Reference Detail

Ref Type

Journal Article

PMID

(28424962)

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	Vol	Issue	Date	Pages	Journal Short Title
Cancer chemotherapy and pharmacology	79	6	2017 Jun	1257-1265	Cancer Chemother Pharmacol

URL

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Milciclib	Milciclib	1	2

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Milciclib		PHA-848125AC\|PHA-848125\|PHA 848125	CDK1 Inhibitor 13 CDK2 Inhibitor 30 CDK4 Inhibitor 17 CDK5 Inhibitor 8 CDK7 Inhibitor 16 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