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

Background: 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. Design: 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. Results: 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. Conclusion: 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.