The combination of MTX-HSA with cisplatin is feasible and shows antitumor activity against urothelial carcinomas combined with an acceptable toxicity profile.

Pemetrexed plus enzastaurin is well tolerated with preliminary evidence of anticancer activity, particularly in thyroid cancer.

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]

The objectives of this phase I study were to determine the maximum tolerated dose (MTD), recommended phase II dose (RD), antitumor activity, safety, and pharmacokinetics of pemetrexed-paclitaxel combination. Patients (N = 95) with advanced solid tumors were assigned to three schedules (21-day cycles [q21d]). Starting doses for each schedule of pemetrexed and paclitaxel, respectively, were: (S1) 400 and 135 mg/m(2) on d1; (S2) 400 mg/m(2) d1 and 40 mg/m(2) d1 and d8; S3) 400 mg/m(2) d8 and 30 mg/m(2) d1 and d8. MTD was 500/135 mg/m(2) (S1), 400/40 mg/m(2) (S2), and 500/120 mg/m(2) (S3). Most common dose limiting toxicities were febrile neutropenia, fatigue, and neuromotor toxicities. Most common toxicity was grade 3/4 lymphopenia. Four patients had partial response, 43 patients had stable disease. The RD determined was pemetrexed 500 mg/m(2) (d8) and paclitaxel 90 mg/m(2) (d1 and d8), q21d. The combination was well tolerated and showed efficacy in thyroid carcinoma and mesothelioma.

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