Phase I and pharmacokinetic study of hepsulfam (NSC 329680).
Hepsulfam (NSC 329680), a bifunctional alkylating agent structurally related to busulfan, has entered clinical trial based on its broader preclinical antitumor activity compared with that of busulfan and its i.v. formulation which may circumvent the many problems arising from the p.o. administration of busulfan, such as significant individual differences in bioavailability. In this Phase I study, 53 patients received 95 courses of hepsulfam at doses ranging from 30 to 480 mg/m2 administered i.v. over 30 min every 28 days. Hematological toxicity was dose limiting. Leukopenia and thrombocytopenia were dose related, delayed in onset, and sustained for long durations. Toxicity was cumulative in most patients receiving more than one course. This pattern of myelosuppression suggests that hepsulfam is cytotoxic to hematopoietic stem cells. Although hematological toxicity was not particularly severe during most courses, its lengthly duration precluded the prompt administration of subsequent courses. Minimal nonhematological effects were observed. Pharmacokinetic studies revealed that the clearance rate of hepsulfam is linear over the dose range studied and that its plasma disposition is biphasic with mean alpha and beta half-lives of 19 +/- 18 (SE) min and 337 +/- 248 (SE) min, respectively. The area under the plasma clearance curve correlated with the percentage of change in WBC using a sigmoidal Emax model and with the duration of thrombocytopenia in patients with hematological toxicity. Based on the protracted duration of the toxicity of multiple doses that were greater than 210 mg/m2, the recommended starting dose for Phase II trials is 210 mg/m2. However, these trials should be pursued with caution because of the protracted nature of hepsulfam's myelosuppression. Because hepsulfam produced minimal nonhematological toxicity, substantial dose escalation above 480 mg/m2 may be possible with hematopoietic stem cell support.
Hendricks
C B
CB
Division of Pharmacology and Experimental Therapeutics, Johns Hopkins Oncology Center, Baltimore, Maryland 21205.
Grochow
L B
LB
Rowinsky
E K
EK
Forastiere
A A
AA
McGuire
W P
WP
Ettinger
D S
DS
Sartorius
S
S
Lubejko
B
B
Donehower
R C
RC
D000328:Adult; D000970:Antineoplastic Agents / Q000633:toxicity*; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008657:Metabolic Clearance Rate; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced; D013451:Sulfonic Acids / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity*; D013921:Thrombocytopenia / Q000139:chemically induced
D000970:Antineoplastic Agents; D013451:Sulfonic Acids; C052475:hepsulfam