A Randomized Phase I Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Recombinant Erwinia Asparaginase (JZP-458) in Healthy Adult Volunteers.

L-asparaginase has been an important component of acute lymphoblastic leukemia (ALL) therapy for over 40 years, and is standard therapy during ALL induction and consolidation treatment. L-asparaginases are immunogenic and can induce hypersensitivity reactions; inability to receive asparaginase has been associated with poor patient outcomes. There are L-asparaginases of varied bacterial origins, with the most commonly used being Escherichia coli (E. coli); therefore, to ensure that patients who develop hypersensitivity to E. coli-derived asparaginases receive an adequate therapeutic course, alternative preparations are warranted. JZP-458 is a recombinant Erwinia asparaginase produced using a novel Pseudomonas fluorescens expression platform that yields an enzyme with no immunologic cross-reactivity to E. coli-derived asparaginases. To evaluate the safety, tolerability, and pharmacokinetics (PK) of a single dose of JZP-458, a randomized, single-center, open-label, phase I study was conducted with JZP-458 given via i.m. injection or i.v. infusion to healthy adult volunteers. At the highest doses tested for each route of administration (i.e., 25 mg/m2 i.m. and 37.5 mg/m2 i.v.), JZP-458 achieved serum asparaginase activity (SAA) levels ≥ 0.1 IU/mL at 72 hours postdose for 100% of volunteers. Bioavailability for i.m. JZP-458 was estimated at 36.8% based on SAA data. All dose levels were well-tolerated, with no unanticipated adverse events (AEs), no serious AEs, and no grade 3 or higher AEs. Based on PK and safety data, the recommended JZP-458 starting dose for the pivotal phase II/III study in adult and pediatric patients is 25 mg/m2 i.m. and 37.5 mg/m2 i.v. on a Monday/Wednesday/Friday dosing schedule.

Sensitive and rapid method for the determination of thalidomide in human plasma and semen using solid-phase extraction and liquid chromatography-tandem mass spectrometry.

Liquid chromatography-tandem mass spectrometric assays were developed for the sensitive, rapid and high throughput bioanalyses of thalidomide in human plasma and semen. The matrices were first stabilized with 0.025 M Sorensen's citrate buffer at pH 1.5 to prevent spontaneous hydrolysis. Buffered thalidomide was stable when stored at room temperature for 24 h and for up to three freeze-thaw cycles. Samples were extracted using SPE cartridges. Extracts were then injected into the LC-MS-MS equipped with a reversed-phase column and an APCI interface in the negative ion mode. Calibration curves for both matrices were linear with r>0.99 from 2 to 250 ng/ml and ng/g. Inter-assay precision (RSD) of plasma and semen calibration standards were 2.6-11.6 and 1.9-12.4%, respectively. Recoveries from plasma and semen were greater than 69 and 78%, respectively. Batch sizes of 100 samples per matrix were analyzed with a total run time of 5 h. The methods successfully determined concentrations of thalidomide from a clinical study to levels as low as 7 ng/ml plasma and 8 ng/g semen, respectively.

Phase I Trial of G3139, a bcl-2 antisense oligonucleotide, combined with doxorubicin and cyclophosphamide in children with relapsed solid tumors: a Children's Oncology Group Study.

PURPOSE: To determine the maximum-tolerated dose, toxicity, pharmacokinetics, and biologic effects of G3139 when administered with doxorubicin and cyclophosphamide to children with relapsed solid tumors. PATIENTS AND METHODS: Patients received a 7-day continuous infusion of 3, 5, or 7 mg/kg/d of G3139 every 21 days. Doxorubicin, cyclophosphamide, and dexrazoxane were administered on days 5 and 6 of the infusion. Pharmacokinetics and biology studies were performed during the first course. RESULTS: Thirty-seven patients, median age 14 years (range, 1 to 19 years), were enrolled, of whom 29 were fully assessable for toxicity. Because of dose-limiting neutropenia, doses of doxorubicin 30 mg/m2/d for 2 days, dexrazoxane 300 mg/m2/d for 2 days, and cyclophosphamide 500 mg/m2/d for 2 days were reduced initially, but with the addition of granulocyte colony-stimulating factor (GCSF), could be re-escalated to starting doses. At the 7 mg/kg/d dose level, only one of six patients experienced DLT (neutropenia > 7 days). At this dose, the average (+/- standard deviation) steady-state G3139 concentration was 2.04 +/- 1 microg/mL, a concentration associated with biologic activity. Eleven of 15 patients had reduced bcl-2 expression in peripheral-blood mononuclear cells at the first assessable time point of G3139 exposure, and in eight of 14 patients with serial specimens this reduction persisted through day 6. CONCLUSION: The recommended phase II dose of G3139 is 7 mg/kg/d as a 7-day continuous infusion, with cyclophosphamide 500 mg/m2/d and doxorubicin 30 mg/m2/d on days 5 and 6, followed by GCSF. G3139 may accentuate the myelosuppressive effects of doxorubicin and cyclophosphamide. Evidence for biologic effects of G3139 was demonstrated.

Chiral inversion of the second generation IMiD CC-4047 (ACTIMID ) in human plasma and phosphate-buffered saline.

CC-4047 is a racemic second-generation immunomodulatory drug currently in clinical development for various oncologic indications. It has potent effects on key cytokines including tumor necrosis factor-alpha, interleukin (IL-10), and interferon (IFN-gamma). The S-isomer of CC-4047 has been reported to be the more potent enantiomer of the racemate. In this article we report on the rapid racemization of the S-isomer of CC-4047 in human plasma and phosphate-buffered saline. These results support the further development of the racemate instead of the S-isomer.