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

Claire Fabre, Marco Gobbi, Cyrine Ezzili, Mustapha Zoubir, Marie Paule Sablin, Karen Small, Ellie Im, Nabeegha Shinwari, Da Zhang, Honghong Zhou, Christophe Le Tourneau

Research output: Contribution to journalArticle

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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/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. 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.

Original languageEnglish
Pages (from-to)1057-1064
Number of pages8
JournalCancer Chemotherapy and Pharmacology
Volume74
Issue number5
DOIs
Publication statusPublished - 2014

Fingerprint

Cyclin-Dependent Kinases
B-Cell Chronic Lymphocytic Leukemia
Refractory materials
Pharmacokinetics
Toxicity
Tumor Lysis Syndrome
CDC2 Protein Kinase
Rituximab
Clinical Studies
dinaciclib
Drug-Related Side Effects and Adverse Reactions
Tumors
Pharmaceutical Preparations

Keywords

  • Chronic lymphocytic leukemia
  • Cyclin-dependent kinase
  • Dinaciclib
  • Relapsed/refractory patients
  • Rituximab

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Toxicology
  • Medicine(all)

Cite this

Clinical study of the novel cyclin-dependent kinase inhibitor dinaciclib in combination with rituximab in relapsed/refractory chronic lymphocytic leukemia patients. / Fabre, Claire; Gobbi, Marco; Ezzili, Cyrine; Zoubir, Mustapha; Sablin, Marie Paule; Small, Karen; Im, Ellie; Shinwari, Nabeegha; Zhang, Da; Zhou, Honghong; Le Tourneau, Christophe.

In: Cancer Chemotherapy and Pharmacology, Vol. 74, No. 5, 2014, p. 1057-1064.

Research output: Contribution to journalArticle

Fabre, Claire ; Gobbi, Marco ; Ezzili, Cyrine ; Zoubir, Mustapha ; Sablin, Marie Paule ; Small, Karen ; Im, Ellie ; Shinwari, Nabeegha ; Zhang, Da ; Zhou, Honghong ; Le Tourneau, Christophe. / Clinical study of the novel cyclin-dependent kinase inhibitor dinaciclib in combination with rituximab in relapsed/refractory chronic lymphocytic leukemia patients. In: Cancer Chemotherapy and Pharmacology. 2014 ; Vol. 74, No. 5. pp. 1057-1064.
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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/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. 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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AU - Fabre, Claire

AU - Gobbi, Marco

AU - Ezzili, Cyrine

AU - Zoubir, Mustapha

AU - Sablin, Marie Paule

AU - Small, Karen

AU - Im, Ellie

AU - Shinwari, Nabeegha

AU - Zhang, Da

AU - Zhou, Honghong

AU - Le Tourneau, Christophe

PY - 2014

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N2 - 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/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. 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.

AB - 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/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. 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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KW - Cyclin-dependent kinase

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KW - Relapsed/refractory patients

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