Article

Wilson WH, O'Connor OA, Czuczman MS et al.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. Lancet Oncol 11:1149-1159

National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
The Lancet Oncology (Impact Factor: 24.73). 12/2010; 11(12):1149-59. DOI: 10.1016/S1470-2045(10)70261-8
Source: PubMed

ABSTRACT 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.
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.
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).
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.
Abbott Laboratories, Genentech, and National Cancer Institute, National Institutes of Health.

Download full-text

Full-text

Available from: Owen A O'Connor, Dec 25, 2013
0 Followers
 · 
128 Views
  • Source
    • "Autologous stem cell transplantation did not improve outcomes in patients who achieve complete Case Reports in Oncological Medicine remission [15]. Role of targeted agents in DHL is currently being explored and preclinical and clinical studies are underway testing PI3K inhibitors, Aurora kinase inhibitors, and BCL-2 inhibitors [16] [17] [18]. Phase II trial (NCT02272686) of Bruton's tyrosine kinase inhibitor (ibrutinib) after stem cell transplantation is also being considered [19]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Tolosa-Hunt syndrome (THS) is a painful condition characterized by hemicranial pain, retroorbital pain, loss of vision, oculomotor nerve paralysis, and sensory loss in distribution of ophthalmic and maxillary division of trigeminal nerve. Lymphomas rarely involve cavernous sinus and simulate Tolosa-Hunt syndrome. Here we present a first case of double-hit B cell lymphoma (DHL) relapsing and masquerading as Tolosa-Hunt syndrome. The neurological findings were explained by a lymphomatous infiltration of the right Gasserian ganglion which preceded systemic relapse. As part of this report, the diagnostic criteria for Tolosa-Hunt syndrome and double-hit lymphoma are reviewed and updated treatment recommendations are presented.
    03/2015; Case Reports in Oncological Medicine. DOI:10.1155/2015/249891
    • "It turns out that many cancer cells do not only upregulate Bcl-2 survival factors but also Bim, tBid and Puma, a mechanism called " addiction " (Certo et al., 2006). This may explain the high sensitivity of cancer cells to be killed by BH3-mimetics such as ABT-267, ABT-199 and others (Tse et al., 2008; Wilson et al., 2010; Vandenberg and Cory, 2013). Apart from interacting with BH3-only proteins, Bcl- 2 survival factors also sequester accidently activated Bax and Bak in healthy cells. "
    [Show abstract] [Hide abstract]
    ABSTRACT: There is no doubt that viruses require cells to successfully reproduce and effectively infect the next host. The question is what is the fate of the infected cells? All eukaryotic cells can"sense" viral infections and exhibit defence strategies to oppose viral replication and spread. This often leads to the elimination of the infected cells by programmed cell death or apoptosis. This"sacrifice" of infected cells represents the most primordial response of multicellular organisms to viruses. Subverting host cell apoptosis, at least for some time, is therefore a crucial strategy of viruses to ensure their replication, the production of essential viral proteins, virus assembly and the spreading to new hosts. For that reason many viruses harbor apoptosis inhibitory genes, which once inside infected cells are expressed to circumvent apoptosis induction during the virus reproduction phase. On the other hand, viruses can take advantage of stimulating apoptosis to (i) facilitate shedding and hence dissemination, (ii) to prevent infected cells from presenting viral antigens to the immune system or (iii) to kill non-infected bystander and immune cells which would limit viral propagation. Hence the decision whether an infected host cell undergoes apoptosis or not depends on virus type and pathogenicity, its capacity to oppose antiviral responses of the infected cells and/or to evade any attack from immune cells. Viral genomes have therefore been adapted throughout evolution to satisfy the need of a particular virus to induce or inhibit apoptosis during its life cycle. Here we review the different strategies used by viruses to interfere with the two major apoptosis as well as with the innate immune signaling pathways in mammalian cells. We will focus on the intrinsic mitochondrial pathway and discuss new ideas about how particular viruses could activately engage mitochondria to induce apoptosis of their host. Copyright © 2015. Published by Elsevier B.V.
    Virus Research 03/2015; 13. DOI:10.1016/j.virusres.2015.02.026 · 2.83 Impact Factor
  • Source
    • "ABT-263 has shown efficacy in early stage clinical trials, particularly for the treatment of CLL. In a phase I study of relapsed or refractory lymphoid malignancies (including CLL) 22% of patients had partial responses (Wilson et al., 2010), and in a phase I study of relapsed or refractory CLL 35% of patients exhibited partial responses (Roberts et al., 2012). In contrast, the results of trials targeting SCLC and other solid tumours have been modest. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Oncogenic mutations in RAS or BRAF can drive the inappropriate activation of the ERK1/2. In many cases, tumour cells adapt to become addicted to this deregulated ERK1/2 signalling for their proliferation, providing a therapeutic window for tumour-selective growth inhibition. As a result, inhibition of ERK1/2 signalling by BRAF or MEK1/2 inhibitors is an attractive therapeutic strategy. Indeed, the first BRAF inhibitor, vemurafenib, has now been approved for clinical use, while clinical evaluation of MEK1/2 inhibitors is at an advanced stage. Despite this progress, it is apparent that tumour cells adapt quickly to these new targeted agents so that tumours with acquired resistance can emerge within 6–9 months of primary treatment. One of the major reasons for this is that tumour cells typically respond to BRAF or MEK1/2 inhibitors by undergoing a G1 cell cycle arrest rather than dying. Indeed, although inhibition of ERK1/2 invariably increases the expression of pro-apoptotic BCL2 family proteins, tumour cells undergo minimal apoptosis. This cytostatic response may simply provide the cell with the opportunity to adapt and acquire resistance. Here we discuss recent studies that demonstrate that combination of BRAF or MEK1/2 inhibitors with inhibitors of pro-survival BCL2 proteins is synthetic lethal for ERK1/2-addicted tumour cells. This combination effectively transforms the cytostatic response of BRAF and MEK1/2 inhibitors into a striking apoptotic cell death response. This not only augments the primary efficacy of BRAF and MEK1/2 inhibitors but delays the onset of acquired resistance to these agents, validating their combination in the clinic. Linked ArticlesThis article is part of a themed section on Emerging Therapeutic Aspects in Oncology. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue-8
    British Journal of Pharmacology 08/2013; 169(8). DOI:10.1111/bph.12220 · 4.99 Impact Factor
Show more