Phase I trial of weekly paclitaxel and BMS-214662 in patients with advanced solid tumors
ABSTRACT To assess the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacodynamics, and antitumor activity of continuous weekly-administered paclitaxel and BMS-214662, a novel farnesyl transferase inhibitor.
Patients were treated every week as tolerated with i.v. paclitaxel (fixed dose, 80 mg/m(2)/wk) administered over 1 h followed by i.v. BMS-214662 (escalating doses, 80-245 mg/m(2)/wk) over 1 h starting 30 min after completion of paclitaxel.
Twenty-six patients received 94 courses (one course, 21 days) of study treatment. Two patients received five courses of BMS-214662 as a weekly 24-h infusion (209 mg/m(2)/wk). The most common toxicities were grade 1 to 2 nausea/vomiting and/or diarrhea. DLTs observed at or near the MTD (200 mg/m(2)/wk) were grade 4 febrile neutropenia with sepsis occurring on day 2 of course 1 (245 mg/m(2)/wk), reversible grade 3 to 4 serum transaminase increases on day 2, and grade 3 diarrhea (200 and 245 mg/m(2)/wk). Objective partial responses were observed in patients with pretreated head and neck, ovarian, and hormone-refractory prostate carcinomas, and leiomyosarcoma. The observed pharmacokinetics of paclitaxel and BMS-214662 imply no interaction between the two. Significant inhibition (>80%) of farnesyl transferase activity in peripheral mononuclear cells was observed at the end of BMS-214662 infusion.
Pretreated patients with advanced malignancies can tolerate weekly paclitaxel and BMS-214662 at doses that achieve objective clinical benefit. Due to multiple DLTs occurring at the expanded MTD, the recommended phase 2 dose and schedule is paclitaxel (80 mg/m(2) over 1 h) and BMS-214662 (160 mg/m(2) over 1 h) administered weekly.
SourceAvailable from: Xiaofeng Liu[Show abstract] [Hide abstract]
ABSTRACT: In this study, 22 novel hFTase inhibitors containing 18 scaffolds were identified with IC50 values ranging from 0.0119 to 13.35 μM by structure-based virtual screening, and compounds 2, 7, 9, 10, 14 and 15 showed moderate antiproliferative activity against MCF-7 cells. In particular, compound 2 was the most promising lead compound with nanomolar activity against FTase and antiproliferative activity in the low micromolar range. Possible binding modes of the hit compounds were explored and their structure–activity relationships (SAR) were elucidated by molecular docking simulation. The hit compounds discovered in this work will provide novel scaffolds for further hit-to-lead optimization and lay the foundation for further development of therapeutic candidates for cancer treatments.Medicinal Chemistry Communication 05/2013; 4(6):962-971. DOI:10.1039/C3MD00058C · 2.63 Impact Factor
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ABSTRACT: In order to search new inhibitors against farnesyl protein transferase (FPTase), a series of 2,3-bis-benzylidenesuccinaldehyde derivatives (1-29) were synthesized and their inhibition activities () against FPTase were measured. From based on the reported results that the inhibitory activities of dimers 2,3-bis-benzylidenesuccinaldehydes were higher than those of monomers cinnamaldehydes, 3D-QSARs on FPTase inhibitory activities of the dimers (1-29) were studied quantitatively using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods. The statistical qualities of the optimized CoMFA model II (= 0.693 and = 0.974) was higher than those of the CoMSIA model II ( = 0.484 and = 0.928). The dependence of CoMFA models on chance correlations was evaluated with progressive scrambling analyses. And the inhibitory activity exhibited a strong correlation with steric factors of the substrate molecules. Therefore, from the results of graphical analyses on the contour maps and of predicted higher inhibitory active compounds, it is suggested that the structural distinctions and descriptors that contribute to inhibitory activities () against FPTase will be able to applied new inhibitor design.Bulletin- Korean Chemical Society 10/2010; 31(5):1355-1360. DOI:10.5012/bkcs.2010.31.5.1355 · 0.84 Impact Factor
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ABSTRACT: There is preclinical synergism between taxanes and MK-2206. We aim to determine the maximum tolerated dose, safety, and activity of combining MK-2206 and paclitaxel in metastatic cancer. Patients received weekly doses of paclitaxel at 80mg/m2 on day 1, followed by MK-2206 orally on day 2 escalated at 90mg, 135mg, and 200mg. Treatment continued until progression, excessive toxicity, or patient request. Blood and tissue were collected for pharmacokinetic and pharmacodynamics markers. A cycle consisted of three weeks of therapy. Dose-limiting toxicity (DLT) was defined as unacceptable toxicity during the first cycle. All statistical tests were two-sided. Twenty-two patients were treated, nine in dose escalation and 13 in dose expansion. Median age was 55 years. Median number of cycles was four. Dose escalation was completed with no DLT. CTCAE Grade 3 or higher adverse events were fatigue (n = 2), rash (n = 2), hyperglycemia (n = 1), and neutropenia (n = 7). Four patients in the expansion phase required MK-2206 dose reduction. Phase II recommended dose was established as paclitaxel 80mg/m2 weekly on day 1, and MK-2206 135mg weekly on day 2. Paclitaxel systemic exposure was similar in the presence or absence of MK-2206. Plasma MK-2206 concentrations were similar to data from previous phase I monotherapy. There was a statistically significant decrease in expression of pAKT S473 (P = .01) and pAKT T308 (P = .002) after therapy. PI3K/AKT/mTOR downregulation in tumor tissues and circulating markers did not correlate with tumor response or clinical benefit. There were five objective responses, and nine patients had stable disease. MK-2206 was well tolerated with paclitaxel. Preliminary antitumor activity was documented. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: firstname.lastname@example.org.JNCI Journal of the National Cancer Institute 03/2015; 107(3). DOI:10.1093/jnci/dju493 · 15.16 Impact Factor