Phase I and pharmacologic study of intermittently administered 9-nitrocamptothecin in patients with advanced solid tumors.
OBJECTIVE
9-Nitrocamptothecin (9NC) is an oral camptothecin analogue currently administered at 1.5 mg/m(2)/day x 5 days/week in Phase III studies for pancreatic carcinoma. In an effort to increase the dose administered per day and determine whether the daily dose or number of days of treatment influence toxicity, we performed a Phase I study of 9NC using intermittent schedules of administration.


METHODS
On schedule A, 9NC was administered orally daily x 5 days for 2 weeks every 4 weeks (one cycle). On schedule B, 9NC was administered orally daily x 14 days every 4 weeks (one cycle). Dose levels were determined by adaptive dose finding. Serial blood samples were obtained on day 1 of each schedule for pharmacokinetic studies of 9NC and its 9-aminocamptothecin (9AC) metabolite, and lactone forms were measured by high-performance liquid chromatography.


RESULTS
The recommended Phase II doses for schedules A and B were 2.43 and 1.70 mg/m(2)/day, respectively, each providing the same dose intensity (i.e., 24 mg/m(2)/cycle). The primary toxicities on schedules A and B were neutropenia, thrombocytopenia, and diarrhea. On schedule A, two patients with gastric cancer and two patients with pancreatic cancer had stable disease for more than six cycles. On schedule B, one patient with pancreatic cancer had stable disease for more than six cycles, and a patient with pancreatic cancer had a partial response. There was significant interpatient variability in the disposition of 9NC and 9AC. Most of the drug remained in the 9NC form with a ratio of 9NC to 9AC of approximately 4 to 1.


CONCLUSIONS
These studies suggest that 9NC administered on an intermittent schedule is tolerable and may be an active regimen in patients with gastric or pancreatic cancers. Dosing 9NC on a mg/m(2) basis does not reduce pharmacokinetic variability.
Zamboni
William C
WC
Program of Molecular Therapeutics and Drug Discovery, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA. zamboniwc@msx.upmc.edu
Jung
Laura L
LL
Egorin
Merrill J
MJ
Potter
Douglas M
DM
Friedland
David M
DM
Belani
Chandra P
CP
Agarwala
Sanjiv S
SS
Wong
Michael M W
MM
Fakih
Marwan
M
Trump
Donald L
DL
Jin
Ruzhi
R
Strychor
Sandra
S
Vozniak
Michael
M
Troetschel
Monica
M
Ramanathan
Ramesh K
RK
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D002166:Camptothecin / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D013997:Time Factors; D016896:Treatment Outcome
D000970:Antineoplastic Agents; C079905:rubitecan; D002166:Camptothecin