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
- Author(s)
- Roberts, AW; Advani, RH; Kahl, BS; Persky, D; Sweetenham, JW; Carney, DA; Yang, J; Busman, TB; Enschede, SH; Humerickhouse, RA; Seymour, JF;
- Journal Title
- Br J Haematol
- Publication Type
- Journal Article
- 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+ counts were severely reduced, while CD3+ 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.
- Publisher
- Wiley
- Research Division(s)
- Cancer And Haematology
- PubMed ID
- 25942994
- Link To PubMed Central Version
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4534314/
- Publisher's Version
- https://doi.org/10.1111/bjh.13487
- NHMRC Grants
- NHMRC/637309, NHMRC/1016647, NHMRC/461219,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2015-05-22 11:19:38
Last Modified: 2019-02-05 01:37:53