A phase 1 study with dose expansion of the CDK inhibitor dinaciclib (SCH 727965) in combination with epirubicin in patients with metastatic triple negative breast cancer

• DOI: 10.1007/s10637-015-0244-4
• Publication Date: 2015-05-06T07:19:03Z
• Authors: Zahi Mitri; Cansu Karakas; Caimiao Wei; Brian Briones; Holly Simmons; Nuhad Ibrahim; Ricardo Alvarez; James L. Murray; Khandan Keyomarsi; Stacy Moulder
• Keywords: Adult; Antibiotics, Antineoplastic; Maximum Tolerated Dose; Indolizines; Pyridinium Compounds; Triple Negative Breast Neoplasms; Middle Aged; Bridged Bicyclo Compounds, Heterocyclic; Cyclin-Dependent Kinases; 3. Good health; Cyclic N-Oxides; 03 medical and health sciences; Treatment Outcome; 0302 clinical medicine; Antineoplastic Combined Chemotherapy Protocols; Humans; Female; Protein Kinase Inhibitors; Aged; Epirubicin

Low molecular weight cyclin E (LMW-E) isoforms, overexpressed in a majority (~70 %) of triple-negative breast cancers (TNBC), were found in preclinical models to mediate tumorigenesis through binding and activation of CDK2. CDK1/CDK2 inhibitors, such as dinaciclib, combined with anthracyclines, were synergistic in decreasing viability of TNBC cell lines. Based on this data, a phase 1 study was conducted to determine the maximum tolerated dose of dinaciclib in combination with epirubicin in patients with metastatic TNBC.Cohorts of at least 2 patients were treated with escalating doses of dinaciclib given on day 1 followed by standard dose of epirubicin given on day 2 of a 21 day cycle. No intra-patient dose escalation was allowed. An adaptive accrual design based upon toxicity during cycle 1 determined entry into therapy cohorts. The target acceptable dose limiting toxicity (DLT) to advance to the next treatment level was 30 %.Between 9/18/2012 and 7/18/2013, 9 patients were enrolled and treated at MD Anderson Cancer Center. DLTs included febrile neutropenia (grade 3, n = 2), syncope (grade 3, n = 2) and vomiting (grade 3, n = 1). Dose escalation did not proceed past the second cohort due to toxicity. After further accrual, the first dose level was also found to be too toxic. No treatment responses were noted, median time to progression was 5.5 weeks (range 3-12 weeks). Thus, accrual was stopped rather than explore the -1 dose level.The combination of dinaciclib and epirubicin is associated with substantial toxicities and does not appear to be an effective treatment option for TNBC.