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

• Published in: Investigational new drugs 2015-08, Vol.33 (4), p.890-894
• Main Authors: Mitri, Zahi, Karakas, Cansu, Wei, Caimiao, Briones, Brian, Simmons, Holly, Ibrahim, Nuhad, Alvarez, Ricardo, Murray, James L., Keyomarsi, Khandan, Moulder, Stacy
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antibiotics, Antineoplastic - adverse effects; Antibiotics, Antineoplastic - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis; Binding sites; Breast cancer; Bridged Bicyclo Compounds, Heterocyclic - adverse effects; Bridged Bicyclo Compounds, Heterocyclic - therapeutic use; Cancer therapies; Cell death; Chemotherapy; Clinical trials; Cyclin-Dependent Kinases - antagonists & inhibitors; Drug dosages; Epirubicin - adverse effects; Epirubicin - therapeutic use; Female; Humans; Inhibitor drugs; Maximum Tolerated Dose; Medical prognosis; Medicine; Medicine & Public Health; Metastasis; Middle Aged; Molecular weight; Neutropenia; Oncology; Patients; Pharmacology/Toxicology; Phase I Studies; Phase transitions; Polyclonal antibodies; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - therapeutic use; Pyridinium Compounds - adverse effects; Pyridinium Compounds - therapeutic use; Studies; Toxicity; Treatment Outcome; Triple Negative Breast Neoplasms - drug therapy; Tumors; Vomiting
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-015-0244-4

Summary Purpose , 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. Methods , 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 %. Results , 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. Conclusion , The combination of dinaciclib and epirubicin is associated with substantial toxicities and does not appear to be an effective treatment option for TNBC.