Phase I study of oral CI-994 in combination with gemcitabine in treatment of patients with advanced cancer.
OBJECTIVE
The purpose of this study was to determine the maximum tolerated dose, pharmacokinetic profile, and evidence of antitumor activity of CI-994 used in combination with gemcitabine.


METHODS
This was a dose escalation trial in which gemcitabine (1,000 mg/m2) was given as a 30-minute infusion on days 1, 8, and 15 of a 28-day cycle. CI-994 was taken orally on consecutive days 1-21 at escalating doses of 2, 4, 6, and 8 mg/m2 per cohort (three patients/cohort). Plasma samples were collected on days 1 and 15 of course 1 and analyzed for CI-994 pharmacokinetic assessment.


RESULTS
Twenty patients with advanced cancer received a total of 76 courses of treatment. Dose-limitingtoxicity occurred at the 8-mg/ m2 dose. Four of seven patients experienced thrombocytopenia during the first cycle. Grade 4 thrombocytopenia was observed in three of 10 (30%) courses at 8 mg/m2. In contrast, only two of 28 (7%) courses at 6 mg/m2 were associated with grade 4 thrombocytopenia. Pharmacokinetic analysis indicated that absorption of CI-994 was rapid, with peak plasma concentrations occurring at the first sample 2 hours after dosing. Two patients achieved a minor response, 12 had stable disease (median duration, 105 days), four had progressive disease, and two were not evaluable.


CONCLUSIONS
The 6-mg/m2 dose of CI-994 (p.o. x 21 days) was defined as the maximum tolerated dose that could safely be administered in combination with gemcitabine (1,000 mg/m2 i.v. on days 1, 8, and 15) during a 28-day cycle.
Nemunaitis
John J
JJ
US Oncology, Baylor University Medical Center, Dallas, Texas, USA. John.Nemunaitis@USOncology.com
Orr
Douglas
D
Eager
Rob
R
Cunningham
C Casey
CC
Williams
Adrienne
A
Mennel
Robert
R
Grove
William
W
Olson
Stephen
S
D000284:Administration, Oral; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001549:Benzamides; D003841:Deoxycytidine / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy*; D010655:Phenylenediamines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors; D000093542:Gemcitabine
D001549:Benzamides; D010655:Phenylenediamines; D003841:Deoxycytidine; D012264:Ribonucleotide Reductases; C081895:tacedinaline; D000093542:Gemcitabine