Phase I and pharmacokinetic study of tiazofurin (NSC 286193) administered by 5-day continuous infusion

Bishop, Joel A. M.; Sampson, D; Grygiel, John J.; Woods, Robert L.; Coates, Alan S.; Fox, Richard M.

doi:10.1007/bf00256168

Cited by 8 publications

(11 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We feel that they represent the dose limiting toxic effects in this study. Such conclusions are in accordance with other reported phase I studies of tiazofurin [13][14][15][16][17], though some relationship with the schedule used seemed to influence the type of toxicity encountered. In a five day continuous infusion schedule the dose limiing toxicity was more consistently neurologic [13][14][15], whereas, in a bolus five day schedule pleuropericarditis, headaches, myalgias and general malaise were considered dose limiting [16,17].…”

Section: Discussionsupporting

confidence: 82%

“…Three patients with extensive small cell lung cancer, nonsmall cell lung cancer (both with performance status of 2) and one patient with ocular malignant melanoma (performance status 1) died on days 4, 11, and 9 following their first cycle of tiazofurin at 1650, 550 and 2200 mg/m 2 respectively. None of Total 106 2 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16) these patients developed myelosuppression in the period of observation and their nonhematologic toxicities were mild to moderate. It was not thought that tiazofurin caused their deaths.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Phase I study of tiazofurin (2-β-D-ribofuranosylthiazole-4-carboxamide, NSC 286193)

Maroun¹

1990

Invest New Drugs

View full text Add to dashboard Cite

A phase I trial of 2-fl-D-ribofuranosylthiazole-4-carboxamide (NCS 286193, tiazofurin) was conducted using a 5-day i.v. bolus schedule, every 21 days. Thirty one patients with advanced cancer were entered on the trial. A total of 106 cycles were administered with doses ranging from 550 to 2750 mg/m 2. Concomitant administration of Allopurinol was necessary to prevent hyperuricemia. Tiazofurin was difficult to evaluate and many side effects were variable and sporadic. The dose limiting toxicities were nonhematologic consisting particularly of myalgias, headaches and general malaise. Other toxicities included nausea, vomiting, stomatitis, lethargy, sleeping difficulty, sinus bradycardia, skin rash, desquamation of the palms and soles, photophobias and burning of the eyes.Hematologic toxicity was mild and not dose related though it led to a neutropenic septic death in one patient at 2750 mg/mL Anemia was documented in 60O7o of cycles. Biochemical abnormalities consisted of mild hyperglycemia, hyperuricemia and elevated skeletal creatinine phosphokinase levels which did not correlate with the incidence or degree of myalgias. Though some patients were able to tolerate higher doses, the recommended dose for phase 2 study is 1650 mg/m 2. Further studies will be required to achieve a better understanding of this interesting drug.

show abstract

Section: Discussionsupporting

confidence: 82%

Section: Resultsmentioning

confidence: 99%

Phase I study of tiazofurin (2-β-D-ribofuranosylthiazole-4-carboxamide, NSC 286193)

Maroun¹

1990

Invest New Drugs

View full text Add to dashboard Cite

show abstract

“…Nausea and vomiting occurred most commonly (18% of courses). Elevation of the serum transaminase levels was observed in less than 20% of courses, and elevations of the SGOT were reported more often than SGPT eleva- [16,25]. An electroencephalogram in one patient revealed abnormalities consistent with encephalopathy, and a computerized tomographic scan and examination of the cerebrospinal fluid were normal [16].…”

Section: Resultsmentioning

confidence: 99%

“…When the absolute decline in hemoglobin from baseline values during the initial cycle was considered, however, 40-50% of patients treated on the daily for five days bolus and CI schedules experienced a drop in hemoglobin of more than 2 g/dl. The decline in hemoglobin occurred in the absence of clinically evident bleeding or hemolysis [18,[22][23][24][25][26]. Green et al compared pharmacokinetic parameters for tiazofurin in plasma and in red blood cells (RBC) [20].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Clinical toxicity associated with tiazofurin

