Pharmacokinetic interaction and safety of enzastaurin and pemetrexed in patients with advanced or metastatic cancer

Abstract

2047 Background: Enzastaurin, an orally administered potent PKC inhibitor, is an anti-angiogenic agent that also suppresses PI3K/AKT to inhibit tumor cell proliferation and induce tumor cell death. Preclinical data suggest that the combination of enzastaurin and pemetrexed (Alimta) produced additive or synergistic antitumor activity in tumor specimens. This phase 1b study evaluated the safety, pharmacokinetic (PK) interaction, and antitumor activity of enzastaurin when combined with pemetrexed. Methods: Patients (pts) with advanced or metastatic cancer and an ECOG status of 0–2 received an intravenous dose of 500 mg/m2 pemetrexed on day 1 and an oral dose of 500 mg enzastaurin once daily, (after day 4 in cycle 1) in repeat 21-day cycles for up to 6 cycles. In cycle 1, a loading dose of 1200 mg enzastaurin (400 mg/3×/day) was given on day 4. Pts were also given oral folic acid daily and vitamin B12 every 9 weeks for the duration of pemetrexed therapy, and 5–7 days before cycle 1. Results: Blood samples for PK analysis of enzastaurin (n = 21) were collected on day 21 of cycle 1 and day 1 of cycle 2, and for analysis of pemetrexed (n = 22) on day 1 of cycle 1 and cycle 2. Steady-state concentration [geometric mean (%CV)] of total analytes (enzastaurin and its metabolites) was 1270 nM (126%) when administered alone and 1130 nM (100%) when administered with pemetrexed. Thus, no significant differences in exposures were observed when combined with pemetrexed. Clearance of pemetrexed was the same when dosed either with enzastaurin (2.48 L/h/m2) or as a single agent (2.62 L/h/m2). Safety data from the first 2 cycles are consistent with the known toxicity profile of pemetrexed. No grade 3 or 4 toxicity was reported following the loading dose of 1200 mg enzastaurin. Conclusions: Preliminary data suggest that there is no significant PK interaction between enzastaurin and pemetrexed, and that the combination is well tolerated. The current study is ongoing and subsequent analyses will document tumor responses and safety for longer-term treatment of enzastaurin combined with pemetrexed. This first PK study of enzastaurin and pemetrexed will help determine if enzastaurin has an additive clinical benefit to pemetrexed treatment and support future studies in NSCLC and mesothelioma. [Table: see text]

Enzastaurin, an Oral Serine/Threonine Kinase Inhibitor, As Second- or Third-Line Therapy of Non–Small-Cell Lung Cancer

“…46 Therefore, clinical trials evaluating enzastaurin in combination with other cytotoxic agents are currently being pursued, especially because enzastaurin does not add to the toxicity of cytotoxic agents. [47][48][49] In conclusion, this phase II study of single-agent enzastaurin as second-or third-line therapy in patients with metastatic NSCLC has shown disease stabilization for 6 months in 13% of patients and prolonged stabilization ranging from 7 to 20 months in six of 55 patients. Future single-agent enzastaurin trials should focus on the identification of potential markers to tailor enzastaurin treatment.…”

A Phase I Study of Enzastaurin Combined with Pemetrexed in Advanced Non-small Cell Lung Cancer

“…13,14,20,31 The synergic antitumor activity of enzastaurin and pemetrexed combination was shown in NSCLC cell lines, 18 -20 and previous combination studies of enzastaurin with cytotoxic agents showed neither increased toxicity nor PK drug-drug interactions. 15,16,31,32 Therefore, in this study, we decided to assess safety of the recommended clinical doses of enzastaurin and pemetrexed (enzastaurin 500 mg/d and pemetrexed 500 mg/m 2 ).…”

“…33 The PK results of this study indicated no significant PK interaction between enzastaurin and pemetrexed, which was consistent with a previously published phase I study report. 32 One possible reason for the absence of any effect on pharmacokinetics was the different pathways used for elimination. Pemetrexed is renally eliminated, whereas a phase I study using [ 14 C] enzastaurin indicated that enzastaurin undergoes extensive hepatic metabolism with minimal renal elimination (Eli Lilly and Company, Internal Clinical Study Report, October 2006).…”