A phase I study of enzastaurin combined with pemetrexed in advanced non-small cell lung cancer.
BACKGROUND
Enzastaurin is an oral serine/threonine kinase inhibitor, which suppress signaling through protein kinase C-beta and the phosphatidylinositol 3-kinase/AKT pathway. Preclinical studies suggested synergic antitumor activity of enzastaurin and pemetrexed. We conducted this phase I study to evaluate the safety, pharmacokinetics, and clinical activity of this combination in patients with previously treated advanced non-small cell lung cancer.


METHODS
An oral daily dose of 500 mg enzastaurin was administered once daily (QD) or twice daily (BID) in combination with 500 mg/m pemetrexed on day 1 in repeated 21-day cycles. Cycle 1 started with a 7-day enzastaurin lead-in treatment that preceded pemetrexed administration: a loading dose of 1125 mg enzastaurin on day 1 followed by a 500 mg total daily dose on days 2-7.


RESULTS
Twelve patients were treated QD (n = 6) or BID (n = 6). One dose-limiting toxicity (grade 3 QTc prolongation) was reported in the QD cohort. Grade 3/4 hematological toxicities were slightly increased in the BID cohort compared with the QD cohort. After beginning the combination therapy, enzastaurin exposures decreased slightly but remained above the target plasma concentration of 1400 nmol/L. Compared with QD, there was a higher exposure with BID. The enzastaurin dosing regimen (QD or BID) had no effect on pemetrexed pharmacokinetics. Two patients had partial responses as defined by RECIST. Five patients received more than 10 cycles of treatment without disease progression.


CONCLUSIONS
Both schedules of enzastaurin in combination with pemetrexed were well tolerated and clinically active in patients with advanced non-small cell lung cancer.
Tanai
Chiharu
C
National Cancer Center Hospital, Tokyo, Japan. tanai@east.ntt.co.jp
Yamamoto
Nobuyuki
N
Ohe
Yuichiro
Y
Takahashi
Toshiaki
T
Kunitoh
Hideo
H
Murakami
Haruyasu
H
Yamamoto
Noboru
N
Nakamura
Yukiko
Y
Nokihara
Hiroshi
H
Shukuya
Takehito
T
Baldwin
John R
JR
Koshiji
Minori
M
Tamura
Tomohide
T
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D018307:Neoplasms, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D000068437:Pemetrexed; D015996:Survival Rate; D014018:Tissue Distribution; D016896:Treatment Outcome
D005971:Glutamates; D007211:Indoles; D000068437:Pemetrexed; D006147:Guanine; C504878:enzastaurin