et al. 1990

View full text Add to dashboard Cite

Tiazofurin, an investigational antimetabolite, is undergoing clinical evaluation in leukemia. We analyzed the data base of 198 patients entered in Phase I trials to characterize the incidence and severity of toxicities associated with tiazofurin according to dose and schedule. Severe myelosuppression occurred infrequently, and was not dose-dependent. A five day bolus schedule had a higher incidence of severe or life-threatening neutropenia than other schedules. Tiazofurin produced lymphopenia which was not dose-dependent in the range of 23 -36% decrease from baseline, and the effect on lymphocyte count was generally greater than the decline in neutrophil count. Non-hematologic toxicity of a moderate or worse severity (_> grade 2) included nausea and vomiting (18% of all courses), serum transaminase elevations (SGOT, 16%; SGPT, 9%), rash (9%), stomatitis (3 %), conjunctivitis (3%), headache (10%), other signs of central nervous system toxicity (8%), and cardiac toxicity, primarily pleuropericarditis (4%). Dose-related cutaneous toxicity, headache, and nausea and vomiting were evident in the five day bolus schedule, and myalgia was more frequently reported at higher doses on the single dose schedule. The five day continuous infusion (CI) schedule had a higher incidence of neurotoxicity, cardiac toxicity, SGPT elevations and ocular toxicity than the daily for five days bolus schedule, but none of these differences attained statistical significance. Although the peak plasma concentrations of tiazofurin achieved with the five day bolus schedule were 3-fold higher than the steady-state plasma levels seen with an equal dose given by CI, the area under the concentration-time curve (AUC) was approximately 1.6-fold higher with CI. These observations suggest that both high peak plasma concentrations (above 400 uM) and prolonged exposure to plasma levels exceeding 50 uM may result in a higher incidence of serious non-hematologic toxicity.

show abstract

Clinical pharmacokinetic study of tiazofurin administered as a 1‐hour infusion

Jayaram

Lapis

Tricot

et al. 1992

Intl Journal of Cancer

View full text Add to dashboard Cite

Tiazofurin, 2-beta-D-ribofuranosylthiazole-4-carboxamide, is cytotoxic to murine and human tumor cells. In earlier Phase-I/-II trials performed in other centers in patients with solid tumors, the drug was given mainly as a 10-min bolus or as a continuous i.v. infusion for 5 days. These protocols were associated with serious side effects, including neurotoxicity, pleuropericarditis, and occasional myelosuppression. In our study, 26 patients with end-stage leukemia were treated with tiazofurin with 1-hr daily i.v. infusions, resulting in lower incidence and less severity of side effects. In this group, 7 attained complete remission and 7 showed hematologic responses. Out of 12 evaluable patients with myeloid blast crisis of chronic granulocytic leukemia, 10 (83%) responded to therapy, with 6 attaining complete response. We present pharmacokinetic parameters of our clinical study and examine some of the reasons for the lower toxicity found in our trials. In leukemic patients during and after infusion at doses of 1,100, 2,200 and 3,300 mg/m2 tiazofurin peak plasma concentrations were 245, 441 and 736 microM, respectively, values one-half of those calculated from other reports with a 10-min bolus administration. In our 1-hr infusion method, biphasic pharmacokinetics were noted with alpha t1/2 and beta t1/2 of 0.5 and 6.2 hr, and tiazofurin was eliminated at a faster rate than in previous trials with continuous infusion. The area under the curve with our 1-hr infusion was 52% of that reported for the same dose given by continuous infusion. Our 1-hr infusion method and prompt and effective treatment of side effects enabled us to administer higher doses and larger total amounts of tiazofurin in longer treatment cycles than in any previous trials elsewhere. Tiazofurin therapy using 1-hr infusion may be feasible for other carefully selected types of malignancies.

show abstract

Phase I and pharmacokinetic study of tiazofurin (NSC 286193) administered by 5-day continuous infusion

Cited by 8 publications

References 7 publications

Phase I study of tiazofurin (2-β-D-ribofuranosylthiazole-4-carboxamide, NSC 286193)

Phase I study of tiazofurin (2-β-D-ribofuranosylthiazole-4-carboxamide, NSC 286193)

Clinical toxicity associated with tiazofurin

Clinical pharmacokinetic study of tiazofurin administered as a 1‐hour infusion

Contact Info

Product

Resources

About