Phase I study of oral CI-994 in combination with carboplatin and paclitaxel in the treatment of patients with advanced solid tumors.
OBJECTIVE
To determine maximum tolerated dose of CI-994, a novel oral histone deacetylase inhibitor, in combination with carboplatin and paclitaxel in patients with advanced solid tumors.


METHODS
Patients with advanced solid tumors who had received two or fewer prior chemotherapy regimens were eligible for trial. Five cohorts of patients were treated with escalating doses (4-6 mg/m2) and alternative schedules (7 days or 14 days) of CI-994. Dose escalation of paclitaxel was performed to achieve tolerability of CI-994 with a paclitaxel dose of 225 mg/m2 when administered in combination with carboplatin. Pharmacokinetic assessment of CI-994 was performed by using liquid chromatography/mass spectrometry. Histone deacetylation inhibition was determined by Western blot analysis.


RESULTS
A total of 30 patients (median age 58 years) were entered into five treatment cohorts. Maximum tolerated dose of CI-994 was determined to be 4 mg/m2 administered for 7 consecutive days following paclitaxel at a dose of 225 mg/m2 and carboplatin at an area under the curve (AUC) of 6 every 21 days. Neutropenia, thrombocytopenia, and grade 3 respiratory insufficiency limited further dose escalation of CI-994. Pharmacokinetics showed that CI-994 absorption and disposition were unaffected by carboplatin and paclitaxel coadministration. Association between histone H3 acetylation levels and disease response was suggested. A subset of patients with lymphocyte H3 acetylation levels at least 1.5-fold times baseline all achieved either a clinical response or stable disease. All evaluable patients with progressive disease (PD) had H3 acetylation levels <1.5-fold times baseline. Twenty-four of the 30 patients received greater than one cycle of treatment. Five of these patients achieved a partial response (3 nonsmall cell lung cancer, 1 colorectal cancer, and 1 unknown primary) and 2 patients achieved a complete response (esophageal and bladder cancer).


CONCLUSIONS
The combination of CI-994 at a dose of 4 mg/m2 administered orally for 7 consecutive days can be safely coadministered with paclitaxel at a dose of 225 mg/m2 and carboplatin at an AUC of 6 on day 1 of a 21-day cycle. Evidence of antitumor activity is suggested and may correlate with histone modulation.
Pauer
Lynne R
LR
Pfizer Global Research and Development, Ann Arbor, Michigan, USA.
Olivares
Jairo
J
Cunningham
Casey
C
Williams
Adrienne
A
Grove
William
W
Kraker
Alan
A
Olson
Stephen
S
Nemunaitis
John
J
D000107:Acetylation; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000556:secondary; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001549:Benzamides; D016190:Carboplatin / Q000008:administration & dosage; D002851:Chromatography, High Pressure Liquid; D015331:Cohort Studies; D004359:Drug Therapy, Combination; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D010655:Phenylenediamines / Q000008:administration & dosage; D016896:Treatment Outcome
D001549:Benzamides; D006657:Histones; D010655:Phenylenediamines; D016190:Carboplatin; D017239:Paclitaxel; C081895:tacedinaline