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Published on: February 12, 2017
A phase I study of enzastaurin combined with pemetrexed in advanced non-small cell lung cancer
Chiharu Tanai1, Nobuyuki Yamamoto, Yuichiro Ohe
1National Cancer Center Hospital, Tokyo, Japan. tanai@east.ntt.co.jp
Introduction:
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.
Insights
This Phase I study found that enzastaurin plus pemetrexed is safe and effective for advanced non-small cell lung cancer. Both once-daily and twice-daily enzastaurin showed clinical activity in patients.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Enzastaurin is an oral kinase inhibitor targeting PKC-beta and PI3K/AKT pathways.
- Preclinical data suggested a synergistic effect between enzastaurin and pemetrexed.
- This study investigated the combination in advanced non-small cell lung cancer (NSCLC).
Purpose of the Study:
- Evaluate the safety and pharmacokinetics of enzastaurin combined with pemetrexed.
- Assess the clinical activity of this combination in previously treated advanced NSCLC patients.
Main Methods:
- Phase I clinical trial design.
- Patients received oral enzastaurin (500 mg QD or BID) with pemetrexed (500 mg/m² on day 1) in 21-day cycles.
- A 7-day enzastaurin lead-in was administered before pemetrexed in Cycle 1.
Main Results:
- Twelve patients were treated (6 QD, 6 BID).
- One dose-limiting toxicity (Grade 3 QTc prolongation) occurred in the QD cohort.
- Partial responses were observed, and 5 patients had prolonged treatment (>10 cycles) without progression.
- Enzastaurin exposure was higher with BID dosing but both regimens maintained target concentrations.
Conclusions:
- Both enzastaurin dosing schedules (QD and BID) combined with pemetrexed were well-tolerated.
- The combination demonstrated clinical activity in advanced non-small cell lung cancer patients.
