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BAL101553

 
 
BAL101553BAL101553 is a clinical stage small-molecule tumor checkpoint controller being developed as a potential therapy for diverse cancers, including tumor types unresponsive to standard therapeutics. Basilea is exploring once-daily oral dosing of drug candidate BAL101553 (prodrug of BAL27862)1 in an open-label phase 1/2a study in adult patients with advanced solid tumors. This study was amended in late 2016 to include the enrollment of adult patients with recurrent or progressive glioblastoma (brain cancer) after prior radiotherapy with or without chemotherapy. In another phase 1/2a clinical study, Basilea is exploring weekly 48-hour continuous infusion of BAL101553 as an alternative dosing regimen for the treatment of solid tumors.
 
Basilea entered into a clinical study agreement with the Adult Brain Tumor Consortium (ABTC) in the U.S., which will support a clinical phase 1 study with BAL101553 to determine the safety and tolerability of BAL101553 in combination with standard radiation. The study will enroll patients with newly diagnosed glioblastoma who have a reduced sensitivity to the standard chemotherapy with temozolomide due to an unmethylated MGMT promoter. MGMT promoter status is an important prognostic molecular genetic biomarker in glioblastoma.
In preclinical studies, the active moiety of the prodrug, BAL27862, demonstrated in-vitro and in-vivo activity against diverse treatment-resistant cancer models, including tumors refractory to conventional approved therapeutics and radiotherapy.2, 3, 4 BAL101553 efficiently distributed to the brain, with anticancer activity in glioblastoma models.5, 6, 7 BAL27862 binds the colchicine site of tubulin with distinct effects on microtubule organization,8 resulting in the activation of the "spindle assembly checkpoint" which promotes tumor cell death.9

Basilea's approach to oncology includes the early evaluation of potential biomarkers, which are already being tested in phase 1/2a clinical studies in order to optimize dose selection and identify cancer patient groups more likely to respond.

References

  1. J. Pohlmann et al. BAL101553: An optimized prodrug of the microtubule destabilizer BAL27862   with superior antitumor activity. American Association for Cancer Research (AACR) annual meeting 2011, abstract 1347; Cancer Research 2011, 71 (8 Supplement)
  2. A. Broggini-Tenzer et al. The novel microtubule-destabilizing drug BAL101553 (prodrug of BAL27862) sensitizes a treatment refractory tumor model to ionizing radiation. EORTC-NCI-AACR symposium 2014, abstract 202
  3. G. E. Duran et al. In vitro activity of the novel tubulin active agent BAL27862 in MDR1(+) and MDR1(-) human breast and ovarian cancer variants selected for resistance to taxanes. American Association for Cancer Research (AACR) annual meeting 2010, abstract 4412
  4. F. Bachmann et al. BAL101553 (prodrug of BAL27862): A unique microtubule destabilizer active against drug refractory breast cancers alone and in combination with trastuzumab. American Association for Cancer Research (AACR) annual meeting 2014, abstract 831
  5. R. Bergès et al. The novel tubulin-binding checkpoint activator BAL101553 inhibits EB1-dependent migration and invasion and promotes differentiation of glioblastoma stem-like cells. Molecular Cancer Therapeutics 2016 (15), 2740-2749
  6. A. Schmitt-Hoffmann et al. BAL27862: a unique microtubule-targeted agent with a potential for the treatment of human brain tumors. AACR-NCI-EORTC conference 2009, abstract C233; Molecular Cancer Therapeutics 2009, 8 (12 Supplement)
  7. A. C. Mladek et al. The novel tubulin-binding 'tumor checkpoint controller' BAL101553 has anti-cancer activity alone and in combination treatments across a panel of GBM patient-derived xenografts. American Association for Cancer Research (AACR) annual meeting 2016, abstract 4781
  8. A. E. Prota et al. The novel microtubule-destabilizing drug BAL27862 binds to the colchicine site of tubulin with distinct effects on microtubule organization. Journal of Molecular Biology 2014 (426), 1848-1860
  9. F. Bachmann et al. BAL101553 (prodrug of BAL27862): the spindle assembly checkpoint is required for anticancer activity. American Association for Cancer Research (AACR) annual meeting 2015, abstract 3789

 

 

 

 

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