Sandrine Aspeslagh1, Kunwar Shailubhai2, Rastilav Bahleda3, Anas Gazzah3, Andréa Varga3, Antoine Hollebecque3, Christophe Massard3, Anna Spreafico4, Michele Reni4, Jean-Charles Soria3. 1. Drug Development Department (DITEP), Gustave Roussy Cancer Centre, Université Paris-Saclay, 114 Rue Eduard Vaillant, 94805, Villejuif, France. sandrine.aspeslagh@gustaveroussy.fr. 2. Tiziana Life Sciences Plc, 55 Park Lane, London, W1K 1NA, UK. 3. Drug Development Department (DITEP), Gustave Roussy Cancer Centre, Université Paris-Saclay, 114 Rue Eduard Vaillant, 94805, Villejuif, France. 4. Department of Medical Oncology, IRCCS Ospedale San Raffaele, Milan, Italy.
Abstract
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.
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 NSCLCpatient 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 cancerpatients.
Entities:
Keywords:
Advanced cancer patient; Cyclin-dependent kinase inhibitors; Gemcitabine; Milciclib
Authors: Jin-Yi Zhu; Rebecca A Cuellar; Norbert Berndt; Hee Eun Lee; Sanne H Olesen; Mathew P Martin; Jeffrey T Jensen; Gunda I Georg; Ernst Schönbrunn Journal: J Med Chem Date: 2017-09-14 Impact factor: 7.446
Authors: Mohammad M Al-Sanea; Ahmad J Obaidullah; Mohamed E Shaker; Garri Chilingaryan; Mohammed M Alanazi; Nawaf A Alsaif; Hamad M Alkahtani; Sultan A Alsubaie; Mohamed A Abdelgawad Journal: Molecules Date: 2021-01-14 Impact factor: 4.411