title: 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.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  The combination of dinaciclib and epirubicin is associated with substantial toxicities and does not appear to be an effective treatment option for TNBC.
authors.affiliation: Department of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Zahi
authors.initials: Z
authors.lastname: Mitri
authors.forename: Cansu
authors.initials: C
authors.lastname: Karakas
authors.forename: Caimiao
authors.initials: C
authors.lastname: Wei
authors.forename: Brian
authors.initials: B
authors.lastname: Briones
authors.forename: Holly
authors.initials: H
authors.lastname: Simmons
authors.forename: Nuhad
authors.initials: N
authors.lastname: Ibrahim
authors.forename: Ricardo
authors.initials: R
authors.lastname: Alvarez
authors.forename: James L
authors.initials: JL
authors.lastname: Murray
authors.forename: Khandan
authors.initials: K
authors.lastname: Keyomarsi
authors.forename: Stacy
authors.initials: S
authors.lastname: Moulder
mesh_terms: D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000009:adverse effects / Q000627:therapeutic use*; D003497:Cyclic N-Oxides; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D015251:Epirubicin / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007212:Indolizines; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011726:Pyridinium Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy*
chemical_list: D000903:Antibiotics, Antineoplastic; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003497:Cyclic N-Oxides; D007212:Indolizines; D047428:Protein Kinase Inhibitors; D011726:Pyridinium Compounds; D015251:Epirubicin; C553669:dinaciclib; D018844:Cyclin-Dependent Kinases