Clinical study of the novel cyclin-dependent kinase inhibitor dinaciclib in combination with rituximab in relapsed/refractory chronic lymphocytic leukemia patients

Autor: Christophe Le Tourneau, Karen Small, Marie Paule Sablin, Marco Gobbi, Da Zhang, Cyrine Ezzili, Claire Fabre, Honghong Zhou, Ellie Im, Nabeegha Shinwari, Mustapha Zoubir
Jazyk: angličtina
Rok vydání: 2014
Předmět:
Oncology
Diarrhea
Male
Cancer Research
medicine.medical_specialty
Metabolic Clearance Rate
Chronic lymphocytic leukemia
Pyridinium Compounds
Toxicology
Drug Administration Schedule
Cyclic N-Oxides
chemistry.chemical_compound
Antibodies
Monoclonal
Murine-Derived
Pharmacokinetics
hemic and lymphatic diseases
Internal medicine
Antineoplastic Combined Chemotherapy Protocols
Medicine
Humans
Pharmacology (medical)
Dinaciclib
Adverse effect
Aged
Pharmacology
business.industry
Indolizines
Anemia
Middle Aged
medicine.disease
Bridged Bicyclo Compounds
Heterocyclic
Leukemia
Lymphocytic
Chronic
B-Cell
Cyclin-Dependent Kinases
LLC dinaciclib
Tumor lysis syndrome
Leukemia
Treatment Outcome
chemistry
Drug Resistance
Neoplasm
Area Under Curve
Asthenia
Rituximab
Administration
Intravenous
Female
Refractory Chronic Lymphocytic Leukemia
Neoplasm Recurrence
Local
business
medicine.drug
Popis: 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. 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/m2 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. 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. Limited data from this study shows dinaciclib in combination with rituximab was well tolerated and revealed encouraging clinical activity in relapsed/refractory CLL patients.
Databáze: OpenAIRE
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