Aw. Tolcher et al., Phase I and pharmacokinetic study of NSC 655649, a rebeccamycin analog with topoisomerase inhibitory properties, J CL ONCOL, 19(11), 2001, pp. 2937-2947
Purpose: To assess the feasibility of administering NSC 655649, a water-sol
uble, rebeccamycin analog with topoisomerase inhibitory properties, as a br
ief intravenous (IV) infusion once every 3 weeks and to determine the maxim
um-tolerated dose (MTD) of NSC 655649, characterize its pharmacokinetic beh
avior, and seek preliminary evidence of antitumor activity.
Patients and Methods: Patients with advanced solid malignancies were treate
d with escalating doses of NSC 655649 administered over 30 to 60 minutes IV
once every 3 weeks. An accelerated dose-escalation method was used to guid
e dose escalation. After three patients were treated at the first dose leve
l, doses were escalated in increments that ranged up to 150% using single p
atient cohorts until moderate toxicity was observed, when a more conservati
ve dose-escalation scheme was invoked. MTD was defined as the highest dose
level at which the incidence of dose-limiting toxicity did not exceed 20%.
MTD was determined for both minimally pretreated (MP) and heavily pretreate
d (HP) patients. plasma and urine were sampled to characterize the pharmaco
kinetic and excretory behavior of NSC 655649.
Results: Forty-five patients were treated with 130 courses of NSC 655649 at
doses ranging from 20 mg/m(2) to 744 mg/m(2). Myelosuppression was the pri
ncipal toxicity. Severe neutropenia, which was often associated with thromb
ocytopenia, was unacceptably high in HP and MP patients treated at 572 mg/m
(2) and 744 mg/m(2), respectively. Nausea, vomiting, and diarrhea were comm
on but rarely severe. The pharmacokinetics of NSC 655649 were dose dependen
t and fit a three-compartment model, The clearance and terminal elimination
half-lives for NSC 655649 averaged 7.57 (SD = 4.2) L/h/m(2) and 48.85 (50
= 23.65) hours, respectively. Despite a heterogeneous population of MP and
HP patients, the magnitude of drug exposure correlated well with the severi
ty of myelosuppression. Antitumor activity was observed in two HP ovarian c
ancer patients and one patient with a soft tissue sarcoma refractory to eto
poside and doxorubicin,
Conclusion: Recommended phase II doses are 500 mg/m(2) and 572 mg/m(2) IV o
nce every 3 weeks for HP and MP patients, respectively. The absence of seve
re nonhematologic toxicities, the encouraging antitumor activity in HP pati
ents, and the unique mechanism of antineoplastic activity of NSC 655649 war
rant further clinical development. (C) 2001 by American Society of Clinical
Oncology.