Phase I Trial of Imexon in Patients With Advanced Malignancy

Abstract

The phase II recommended dose of imexon is 875 mg/m2/d for 5 days every other week. A decrease in plasma thiols did correlate with imexon exposure.

A phase 1‐2 study of imexon plus dacarbazine in patients with unresectable metastatic melanoma

“…Mean imexon peak plasma levels in the current trial were 62.0 lg/mL for a 30-minute infusion of 1000 mg/m 2 , compared with 97.3 lg/mL in the prior phase 1 trial of singleagent imexon. 20 Clearance and volume of distribution values were also similar in the 2 trials. The mean (standard deviation) imexon AUC of 8947 (AE3639) lg/mL/min in the prior trial, which included 1 high AUC outlier, 20 is comparable to the mean (standard deviation) imexon AUC of 5436 (AE1578 lg/mL/min) seen in the 8 patients studied in the current trial.…”

“…Also, nonsignificant differences were observed for the AUC 0-t (which ranged from 55.3 to 82.1 hours  lg/mL), the t 1/2 , which averaged about 1 hour, drug clearance, which ranged from 15.0 to 22.8 L/h/m 2 , and the V ss , which ranged from 15.0 to 22.8 L/m 2 . As in the prior phase 1 pharmacokinetic study, 20 the V ss of imexon was greater than extracellular water, but less than total body water, which suggests limited penetration into tissues. There was no difference between pharmacokinetic parameters in the 4 men and 2 women for the 30-minute imexon infusion (data not shown).…”

“…16 These concentrations can be achieved in humans. 20 In vitro, imexon was synergistic with a variety of agents, including alkylating agents such as cyclophosphamide and dacarbazine, antimetabolites such as gemcitabine and fluorouracil, and tubulin modulators such as docetaxel.…”

“…The MTDs were 875 mg/m 2 given daily for 5 days every other week 20 and 1150 mg/m 2 given daily for 5 days every 3 weeks (unpublished observations). The DLTs in these studies were fatigue and abdominal pain, and neutropenia and hypertension, respectively.…”

Phase 2 study of imexon, a prooxidant molecule, in relapsed and refractory B-cell non-Hodgkin lymphoma

“…13,14 Phase 1 trials demonstrated imexon to be well tolerated, associated with symptoms of reversible fatigue and gastrointestinal side effects with a relative lack of severe myelosuppressive toxicities. 15,16 Although few lymphoma patients were enrolled in the early phase 1 studies, a partial response (PR) was noted in a patient with follicular lymphoma (FL).…”