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Phase 1 study of the safety, pharmacokinetics, and antitumour activity of the BCL2 inhibitor navitoclax in combination with rituximab in patients with relapsed or refractory CD20+ lymphoid malignancies.
- Source :
- British Journal of Haematology; Sep2015, Vol. 170 Issue 5, p669-678, 10p, 1 Diagram, 4 Charts, 1 Graph
- Publication Year :
- 2015
-
Abstract
- The oral BCL2 inhibitor navitoclax has moderate single-agent efficacy in chronic lymphocytic leukaemia ( CLL) and minor activity in lymphoma in Phase 1 trials. Navitoclax synergizes with rituximab in preclinical models of B-cell lymphoid cancers. We report the safety, pharmacokinetics and clinical activity of this combination. Patients received navitoclax (200-325 mg) daily and four standard weekly doses of rituximab. Twenty-nine patients were enrolled across three dose-escalation cohorts and a safety expansion cohort (250 mg/d navitoclax). The combination was well tolerated. Common toxicities were mild diarrhoea (79%) and nausea (72%). Grade 4 thrombocytopenia occurred in 17% of patients (dose limiting at 325 mg/d). CD19<superscript>+</superscript> counts were severely reduced, while CD3<superscript>+</superscript> cells ( ~ 20%) and serum immunoglobulin M levels ( ~ 33%) were also reduced during the first year. The maximum tolerated dose for navitoclax in combination was 250 mg/d. Pharmacokinetic analyses revealed no apparent interactions between the drugs. The response rate in patients with follicular lymphoma was 9/12, including five complete responses. All five patients with CLL/small lymphocytic leukaemia achieved partial responses. One of nine patients with aggressive lymphoma responded. The addition of rituximab to navitoclax 250 mg/d is safe; the combination demonstrates higher response rates for low-grade lymphoid cancers than observed for either agent alone in previous Phase 1 trials. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00071048
- Volume :
- 170
- Issue :
- 5
- Database :
- Complementary Index
- Journal :
- British Journal of Haematology
- Publication Type :
- Academic Journal
- Accession number :
- 108813699
- Full Text :
- https://doi.org/10.1111/bjh.13487