| Abstract |
Purpose: 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.
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| MeSH term(s) |
Administration, Intravenous ; Aged ; Anemia/chemically induced ; Antibodies, Monoclonal, Murine-Derived/administration & dosage ; Antibodies, Monoclonal, Murine-Derived/adverse effects ; Antibodies, Monoclonal, Murine-Derived/pharmacokinetics ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Area Under Curve ; Asthenia/chemically induced ; Bridged Bicyclo Compounds, Heterocyclic/administration & dosage ; Bridged Bicyclo Compounds, Heterocyclic/adverse effects ; Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics ; Cyclin-Dependent Kinases/antagonists & inhibitors ; Cyclin-Dependent Kinases/metabolism ; Diarrhea/chemically induced ; Drug Administration Schedule ; Drug Resistance, Neoplasm ; Female ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy ; Leukemia, Lymphocytic, Chronic, B-Cell/metabolism ; Leukemia, Lymphocytic, Chronic, B-Cell/pathology ; Male ; Metabolic Clearance Rate ; Middle Aged ; Neoplasm Recurrence, Local ; Pyridinium Compounds/administration & dosage ; Pyridinium Compounds/adverse effects ; Pyridinium Compounds/pharmacokinetics ; Rituximab ; Treatment Outcome |
| Chemical Substances |
Antibodies, Monoclonal, Murine-Derived ; Bridged Bicyclo Compounds, Heterocyclic ; Pyridinium Compounds ; Rituximab (4F4X42SYQ6) ; dinaciclib (4V8ECV0NBQ) ; Cyclin-Dependent Kinases (EC 2.7.11.22) |
| Language |
English |
| Publishing date |
2014-11 |
| Publishing country |
Germany |
| Document type |
Clinical Trial, Phase I ; Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID |
6820-2 |
| ISSN |
1432-0843 ; 0344-5704 ; 0943-9404 |
| ISSN (online) |
1432-0843 |
| ISSN |
0344-5704 ; 0943-9404 |
| DOI |
10.1007/s00280-014-2583-9 |
| Database |
MEDical Literature Analysis and Retrieval System OnLINE |
