DX-8951f, a hexacyclic camptothecin analog, on a daily-times-five schedule: a phase I and pharmacokinetic study in patients with advanced solid malignancies.
OBJECTIVE
To assess the feasibility of administering DX-8951f (exatecan mesylate), a water-soluble, camptothecin analog, as a 30-minute intravenous infusion daily for 5 days every 3 weeks, determine the maximum-tolerated dose (MTD) and pharmacokinetic (PK) behavior of DX-8951f, and seek preliminary evidence of anticancer activity.


METHODS
Patients with advanced solid malignancies were treated with escalating doses of DX-8951f. After three patients were treated at the first dose level, doses were to be escalated in increments of 100%, using a single patient at each dose level unless moderate toxicity was observed. The MTD, defined as the highest dose level at which the incidence of dose-limiting toxicity did not exceed 20%, was calculated separately for minimally pretreated (MP) and heavily pretreated (HP) patients. The PK and excretory profiles of DX-8951, the anhydrous form of DX-8951f, were also characterized.


RESULTS
Thirty-six patients were treated with 130 courses of DX-8951f at six dose levels ranging from 0.1 to 0.6 mg/m(2)/d. Brief, noncumulative neutropenia was the most common toxicity observed. Severe myelosuppression (neutropenia that was protracted and/or associated with fever and/or severe thrombocytopenia) was consistently experienced by HP and MP patients at doses exceeding 0.3 and 0.5 mg/m(2)/d, respectively. Nonhematologic toxicities (nausea, vomiting, and diarrhea) were also observed, but these effects were rarely severe. Objective antitumor activity included partial responses in one patient each with platinum-resistant extrapulmonary small-cell and fluoropyrimidine- and irinotecan-resistant colorectal carcinoma, and minor responses in patients with prostate, hepatocellular, thymic, primary peritoneal, and irinotecan-resistant colorectal carcinomas. The PKs of total DX-8951 were linear and well fit by a three-compartment model.


CONCLUSIONS
The recommended doses for phase II studies of DX-8951f as a 30-minute infusion daily for 5 days every 3 weeks are 0.5 and 0.3 mg/m(2)/d for MP and HP patients, respectively. The characteristics of the myelosuppressive effects of DX-8951f, paucity of severe nonhematologic toxicities, and antitumor activity against a wide range of malignancies warrant broad disease-directed evaluations of DX-8951f on this schedule.
Rowinsky
E K
EK
Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX 78229, USA. erowinsk@saci.org
Johnson
T R
TR
Geyer
C E
CE
Hammond
L A
LA
Eckhardt
S G
SG
Drengler
R
R
Smetzer
L
L
Coyle
J
J
Rizzo
J
J
Schwartz
G
G
Tolcher
A
A
Von Hoff
D D
DD
De Jager
R L
RL
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002166:Camptothecin / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009503:Neutropenia / Q000139:chemically induced; D013921:Thrombocytopenia / Q000139:chemically induced; D014839:Vomiting / Q000139:chemically induced
D000972:Antineoplastic Agents, Phytogenic; C095887:exatecan; D002166:Camptothecin