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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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“Later, navitoclax (ABT-263) was reported as an analog of ABT-737, which showed an antitumor effect after oral administration [14, 15]; however, it was found to trigger thrombocytopenia due to its inhibition of BCL-XL [16].”
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“These values are comparable to those reported in other navitoclax Phase 1 monotherapy studies.(5,6) When navitoclax was co-administered with rifampin, there was no statistically significant difference from navitoclax alone regimen for the Tmax, Cmax or t1/2 of navitoclax (P ≥ 0 242); however, the AUCt and AUC∞ of navi…”
ResultSelf-citationTargeting the B-cell lymphoma 2 anti-apoptotic proteins for cervical cancer treatment
Rahman, S. F. A., Lian, B. S. X., & Mohana‐Kumaran, N. (2020) · Future Oncology · doi:10.2217/fon-2020-0389 · Cited by 13
Low-Intensity Pulsed Ultrasound Alleviates Human Testicular Leydig Cell Senescence In Vitro
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Hepatic Stellate Cells Functional Heterogeneity in Liver Cancer
Sererols-Viñas, L., Garcia‐Vicién, G., Ruiz-Blázquez, P., Lee, T., Lee, Y. A., Gonzalez‐Sanchez, E., Vaquero, J., Moles, A., Filliol, A. A., & Affò, S. (2025) · Seminars in Liver Disease · doi:10.1055/a-2551-0724 · Cited by 16
“173 Recent studies in breast cancer and PDAC have expanded the scope of senolytic strategies, showing that targeting senescent CAFs can reduce immuno-suppression and enhance immune in fi ltration, which under-scores their potential in solid tumors, including liver cancer.”
Manipulating the apoptotic pathway: potential therapeutics for cancer patients
Bates, D. J. P., & Lewis, L. D. (2013) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.12193 · Cited by 11
Molecular mechanisms by which splice modulator GEX1A inhibits leukaemia development and progression
Sellin, M., Mack, R. M., Rhodes, M. C., Zhang, L., Berg, S. A., Joshi, K., Liu, S., Wei, W., Breslin, P., Larsen, P., et al. (2022) · British Journal of Cancer · doi:10.1038/s41416-022-01796-5 · Cited by 11
“However, challenges arose as important pro-survival proteins were either poorly targeted by BH3-mimetics, as is the case with MCL-1, or when their use resulted in severe thrombocytopenia, as in the case when targeting BCL-xL [30, 31].”
BackgroundPesch, A. M., Chandler, B. C., Michmerhuizen, A. R., Carter, H. M., Hirsh, N. H., Wilder-Romans, K., Liu, M., Ward, T., Ritter, C. L., Nino, C. A., et al. (2022) · Cancer Research Communications · doi:10.1158/2767-9764.crc-22-0024 · Cited by 12
Eleveld, T. F., Vernooij, L., Schild, L. G., Koopmans, B., Alles, L. K., Ebus, M. E., Dandis, R., van Tinteren, H., Caron, H. N., Köster, J., et al. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2023.1130034 · Cited by 11
Spina, J. S., Carr, T. L., Phillips, L. A., Knight, H., Crosbie, N. E., Lloyd, S. M., Jhala, M. A., Lam, T. J., Kármán, J., Clements, M. E., et al. (2024) · Aging · doi:10.18632/aging.205994 · Cited by 12
Kannan, S., Li, Y., Baran, N., Yang, X., Ghotbaldini, S., Tatarata, Q. Z., Yoshimura, S., Li, Z., Hsiao, Y.-C., Balachander, S. B., et al. (2024) · Blood Advances · doi:10.1182/bloodadvances.2024013423 · Cited by 12
Žigart, N., & Časar, Z. (2019) · Expert Opinion on Therapeutic Patents · doi:10.1080/13543776.2019.1627327 · Cited by 11
The Interactome between Metabolism and Gene Mutations in Myeloid Malignancies
Gurnari, C., Pagliuca, S., & Visconte, V. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22063135 · Cited by 12
“All these compounds were pan-inhibitors, with some causing thrombocytopenia as off-target effects involving BCL-XL and limited applicability to humans [75].”
