Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity
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Background Proteins of the BCL-2 family regulate clonal selection and survival of lymphocytes, and are frequently overexpressed in lymphomas. Navitoclax is a targeted high-affinity small molecule that inhibits the anti-apoptotic activity of BCL-2 and BCL-XL. We aimed to assess the safety and antitumour activity of navitoclax in patients with lymphoid tumours, and establish the drug's pharmacokinetic and pharmacodynamic profiles.Methods In this phase 1 dose-escalation study, patients (aged ≥18 years) with relapsed or refractory lymphoid malignancies were enrolled and treated at seven sites in the USA between November, 2006, and November, 2009. A modified Fibonacci 3+3 design was used to assign patients to receive oral navitoclax once daily by one of two dosing schedules: intermittently for the first 14 days of a 21-day cycle (14/21) at doses of 10, 20, 40, 80, 110, 160, 225, 315, or 440 mg/day; or continuously for 21 days of a 21-day cycle (21/21) at doses of 200, 275, 325, or 425 mg/day. Study endpoints were safety, maximum tolerated dose, pharmacokinetic profile, pharmacodynamic effects on platelets and T cells, and antitumour activity. This trial is registered with ClinicalTrials.gov, number NCT00406809.Findings 55 patients were enrolled (median age 59 years, IQR 51-67), 38 to receive the 14/21 dosing schedule, and 17 to receive the 21/21 dosing schedule. Common toxic effects included grade 1 or 2 anaemia (41 patients), infection (39), diarrhoea (31), nausea (29), and fatigue (21); and grade 3 or 4 thrombocytopenia (29), lymphocytopenia (18), and neutropenia (18). On the intermittent 14/21 schedule, dose-limiting toxic effects were hospital admissions for bronchitis (one) and pleural effusion (one), grade 3 increase in aminotransferases (one), grade 4 thrombocytopenia (one), and grade 3 cardiac arrhythmia (one). To reduce platelet nadir associated with intermittent 14/21 dosing, we assessed a 150 mg/day lead-in dose followed by a continuous 21/21 dosing schedule. On the 21/21 dosing schedule, two patients did not complete the first cycle and were excluded from assessment of dose-limiting toxic effects; dose-limiting toxic effects were grade 4 thrombocytopenia (one), grade 3 increase in aminotransferases (one), and grade 3 gastrointestinal bleeding (one). Navitoclax showed a pharmacodynamic effect on circulating platelets and T cells. Clinical responses occurred across the range of doses and in several tumour types. Ten of 46 patients with assessable disease had a partial response, and these responders had median progression-free survival of 455 days (IQR 40-218).Interpretation Navitoclax has a novel mechanism of peripheral thrombocytopenia and T-cell lymphopenia, attributable to high-affinity inhibition of BCL-XL and BCL-2, respectively. On the basis of these findings, a 150 mg 7-day lead-in dose followed by a 325 mg dose administered on a continuous 21/21 dosing schedule was selected for phase 2 study.Funding Abbott Laboratories, Genentech, and National Cancer Institute, National Institutes of Health.
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Drugs with single or limited targets, such as Nutlin3a or navitoclax, can cause off-target apoptosis in multiple nonsenescent cell types, such as neutrophils and platelets with navitoclax, making them panolytic.
“Drugs with single or limited targets, such as Nutlin3a (an MDM2 inhibitor) or navitoclax (a BCL-2 inhibitor), can have off-target apoptotic effects on multiple non-Snc types, such as neutrophils and platelets in the case of navitoclax (75), making them panolytic.”
From Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span (2021) · cites this paper as [75]
The Discussion describes navitoclax’s effects on platelets as consistent with an on-target BCL-XL mechanism, not off-target apoptosis. It reports neutropenia but says only that it could result from BCL-2 inhibition; it does not establish apoptosis of neutrophils. The Research in Context interpretation likewise calls platelet and T-cell death targeted effects. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredABT-263 can cause thrombocytopenia and neutropenia even after brief exposure.
