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.
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.
Department of Clinical Haematology and BMT, The Royal Melbourne Hospital, Parkville, Vic., Australia.|Division of Cancer and Haematology, The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic., Australia.|Victorian Comprehensive Cancer Centre, Parkville, Vic., Australia.|Faculty of Medicine, University of Melbourne, Parkville, Vic., Australia.
Andrew W
AW
Roberts
Stanford University Medical Center, Stanford, CT, USA.
Ranjana H
RH
Advani
University of Wisconsin, Madison, WI, USA.
Brad S
BS
Kahl
University of Arizona Cancer Center, Tucson, AZ, USA.
Daniel
D
Persky
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
John W
JW
Sweetenham
Victorian Comprehensive Cancer Centre, Parkville, Vic., Australia.|Faculty of Medicine, University of Melbourne, Parkville, Vic., Australia.|Division of Cancer Medicine, Peter MacCallum Cancer Centre, Melbourne, Vic., Australia.
Dennis A
DA
Carney
AbbVie Inc., North Chicago, IL, USA.
Jianning
J
Yang
AbbVie Inc., North Chicago, IL, USA.
Todd B
TB
Busman
AbbVie Inc., North Chicago, IL, USA.
Sari H
SH
Enschede
AbbVie Inc., North Chicago, IL, USA.
Roderick A
RA
Humerickhouse
Victorian Comprehensive Cancer Centre, Parkville, Vic., Australia.|Faculty of Medicine, University of Melbourne, Parkville, Vic., Australia.|Division of Cancer Medicine, Peter MacCallum Cancer Centre, Melbourne, Vic., Australia.
John F
JF
Seymour
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000814:Aniline Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D018951:Antigens, CD20; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000188:drug therapy*; D008224:Lymphoma, Follicular / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D000069283:Rituximab; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
D000814:Aniline Compounds; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; C000595707:BCL2 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D000069283:Rituximab; C528561:navitoclax
B-cell malignancy; BCL2; navitoclax; rituximab