A Phase 1 dose-escalation trial of glufosfamide in combination with gemcitabine in solid tumors including pancreatic adenocarcinoma.

Abstract

PURPOSE:

To evaluate safety and pharmacokinetics and to establish the maximum tolerated dose of glufosfamide when administered in combination with gemcitabine in advanced solid tumors.

METHODS:

This Phase 1 dose-escalation study evaluated the combination of glufosfamide + gemcitabine in patients with advanced solid tumors. Cohorts of three to six patients were treated with glufosfamide doses from 1,500 to 4,500 mg/m(2) i.v. over 4 h on Day 1 and gemcitabine 1,000 mg/m(2) i.v. over 30 min on Days 1, 8 and 15 of every 28-day cycle. Detailed PK sampling was performed on days 1 and 8 of the first two cycles.

RESULTS:

Nineteen patients were enrolled. Two patients had dose-limiting toxicity: Grade 3 fatigue at 2,500 mg/m(2) and Grade 4 thrombocytopenia at 4,500 mg/m(2). Five patients completed six cycles and one patient remained on study for ten cycles. Two patients discontinued for adverse events. Grade 3/4 neutropenia and thrombocytopenia occurred in seven patients and five patients, respectively. The CrCL fell below 60 mL/min in two patients. There was one unconfirmed partial response and 10 of 19 (52.6%) patients had stable disease or better at 8 weeks and three patients had continuing stable disease at 24 weeks. Pharmacokinetic analyses suggest no interaction between glufosfamide and gemcitabine.

CONCLUSION:

Phase I data indicate that full dose glufosfamide (4,500 mg/m(2)) can be given safely in combination with gemcitabine. A Phase II study in patients with pancreatic adenocarcinoma is ongoing.

• Authors: E Gabriela Chiorean, Tomislav Dragovich, John Hamm, Virginia K Langmuir, Stewart Kroll, Donald T Jung, Alan B Colowick, George F Tidmarsh, Patrick J Loehrer
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 61 Issue 6 Pg. 1019-26 (May 2008) ISSN: 0344-5704 [Print] Germany
• PMID: 17661038 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• Antineoplastic Agents
• Phosphoramide Mustards
• beta-D-glucosylisophosphoramide mustard
• Deoxycytidine
• Glucose
• Ifosfamide
• Gemcitabine

Topics

• Adenocarcinoma (drug therapy, pathology)
• Adult
• Aged
• Antimetabolites, Antineoplastic (administration & dosage, adverse effects)
• Antineoplastic Agents (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects, therapeutic use)
• Area Under Curve
• Deoxycytidine (administration & dosage, analogs & derivatives)
• Female
• Glucose (analogs & derivatives)
• Half-Life
• Hematologic Diseases (chemically induced, epidemiology)
• Humans
• Ifosfamide (analogs & derivatives)
• Male
• Middle Aged
• Pancreatic Neoplasms (drug therapy, pathology)
• Phosphoramide Mustards (administration & dosage)
• Gemcitabine