Phase I dose-escalation study of milciclib in combination with gemcitabine in patients with refractory solid tumors

This phase I trial evaluated the safety and tolerability of milciclib, an inhibitor of multiple cyclin-dependent kinases and tropomycin receptor kinase A, in combination with gemcitabine in patients with refractory solid tumors.

Sixteen patients were enrolled and treated with milciclib at three dose levels (45 mg/m²/day, n = 3; 60 mg/m²/day, n = 3; and 80 mg/m²/day, n = 10) with a fixed dose of gemcitabine (1000 mg/m²/day). Milciclib was administered orally once daily for 7 days on/7 days off in a 4-week cycle, and gemcitabine was administered intravenously on days 1, 8 and 15 in a 4-week cycle.

All 16 enrolled patients were evaluable for safety and toxicity. Dose-limiting toxicities, which occurred in only one out of nine patients treated at the maximum dose tested (milciclib 80 mg/m²/day and gemcitabine 1000 mg/m²/day), consisted of Grade 4 thrombocytopenia, Grade 3 ataxia and Grade 2 tremors in the same patient. Most frequent treatment-related AEs were neutropenia and thrombocytopenia. Among 14 evaluable patients, one NSCLC patient showed partial response and 4 patients (one each with thyroid, prostatic, pancreatic carcinoma and peritoneal mesothelioma) showed long-term disease stabilization (>6-14 months). Pharmacokinetics of the orally administered milciclib (~t1/2 33 h) was not altered by concomitant treatment with gemcitabine.

The combination treatment was well tolerated with manageable toxicities. The recommended phase II dose was 80 mg/m²/day for milciclib and 1000 mg/m²/day for gemcitabine. This combination treatment regimen showed encouraging clinical benefit in ~36% patients, including gemcitabine refractory patients. These results support further development of combination therapies with milciclib in advanced cancer patients.