BackgroundShould There Be a Standard Therapy for Mantle Cell Lymphoma?
Smith, M. R. (2011) · Future Oncology · doi:10.2217/fon.10.189 · Cited by 11
Priming BCL-2 to kill: the combination therapy of tamoxifen and ABT-199 in ER+ breast cancer
Deng, J., & Letai, A. G. (2013) · Breast Cancer Research · doi:10.1186/bcr3568 · Cited by 11
BCL‐XL exerts a protective role against anemia caused by radiation‐induced kidney damage
Brinkmann, K., Waring, P., Glaser, S. P., Wimmer, V. C., Cottle, D. L., Tham, M. S., Nhu, D., Whitehead, L. W., Delbridge, A. R. D., Lessène, G., et al. (2020) · The EMBO Journal · doi:10.15252/embj.2020105561 · Cited by 10
“As expected (Mason et al , 2007; Wilson et al , 2010; Leverson et al , 2015; Merino et al , 2018), the administration of A1331852 resulted in on-target platelet toxicity at day 2 post-treatment, followed by high platelet counts at days 5 – 6 post-treatment (Fig 6C ◀ Figure 5 .”
Braga, C. E. H. V. P. F., de Brito, J. S., Ribeiro, M. M., Coutinho‐Wolino, K. S., Regis, B., Calixto, B., Rodrigues, R. C. B., Wang, A. Y.-M., Stenvinkel, P., & Mafra, D. (2025) · Biochimie · doi:10.1016/j.biochi.2025.10.008 · Cited by 13
Cellular senescence in cancer: Friend or fraud?
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Venetoclax Combination Treatment of Acute Myeloid Leukemia in Adolescents and Young Adult Patients
Chatzikalil, E., Roka, K., Diamantopoulos, P. T., Rigatou, E. G., Avgerinou, G., Kattamis, A., & Solomou, E. E. (2024) · Journal of Clinical Medicine · doi:10.3390/jcm13072046 · Cited by 10
“Navitoclax was the first Bcl-2 inhibitor used in clinical trials, with moderate results as monotherapy and severe dose-limiting toxicity [45–47].”
Developing Novel Strategies to Target B-Cell Malignancies
Fowler, N. H., & Oki, Y. (2013) · American Society of Clinical Oncology Educational Book · doi:10.1200/edbook_am.2013.33.366 · Cited by 10
Roschewski, M. J., Dunleavy, K. M., & Wilson, W. H. (2014) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.3109/10428194.2014.883075 · Cited by 10
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Targeted Therapeutics Delivery by Exploiting Biophysical Properties of Senescent Cells
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Synergistic Bcl-2 inhibition by ABT-737 and cyclosporine A
Cippà, P. E., Kamarashev, J. A., Chen, J., Kraus, A., Segerer, S., Feldmeyer, L., & Fehr, T. H. (2012) · APOPTOSIS · doi:10.1007/s10495-012-0778-2 · Cited by 10
“These rationally designed BH3-mimetics initiate the mitochondrial apoptosis cascade by inhibition of the anti-apoptotic Bcl-2 family members Bcl-2, Bcl-XL and Bcl-w [5], induced apoptosis in several tumor models [7] and represent a promising class of anti-neoplastic agents [8, 9].”
