A phase I/randomized phase II, non-comparative, multicenter, open label trial of CP-547,632 in combination with paclitaxel and carboplatin or paclitaxel and carboplatin alone as first-line treatment for advanced non-small cell lung cancer (NSCLC).
OBJECTIVE
To evaluate the toxicity profile and pharmacological properties of oral CP-547,632 alone and in combination with paclitaxel and carboplatin administered every 3 weeks, and to assess efficacy as measured by the objective response and progressive disease rates of oral CP-547,632 administered in combination with paclitaxel and carboplatin.


METHODS
Patients with stage IIIB/IV or recurrent non-small cell lung cancer receiving first-line chemotherapy were treated with oral daily CP-547,632 in combination with paclitaxel 225 mg/m(2) and carboplatin AUC = 6 every 3 weeks. Pharmacokinetics parameters for CP-547,632 and paclitaxel were determined independently and during co-administration.


RESULTS
Seventy patients were enrolled and 68 patients were treated, 37 in phase 1 and 31 in phase 2 (14 with the combination and 17 with chemotherapy alone). Dose-limiting toxicity of CP-547,632 250 mg by mouth daily in combination with paclitaxel and carboplatin was grade 3 rash and grade 3 diarrhea despite medical intervention. CP-547,632 did not significantly affect the pharmacologic profiles of paclitaxel and carboplatin. No subject had CR. In phase I, seven subjects (22.6%) had a confirmed partial response. In phase II, four subjects (28.6%) receiving CP-547,632 plus chemotherapy had a confirmed partial response. In the phase II chemotherapy alone group, four subjects (25%) had a confirmed partial response.


CONCLUSIONS
The combination of CP-547,632 and paclitaxel and carboplatin was well-tolerated at doses up to 200 mg by mouth daily. Dose-limiting toxicity of CP-547,632 at 250 mg consisted of diarrhea and rash. CP-547,632 did not increase the objective response rate to chemotherapy alone in patients with advanced non-small cell lung cancer.
Cohen
Roger B
RB
Fox Chase Cancer Center, Philadelphia, USA. roger.cohen@fccc.edu
Langer
Corey J
CJ
Simon
George Rajan
GR
Eisenberg
Peter David
PD
Hainsworth
John Daniel
JD
Madajewicz
Stefan
S
Cosgriff
Thomas Michael
TM
Pierce
Kristen
K
Xu
Huiping
H
Liau
Katherine
K
Healey
Diane
D
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005076:Exanthema / Q000139:chemically induced; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006207:Half-Life; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D011379:Prognosis; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome; D014508:Urea / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics
C480540:3-(4-bromo-2,6-difluorobenzyloxy)-5-(3-(4-pyrrolidin-1-ylbutyl)ureido)isothiazole-4-carboxylic acid amide; D013844:Thiazoles; D014508:Urea; D016190:Carboplatin; D017239:Paclitaxel