Phase I clinical trial with ametantrone (NSC-287513)

Piccart, Martine; Rozencweig, Marcel; Abele, Reto; Cumps, Evelyne; Dodion, Pierre; Dupont, D; Kisner, Daniel L.; Kenis, Yvon

doi:10.1016/0014-2964(81)90233-4

Cited by 10 publications

(7 citation statements)

References 3 publications

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“…Prior to the initiation of the current daily times 5 day study, two single dose Phase I trials had been completed (2,3). In all, 35 patients received 76 courses of ametantrone as a single intravenous infusion.…”

Section: Discussionmentioning

confidence: 99%

“…Two single dose Phase I trials have been completed. (2,3) Predictable and reversible leukopenia was the dose limiting toxicity in both studies and there was no evidence of cardiotoxicity. of 18 and 70 were eligible if they had histologically confirmed malignant solid tumors which were refractory to conventional forms of therapy or for which no therapy existed.…”

Section: Introductionmentioning

confidence: 99%

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A phase I trial of ametantrone acetate (NSC-287513)

Gams

Ostroy

Bender³

et al. 1985

Invest New Drugs

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Ametantrone acetate is an intensely blue anthracenedione undergoing clinical trials in man. In this Phase I study, 20 patients received 39 courses of drug as a single IV dose given daily for five days and repeated every three weeks (21 days). Dosage escalations proceeded from 15 mg/m2 to 35 mg/m2. Predictable and reversible leukopenia was the dose limiting toxicity. One previously untreated patient with renal cell carcinoma metastatic to the lungs and right arm experienced a partial response of 51 days duration. Nine patients had pharmacokinetic studies performed during the study. Ametantrone was extensively distributed (apparent volume of distribution, 26.3 l/m2) and demonstrated a short half-life (harmonic mean half-life, 0.38 hour). The maximum tolerated dose in this study was 35 mg/m2. Recommended doses for Phase II trials are 30 mg/m2 in good risk patients and 25 mg/m2 in poor risk patients. Because of the partial response seen in one patient with renal cell carcinoma, Phase II trials should include this tumor category in order to better define the activity of ametantrone in this disease. In addition, since the total amount of drug that could be given to patients receiving the five day schedule (125-150 mg/m2) was approximately the same amount that could be administered as a single dose (140 mg/m2), it would appear that the only advantage of the daily times five day dosage schedule would be in the lower incidence of bluish skin discoloration.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A phase I trial of ametantrone acetate (NSC-287513)

Gams

Ostroy

Bender³

et al. 1985

Invest New Drugs

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Section: Introductionmentioning

confidence: 98%

“…The dose-response relationship was steeper in the case of MXT than for AMT and BST (3)(4)(5)(6)(7)(8). With a single dose intermittent schedule, doses of 135-160 mg/m 2, 12-14 mg/m 2., and 260 mg/m 2 were recommended for phase II trials with AMT, MXT and BST, respectively (3)(4)(5)(6)(7)(8). The interest for this group of compounds has been enhanced by the demonstration of antitumor activity for MXT and BST in breast cancer (9)(10)(11) and for MXT in leukemia (12).…”

Section: Introductionmentioning

confidence: 98%

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Quantitation of differential sensitivity of normal marrow myeloid progenitor cells to anthracene derivatives

et al. 1986

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The effect of 3 anthracene derivatives, mitoxantrone, ametantrone, bisantrene, on 4 normal human bone marrows, was studied using the myeloid stem cell assay developed by Pike and Robinson, in order to define to what extent this test could be used to predict the relative clinical hematologic toxicity of new anticancer agents. For the 3 drugs, an exponential relationship between colony survival and drug concentration was found, but was much steeper for mitoxantrone (slope = -195.2 +/- 8.8/micrograms/ml) than for ametantrone (slope = 5.1 +/- 1.0/micrograms/ml, p less than or equal to 0.001) and bisantrene (slope = 7.1 +/- 0.3/micrograms/ml, p less than or equal to 0.001). The difference of slope between ametantrone and bisantrene was of borderline significance (p less than or equal to 0.05). The ratios of concentrations inducing a 50% growth inhibition for mitoxantrone versus bisantrene and for ametantrone versus bisantrene were close to the corresponding ratios of concentrations inducing a 90% growth inhibition. The relative in vitro toxicities reproduce very well the relative myelosuppression observed in clinical trials with mitoxantrone versus bisantrene but the results were less satisfactory for the comparison of these 2 agents with ametantrone. In addition, our data suggest that, for these 3 compounds, intrinsic myeloid progenitor sensitivity is a major determinant of leukopenia.

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Pharmacokinetics of ametantrone acetate (NSC-287513)

Kuhn

Balmer

Ludden

et al. 1987

Cancer Chemother. Pharmacol.

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Ametantrone is the second anthracene derivative to enter clinical trials. The pharmacokinetic parameters for ametantrone acetate (CI-881) were characterized in six patients concurrently with the phase I clinical trial. Biological samples were assayed by a specific and sensitive high-performance liquid chromatography procedure. Plasma levels of ametantrone declined in a triexponential fashion, with a mean terminal half-life (t 1/2 gamma) of 25 h. The estimated mean total-body plasma clearance was 25.9 +/- 14.7 1 h-1 m-2. The steady-state volume of distribution (Vdss) was large, averaging 568 +/- 630 l/m2. Excretion of unchanged ametantrone in the urine over 48 h averaged 5.7% of the total dose, indicating that there is another major route of elimination.

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Phase I clinical trial with ametantrone (NSC-287513)

Cited by 10 publications

References 3 publications

A phase I trial of ametantrone acetate (NSC-287513)

A phase I trial of ametantrone acetate (NSC-287513)

Quantitation of differential sensitivity of normal marrow myeloid progenitor cells to anthracene derivatives

Pharmacokinetics of ametantrone acetate (NSC-287513)

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