Phase I trial of menadiol diphosphate (vitamin K3) in advanced malignancy
- 176 Downloads
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 wordsPhase I solid tumor pharmacokinetics menadione menadiol
Unable to display preview. Download preview PDF.
- 2.Lind C, Hochstein P, Ernster L: DT-diaphorase as a quinone reductase: A cellular control device against semiquinone and superoxide radical formation. Archives Biochem & Biophy 216: 178–185, 1982Google Scholar
- 3.Akman SA, Doroshow JH, Dietrich MF, Chlebowski RT, Block JS: Synergistic cytotoxicity between menadione and dicumarol vs. murine leukemia L1210. J Pharm Exper Therapeut 240: 486–491, 1987Google Scholar
- 8.Yang WH, Purchase EC, Rivingston RN: Positive skin tests and Prausnitz-Kustner reactions in metabisulfite-sensitive subjects. J Allergy Clin Immuno 79: 15, 1987Google Scholar
- 9.Riggs BS, Harcherlroad FP Jr, Poole C: Allergic reaction to sulfiting agents. Annals Emergency Medicine. 15: 77–79, 1986Google Scholar
- 10.Sprenger JD, Altman LC, Marshall SG, Pierson WE, Koenig JQ: Studies of neutrophil chemotactic factor of anaphylaxis in metabisulfite sensitivity. Annals Allergy 62: 117–121, 1989Google Scholar