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|Ref Type||Journal Article|
|Authors||Aspeslagh S, Shailubhai K, Bahleda R, Gazzah A, Varga A, Hollebecque A, Massard C, Spreafico A, Reni M, Soria JC|
|Title||Phase I dose-escalation study of milciclib in combination with gemcitabine in patients with refractory solid tumors.|
|Journal||Cancer chemotherapy and pharmacology|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Milciclib||PHA-848125AC|PHA-848125|PHA 848125||CDK1 Inhibitor 13 CDK2 Inhibitor 19 CDK4 Inhibitor 12 CDK5 Inhibitor 7 CDK7 Inhibitor 13 TrkA Receptor Inhibitor 8||Milciclib (PHA-848125AC) is a TRKA inhibitor with additional activity against CDK1, CDK2, CDK4, CDK5, and CDK7, potentially resulting in decreased tumor cell growth (PMID: 22160853, PMID: 28424962).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||lung non-small cell carcinoma||not applicable||Gemcitabine + Milciclib||Phase I||Actionable||In a Phase I trial, the combination therapy of Gemzar (gemcitabine) and Milciclib (PHA-848125AC) resulted in a clinical benefit in 36% (5/14) of patients with an advanced solid tumor, including long-term stable disease (6-14 months) in four patients and a partial response in a patient with non-small cell lung carcinoma (PMID: 28424962).||28424962|
|Unknown unknown||Advanced Solid Tumor||not applicable||Gemcitabine + Milciclib||Phase I||Actionable||In a Phase I trial, the combination therapy of Gemzar (gemcitabine) and Milciclib (PHA-848125AC) resulted in a clinical benefit in 36% (5/14) of patients with an advanced solid tumor, including long-term stable disease (6-14 months) in four patients and a partial response in a patient with non-small cell lung carcinoma (PMID: 28424962).||28424962|