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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
Open accessAbstract
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 (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]
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“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]
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“these agents exhibited notable drawbacks, such as dose-dependent thrombocytopenia, variable therapeutic efficacy, and the emergence of resistance mechanisms.”
From Emerging strategies in senotherapeutics: from broad-spectrum senolysis to precision reprogramming (2026) · cites this paper as [33]
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“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
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“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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“In oncology trials, 44–50% of patients experienced grade 3 or 4 thrombocytopenia33,34.”
From Emerging strategies in senotherapeutics: from broad-spectrum senolysis to precision reprogramming (2026) · cites this paper as [33]
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Selective Bcl-2 inhibition to treat chronic lymphocytic leukemia and non-Hodgkin lymphoma.
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BCL-2 Inhibitors, Present and Future
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Bcl‑2 family: Novel insight into individualized therapy for ovarian cancer (Review)
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Joly, F., Fabbro, M., Follana, P., Lequesne, J., Médioni, J., Lesoin, A., Frenel, J., Abadie‐Lacourtoisie, S., Floquet, A., Gladieff, L., et al. (2022) · Gynecologic Oncology · doi:10.1016/j.ygyno.2022.01.021 · Cited by 35
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“Furthermore, neutropenia was previously recorded in heavily pretreated patients with CLL or non-Hodgkin lymphoma in navitoclax trials (Wilson et al., 2010; Roberts et al., 2012) and may be a class effect of BCL-2–inhibiting drugs (Leverson et al., 2015).”
BackgroundAirway Epithelium Senescence as a Driving Mechanism in COPD Pathogenesis
Bateman, G., Guo-Parke, H., Rodgers, A. M., Linden, D. A., Bailey, M., Weldon, S., Kidney, J. C., & Taggart, C. C. (2023) · Biomedicines · doi:10.3390/biomedicines11072072 · Cited by 39
“In a previous phase I dose-escalation study in patients with lymphoid malignancies, hematological toxicities such as thrombocytopenia and, less commonly, neutropenia were reported as platelet survival is dependent on the BCL pathway [91].”
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“The oral analogue of ABT-737 (ABT-263, Navitoclax) has now entered phase I/II clinical trials [63,64].”
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“…to mimic the pro-apoptotic function of BH3-only proteins are well-advanced in clinical trials as anti-cancer agents, the analysis of the physiological roles of BH3-only proteins in HSPCs is important to understand effects of these drugs on tissues with a high cellular turnover (Wilson et al, 2010).”
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Novel and emerging targeted-based cancer therapy agents and methods
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“Significant clinical benefit has been demonstrated in chronic lymphocytic leukemia (CLL) patients [15].”
BackgroundClinical candidates modulating protein-protein interactions: The fragment-based experience
Valenti, D., Hristeva, S., Tzalis, D., & Ottmann, C. (2019) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2019.01.084 · Cited by 32
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“ABT263 has been investigated in clinical trials for the treatment of lymphoid malignancies or small cell lung cancer (Kipps et al., 2015; Roberts et al., 2015; Rudin et al., 2012; Tolcher et al., 2015; Wilson et al., 2010).”
BackgroundNon-Alloimmune Mechanisms of Thrombocytopenia and Refractoriness to Platelet Transfusion
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“263, also developed dose-limiting thrombocytopenia [61,62].”
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Rational combination of dual PI3K/mTOR blockade and Bcl-2/-xL inhibition in AML
Vachhani, P. J., Bose, P., Rahmani, M., & Grant, S. (2014) · Physiological Genomics · doi:10.1152/physiolgenomics.00173.2013 · Cited by 34
Reactive Oxygen Species and Oncoprotein Signaling-A Dangerous Liaison
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“The current drug candidates arise from the oncology therapeutic armamentarium and include inhibitors of the Bcl2 family of anti-apoptotic proteins and tyrosine kinases; used chronically, these drugs generate side effects (Caldemeyer et al. 2016; Wilson et al. 2010).”
Rational Combinations of Targeted Agents in AML
Bose, P., & Grant, S. (2015) · Journal of Clinical Medicine · doi:10.3390/jcm4040634 · Cited by 30
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“Plasticity of the protein surface allows recognition of diverse chemical scaffolds There have been dozens of reported inhibitors of Bcl-2 family members (18, 19, 97-115), spanning a broad range of chemotypes.”
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Anti-apoptotic BCL2L2 increases megakaryocyte proplatelet formation in cultures of human cord blood
Bhatlekar, S., Basak, I., Edelstein, L. C., Campbell, R. A., Lindsey, C. R., Italiano, J. E., Weyrich, A. S., Rowley, J. W., Rondina, M. T., Sola-Visner, M. C., et al. (2019) · Haematologica · doi:10.3324/haematol.2018.204685 · Cited by 30
“Secondly, promotion of apoptosis by inhibiting of Bcl-2 family members is under investigation for the treatment of a variety of malignancies;(41-43) a limiting toxicity has been thrombocytopenia.(42,43) Bcl-2 family members, MCL1 and BCL2L1 are the most frequently amplified in 26 tumor types,(44,45) whereas BCL2L2 amp…”
BackgroundFrom Apoptosis to Necroptosis: The Death Wishes to Cancer
Meng, X., Dang, T., & Chai, J. (2021) · Cancer Control · doi:10.1177/10732748211066311 · Cited by 32
Mcl-1 antagonism is a potential therapeutic strategy in a subset of solid cancers
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Development of venetoclax for therapy of lymphoid malignancies
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“As BCL-xL is a key survival factor for platelets,(24) the patients administered navitoclax suffered from acute thrombocytopenia.(22) Venetoclax was developed as a highly BCL-2-selective BH3-mimetic.”
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Protein isoform-centric therapeutics: expanding targets and increasing specificity
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“Inhibition of the tight junction functions of MLCK1 is therefore a potential approach to promote barrier integrity, but because MLCK1 kinase activity is”
Immunosenescence promotes cancer development: from mechanisms to treatment strategies
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“However, Nav-itoclax may lead to thrombocytopenia, which limits its clinical application [106].”
Interplay of ferroptotic and apoptotic cell death and its modulation by BH3-mimetics
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Emerging approaches to target mitochondrial apoptosis in cancer cells
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“However, acute thrombocytopenia was observed in multiple in vivo studies in mice, dogs and rats 49 as well as in clinical trials in patients with lymphoid tumours 50,51 .”
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BH3 Mimetics in Hematologic Malignancies
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Targeting mitochondrial respiration and the BCL2 family in high‐grade MYC‐associated B‐cell lymphoma
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“69 The BCL-X L degrader DT2216, developed to mitigate the on-target thrombocytopenia of navitoclax, interacts with the Von Hippel-Lindau E3 ligase, which is weakly expressed in platelets.”
BackgroundThe molecular biology of diffuse large B-cell lymphoma
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Venetoclax resistance in acute myeloid leukaemia—Clinical and biological insights
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Bcl-xL inhibition by molecular-targeting drugs sensitizes human pancreatic cancer cells to TRAIL
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Metadata
- 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 › Hematology › 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
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