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

Andrew W. Roberts, Ranjana H. Advani, Brad S. Kahl, Daniel Persky, John W. Sweetenham, Dennis A. Carney, Jianning Yang, Todd B. Busman, Sari H. Enschede, Roderick A. Humerickhouse, John F. Seymour

Research output: Contribution to journalArticle

50 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)669-678
Number of pages10
JournalBritish Journal of Haematology
Volume170
Issue number5
DOIs
StatePublished - Sep 1 2015
Externally publishedYes

Keywords

  • B-cell malignancy
  • BCL2
  • Navitoclax
  • Rituximab

ASJC Scopus subject areas

  • Hematology

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