title: Clinical study of the novel cyclin-dependent kinase inhibitor dinaciclib in combination with rituximab in relapsed/refractory chronic lymphocytic leukemia patients.
abstract: OBJECTIVE
  Dinaciclib is a novel selective inhibitor of cyclin-dependent kinase (CDK)1, CDK2, CDK5, and CDK9. We conducted a phase I study to investigate the effects of dinaciclib when administered with rituximab.
  
  
  METHODS
  In this phase I nonrandomized dose-escalation 3 + 3 trial, patients with relapsed/refractory chronic lymphocytic leukemia (CLL) were treated with dinaciclib and rituximab. Dinaciclib was administered intravenously (IV) over 2 h on days 1, 8 and 15 in cycles 2-13 (28-day cycles). Rituximab 375 mg/m(2) was administered IV on days 1, 8, 15 and 22 in cycle 1 (28-day cycle) and on day 1 during cycle 3-13. Rituximab was not administered in cycle 2. Rituximab and dinaciclib were given alone in cycles 1 and 2, respectively, and in combination in cycles 3-13. Primary objectives included determination of the recommended phase II dose of dinaciclib and evaluation of pharmacokinetics (PK) when administered with rituximab.
  
  
  RESULTS
  Five patients completed the study due to early termination. All presented with drug-related adverse events (AEs), but no dose-limiting toxicities were observed. The most commonly observed toxicities included hematological, digestive and metabolic AEs. However, no tumor lysis syndrome has been reported in the study. Four patients achieved stable disease, and one patient achieved complete response according to 2008 iwCLL criteria at cycle 3. PK samples were collected from 5 patients, and no obvious interaction between dinaciclib and rituximab was observed.
  
  
  CONCLUSIONS
  Limited data from this study shows dinaciclib in combination with rituximab was well tolerated and revealed encouraging clinical activity in relapsed/refractory CLL patients.
authors.affiliation: Department of Medical Oncology, Institut Curie, 26 Rue d'Ulm, 75005, Paris, France, fabre-claire@wanadoo.fr.
authors.forename: Claire
authors.initials: C
authors.lastname: Fabre
authors.forename: Marco
authors.initials: M
authors.lastname: Gobbi
authors.forename: Cyrine
authors.initials: C
authors.lastname: Ezzili
authors.forename: Mustapha
authors.initials: M
authors.lastname: Zoubir
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Sablin
authors.forename: Karen
authors.initials: K
authors.lastname: Small
authors.forename: Ellie
authors.initials: E
authors.lastname: Im
authors.forename: Nabeegha
authors.initials: N
authors.lastname: Shinwari
authors.forename: Da
authors.initials: D
authors.lastname: Zhang
authors.forename: Honghong
authors.initials: H
authors.lastname: Zhou
authors.forename: Christophe
authors.initials: C
authors.lastname: Le Tourneau
mesh_terms: D061605:Administration, Intravenous; D000368:Aged; D000740:Anemia / Q000139:chemically induced; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D001247:Asthenia / Q000139:chemically induced; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D003497:Cyclic N-Oxides; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003967:Diarrhea / Q000139:chemically induced; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007212:Indolizines; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011726:Pyridinium Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000069283:Rituximab; D016896:Treatment Outcome
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003497:Cyclic N-Oxides; D007212:Indolizines; D011726:Pyridinium Compounds; D000069283:Rituximab; C553669:dinaciclib; D018844:Cyclin-Dependent Kinases