“N can cause thrombocytopenia and neutropenia, even after brief exposures57,88–91”
From Cellular senescence and senolytics: the path to the clinic (2022) · cites this paper as [89]
The Results (Patients and Toxicity; page unavailable) report both thrombocytopenia and neutropenia during navitoclax treatment. The Results (Pharmacodynamic Effects; page unavailable) describe a platelet decline after a single dose, supporting the brief-exposure qualifier for thrombocytopenia. Neutropenia, however, tended to occur in later treatment cycles, so the paper does not support that qualifier for both toxicities. (LLM, conf=0.89)
Experimental — accuracy not yet measuredTrials assessing navitoclax as an anticancer agent report neutropenia and thrombocytopenia.
“Trials assessing navitoclax as an anticancer agent report neutropenia and thrombocytopenia (Wilson et al. 2010).”
From Senescence and the SASP: many therapeutic avenues (2020) · cites this paper as Wilson et al. 2010
Chronic administration of at least some senolytics in humans can be associated with toxic side effects.
“However, chronic administration of at least some senolytics in humans can be associated with toxic side effects (Kaefer et al., 2014; Wilson et al., 2010) which may be due to off-target killing of non-senescent cells.”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Wilson et al., 2010
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“Number (N) 67 42 3 14 8 Age, y, median (range) 68 (20-87) 68 (20-87) 62 (54-73) 62 (47-74) 70 (65-78) Prior therapies, median (range) 3 (1-12) 3 (1-12) 2 (1-3) 4 (2-8) 4 (1-7) F-refractory, n (n/N%) 33 (49) 16 (38) 2 (67) 8 (57) 7 (88) Bulky disease, n (n/N%) 32 (48) 16 (38) 1 (33) 10 (71) 5 (63) Venetoclax ,400 mg/d,…”
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- Authors
- Wilson, W. H., O'Connor, O. A., Czuczman, M. S., LaCasce, A. S., Gerecitano, J. F., Leonard, J. P., Tulpule, A., Dunleavy, K., Xiong, H., Chiu, Y.-L., Cui, Y., Busman, T., Elmore, S. W., Rosenberg, S. H., Krivoshik, A. P., Enschede, S. H., & Humerickhouse, R. A.
- Affiliations
- National Institutes of Health (US)
- Roswell Park Comprehensive Cancer Center (US)
- Dana-Farber Cancer Institute (US)
- Memorial Sloan Kettering Cancer Center (US)
- Cornell University (US)
- University of Southern California (US)
- Abbott (United States) (US)
- Corresponding author
- Wilson, Wyndham H
- ORCID
- Venue
- The Lancet Oncology
- Publisher
- Elsevier BV
- Published
- 2010-12
- Volume
- 11
- Issue
- 12
- Pages
- 1149-1159
- ISSN
- 1470-2045 (ISSN-L)
- PMC
- PMC3025495
- OpenAlex
- W2150680216
- Cited by
- 876
- References
- 47
- Citations by year
- 2026: 44 · 2025: 58 · 2024: 66 · 2023: 49 · 2022: 66 · 2021: 69 · 2020: 70 · 2019: 43 · 2018: 42 · 2017: 53 · 2016: 52 · 2015: 63 · 2014: 60 · 2013: 55 · 2012: 50
- FWCI
- 18.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Lancet Oncology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Abbott Fund
- Abbott Laboratories
- National Institutes of Health
- National Cancer Institute (ZIABC010716)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Keywords
- navitoclax, BCL-2 inhibitor, Bcl-xL, lymphoid malignancies, relapsed/refractory lymphoma, dose-limiting toxicity, thrombocytopenia, neutropenia, anemia, pharmacokinetics, pharmacodynamics, T cell proliferation, platelet function, antitumour activity, intermittent dosing
- MeSH terms
- Aged, Aniline Compounds, Antineoplastic Agents, Blood Platelets, Dosage Forms, Humans, Lymphoma, Middle Aged, Sulfonamides, T-Lymphocytes, Survival Analysis, Drug Delivery Systems, Proto-Oncogene Proteins c-bcl-2, Maximum Tolerated Dose
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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