Investigational New Drugs

, Volume 23, Issue 3, pp 235–239 | Cite as

Phase I trial of menadiol diphosphate (vitamin K3) in advanced malignancy

  • Dean Lim
  • Robert J. MorganJr.
  • Steven Akman
  • Kim Margolin
  • Brian I. Carr
  • Lucille Leong
  • Oluwole Odujinrin
  • James H. Doroshow

Summary

Based on the activity of menadione (M) in the human tumor stem cell assay, we conducted a phase I trial of M in patients with advanced cancer. Forty patients (19 men, 21 women) were treated with 90 courses of M; 82 treatment courses are evaluable for toxicity. The median patient age, Karnofsky performance status, and number of prior chemotherapy regimens were 61 years (range 32–74 years), 80% (range 50–100%), and two, respectively. M was given by a short (1–5 h) intravenous infusion every 3 weeks, starting at 40 mg/m2 and escalating by modified Fibonacci scheme to 1360 mg/m2. Toxicity was graded according to the Southwest Oncology Group toxicity scale with defined hypersensitivity reaction (HSR) scales. No grade ≧2 hematologic toxicity was observed. Non-hematologic toxicity consisted of a HSR syndrome of paresthesiae of the extremities, facial flushing, burning of the eyes and mucous membranes, chest pain and dyspnea. HSR was defined as Grade I toxicity by the presence of facial numbness, flushing, and/or a tingling sensation or burning of the eyes and mucous membranes. Grade II toxicity was defined as the presence of the same above symptoms plus chest tightness, paresthesiae of extremities and/or dyspnea and chest pain. These toxicities were grade 1 in 3 of 4 patients at a dose of 840 mg/m2. At 1360 mg/m2, 2 of 13 patients suffered grade 1 HSR and 7 of 13 grade 2 HSR No objective partial or complete responses were observed. Plasma menadione concentrations peaked at 1.9–7.4 μ M during the infusion in 3 patients receiving 1360 mg/m2. Further phase 1 and 2 combination trials using longer infusion durations have resulted from this trial.

Key words

Phase I solid tumor pharmacokinetics menadione menadiol 

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Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • Dean Lim
    • 1
    • 5
  • Robert J. MorganJr.
    • 1
  • Steven Akman
    • 2
  • Kim Margolin
    • 1
  • Brian I. Carr
    • 3
  • Lucille Leong
    • 1
  • Oluwole Odujinrin
    • 4
  • James H. Doroshow
    • 1
  1. 1.Department of Medical Oncology and Therapeutics ResearchCity of Hope National Medical CenterDuarteUSA
  2. 2.Division of Hematology/OncologyWake Forest University, Baptist Medical CenterWinston Salem
  3. 3.University of Pittsburgh, Physician FacultyPittsburgh
  4. 4.Cell Therapeutics, Inc.Seattle
  5. 5.Department of Medical Oncology & Therapeutics ResearchDuarteUSA

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