived from eight patients with pancreatic cancer. Finally, FGTI-2734 suppressed oncogenic pathways mediated by AKT, mTOR, and cMYC while upregulating p53 and inducing apoptosis in patient-derived xenografts in vivo. CONCLUSIONS:The development of this novel dual FGTI overcomes a major hurdle in KRAS resistance, thwarting growth of patient-derived mutant KRAS-driven xenografts from patients with pancreatic cancer, and as such it warrants further preclinical and clinical studies.

| S-EPMC6774803 | biostudies-literature

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