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

E. Gabriela Chiorean, Tomislav Dragovich, John Hamm, Virginia K. Langmuir, Stewart Kroll, Donald T. Jung, Alan B. Colowick, George F. Tidmarsh, Patrick Loehrer

Research output: Contribution to journalArticle

13 Citations (Scopus)

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/m2 IV over 4 h on Day 1 and gemcitabine 1,000 mg/m2 IV 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/m2 and Grade 4 thrombocytopenia at 4,500 mg/m2. 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/m2) can be given safely in combination with gemcitabine. A Phase II study in patients with pancreatic adenocarcinoma is ongoing.

Original languageEnglish
Pages (from-to)1019-1026
Number of pages8
JournalCancer Chemotherapy and Pharmacology
Volume61
Issue number6
DOIs
StatePublished - May 2008

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gemcitabine
Tumors
Adenocarcinoma
Pharmacokinetics
Neoplasms
Toxicity
beta-D-glucosylisophosphoramide mustard
Fatigue of materials
Sampling

Keywords

  • Combination chemotherapy
  • Gemcitabine
  • Glufosfamide
  • Pancreatic cancer
  • Phase I
  • Targeted therapy

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

Cite this

A Phase 1 dose-escalation trial of glufosfamide in combination with gemcitabine in solid tumors including pancreatic adenocarcinoma. / Chiorean, E. Gabriela; Dragovich, Tomislav; Hamm, John; Langmuir, Virginia K.; Kroll, Stewart; Jung, Donald T.; Colowick, Alan B.; Tidmarsh, George F.; Loehrer, Patrick.

In: Cancer Chemotherapy and Pharmacology, Vol. 61, No. 6, 05.2008, p. 1019-1026.

Research output: Contribution to journalArticle

Chiorean, E. Gabriela ; Dragovich, Tomislav ; Hamm, John ; Langmuir, Virginia K. ; Kroll, Stewart ; Jung, Donald T. ; Colowick, Alan B. ; Tidmarsh, George F. ; Loehrer, Patrick. / A Phase 1 dose-escalation trial of glufosfamide in combination with gemcitabine in solid tumors including pancreatic adenocarcinoma. In: Cancer Chemotherapy and Pharmacology. 2008 ; Vol. 61, No. 6. pp. 1019-1026.
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AU - Langmuir, Virginia K.

AU - Kroll, Stewart

AU - Jung, Donald T.

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AB - 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/m2 IV over 4 h on Day 1 and gemcitabine 1,000 mg/m2 IV 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/m2 and Grade 4 thrombocytopenia at 4,500 mg/m2. 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/m2) can be given safely in combination with gemcitabine. A Phase II study in patients with pancreatic adenocarcinoma is ongoing.

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