Phase I clinical and pharmacokinetic study of rebeccamycin analog NSC 655649 given daily for five consecutive days.
OBJECTIVE
Rebeccamycin analog (NSC 655649) is active against a variety of both solid and nonsolid tumor cell lines. We performed a phase I trial to determine the maximum-tolerated dose (MTD) of rebeccamycin analog when given on a daily x 5 schedule repeated every 3 weeks, characterize the toxicity profile using this schedule, observe patients for antitumor response, and determine the pharmacokinetics of the agent and pharmacodynamic interactions.


METHODS
Thirty assessable patients received a total of 153 cycles according to the following dose escalation schema: 60, 80, 106, 141, and 188 mg/m(2)/d x 5 days.


RESULTS
Grade 2 phlebitis occurred in all patients before the use of central venous access, placed at dose level 4 and higher. Dose-limiting toxicity (DLT), grade 4 neutropenia, occurred at 188 mg/m(2)/d x 5 days in both previously treated and chemotherapy-naive patients. Pharmacokinetic analysis revealed a three-compartmental model of drug elimination and a long terminal half-life (154 +/- 55 hours). The percentage drop in absolute neutrophil count correlates with the area under the curve infinity. The presence of a second peak during the elimination phase as well as a high concentration of NSC 655649 in biliary fluid compared with the corresponding plasma measurement (one patient) is suggestive of enterohepatic circulation. Two partial responses, two minor responses, and six prolonged (> 6 months) cases of stable disease were observed. Of these, three patients with gallbladder cancer and one patient with cholangiocarcinoma experienced either a minor response or a significant period of freedom from progression.


CONCLUSIONS
The recommended phase II dose for NSC 665649 on a daily x 5 every 3 weeks schedule is 141 and 165 mg/m(2)/d for patients with prior and no prior therapy, respectively, with DLT being neutropenia. During this phase I trial, encouraging antitumor activity was been observed.
Dowlati
A
A
Division of Hematology/Oncology and Clinical Pharmacology, Developmental Therapeutics Program, Ireland Cancer Center at University Hospitals of Cleveland, OH, USA.
Hoppel
C L
CL
Ingalls
S T
ST
Majka
S
S
Li
X
X
Sedransk
N
N
Spiro
T
T
Gerson
S L
SL
Ivy
P
P
Remick
S C
SC
D000328:Adult; D000368:Aged; D000617:Aminoglycosides; D000900:Anti-Bacterial Agents / Q000009:adverse effects* / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics*; D002227:Carbazoles; D018281:Cholangiocarcinoma / Q000188:drug therapy; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005260:Female; D005706:Gallbladder Neoplasms / Q000188:drug therapy; D005960:Glucosides; D006801:Humans; D007262:Infusions, Intravenous; D008113:Liver Neoplasms / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D002227:Carbazoles; D005960:Glucosides; C093269:becatecarin