BackgroundTargeting childhood, adolescent and young adult non‐Hodgkin lymphoma: therapeutic horizons
Galardy, P. J., Bedekovics, T., & Hermiston, M. L. (2016) · British Journal of Haematology · doi:10.1111/bjh.14016 · Cited by 10
Current Status of Targeted Therapies for Mantle Cell Lymphoma
Chang, J. E., & Kahl, B. S. (2011) · Drugs · doi:10.2165/11594630-000000000-00000 · Cited by 10
Liu, P., Zhao, M., Lin, Y., Jiang, X., Xia, T., Li, Y., Lu, Y., & Jiang, L. (2023) · Experimental Hematology · doi:10.1016/j.exphem.2023.04.002 · Cited by 9
How I treat ETP-ALL in children
Summers, R. J., Teachey, D. T., & Hunger, S. P. (2024) · Blood · doi:10.1182/blood.2023023155 · Cited by 9
BCL-XL inhibitors enhance the apoptotic efficacy of BRAF inhibitors in BRAFV600E colorectal cancer
Jenkins, L. J., Luk, I. Y., Chionh, F. J. M., Tan, T., Needham, K. A., Ayton, J., Reehorst, C. M., Vukelic, N., Sieber, O. M., Mouradov, D., et al. (2024) · Cell Death and Disease · doi:10.1038/s41419-024-06478-z · Cited by 10
Synergy of retinoic acid and BH3 mimetics in MYC(N)-driven embryonal nervous system tumours
Seiboldt, T., Zeiser, C., Nguyen, D., Çelikyürekli, S., Herter, S., Najafi, S., Stroh-Dege, A., Meulenbroeks, C., Mack, N. L., Salem-Altintas, R., et al. (2024) · British Journal of Cancer · doi:10.1038/s41416-024-02740-5 · Cited by 11
“While there are already decades of experience with isotretinoin/13-cis -RA therapy and its safety and ef fi cacy in high-risk NB patients [15, 18], its use has been limited to experimental approaches in MB.”
May, L., Hu, B., Jerajani, P., Jagdeesh, A., Alhawiti, O., Cai, L., Semenova, N., Guo, C., Isbell, M., Deng, X., et al. (2024) · Cancer Research · doi:10.1158/0008-5472.can-24-0585 · Cited by 9
Marca, J. E. L., Kelly, G. L., Strasser, A., & Diepstraten, S. T. (2024) · Developmental Cell · doi:10.1016/j.devcel.2024.06.018 · Cited by 9
Current strategies for senescence treatment: Focused on theranostic performance of nanomaterials
Cong, Y., Li, X., & Hong, H. (2025) · Journal of Controlled Release · doi:10.1016/j.jconrel.2025.113710 · Cited by 9
BCL-2 and BCL-xL in Cancer: Regulation, Function, and Therapeutic Targeting
Silva, J. P. N., Pinto, B. F., Silva, P. M. A., & Bousbaa, H. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27021123 · Cited by 16
Comparison of putative BH3 mimetics AT-101, HA14-1, sabutoclax and TW-37 with ABT-737 in platelets
Wei, H., & Harper, M. T. (2020) · Platelets · doi:10.1080/09537104.2020.1724276 · Cited by 9
“[4] The orally available analogue, ABT-263 (navitoclax), also triggers platelet apoptosis and is associated with doselimiting thrombocytopenia[5].”
BackgroundSchneller, A., Zojer, N., Bolomsky, A., & Ludwig, H. (2021) · Haematologica · doi:10.3324/haematol.2020.277152 · Cited by 10
“Furthermore, in KMS-12-BM-EGFP cells BIM was not associated with BCL-XL (right panel supplementary figure 3C; not shown), as BIM is rather sequestered by BCL-2 (not shown) in line with the MCL-1/BCL-2 dependency of this t(11;14) carrying cell line (3).”
BackgroundIn vitro and in vivo toxicity assessment of the senotherapeutic Peptide 14
Zonari, A. A. C., Brace, L. E., Alencar‐Silva, T., Porto, W. F., Foyt, D. A., Guiang, M., Cruz, E. A. O., Franco, O. L., Oliveira, C. R., Boroni, M., et al. (2022) · Toxicology Reports · doi:10.1016/j.toxrep.2022.07.018 · Cited by 9
Gyebi, G. A., Ogunyemi, O. M., Ibrahim, I. M., Afolabi, S. O., Johnson, O. R., Ejike, U. D., & Adebayo, J. O. (2022) · Egyptian Journal of Basic and Applied Sciences · doi:10.1080/2314808x.2022.2106095 · Cited by 9
“In this direction, navitoclax [5] and ABT-199 [6] and other drugable compounds have been developed through combi-”
Background
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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