Phase 1/2a trial of intravenous BAL101553, a novel tumor checkpoint controller (TCC), in advanced solid tumors.

Lopez, Juanita; Evans, T.R. Jeffry; Plummer, Elizabeth Ruth; Diamantis, Nikolaos; Shaw, Heather; Zubairi, Ishtiaq Husain; Haris, Noor Md; Macdonald, J S; Greystoke, Alastair; Roux, René L.; Tunariu, Nina; Molife, L. Rhoda; Hannah, Alison L.; Anderson, Stephanie; Lane, Heidi A.; Maurer, Martina; Schmitt‐Hoffmann, Anne; Bachmann, Felix; Engelhardt, Marc; Kristeleit, Rebecca

doi:10.1200/jco.2016.34.15_suppl.2525

Cited by 3 publications

(14 citation statements)

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“…Moreover, in contrast to approved MTAs, which do not efficiently penetrate the brain, the promising pharmacokinetic properties of BAL101553 provide a strong rationale for its use for glioblastoma treatment. Indeed, the active drug has been shown to be efficiently distributed into the brain, with a 1:1 partitioning between plasma and brain tissue, no brain accumulation reported in rodent models (17) and currently no clinical indication of CNS toxicity in treated patients (19). With regard to activity on glioblastoma CSLCs, further work would be needed to determine whether this activity is shared by other MTAs.…”

Section: Discussionmentioning

confidence: 99%

“…BAL101553, a highly soluble prodrug of BAL27862, is currently undergoing clinical evaluation in advanced cancer patients by i.v. (phase IIA) or oral (phase I) administration (18)(19)(20). Previously, we reported that microtubule þ End-binding 1-protein (EB1) was a factor of bad prognosis in glioblastoma, and that Vinca-alkaloid chemotherapy could improve the treatment of glioblastoma patients with an EB1-overexpressing tumor (21).…”

Section: Introductionmentioning

confidence: 99%

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The Novel Tubulin-Binding Checkpoint Activator BAL101553 Inhibits EB1-Dependent Migration and Invasion and Promotes Differentiation of Glioblastoma Stem-like Cells

Bergès

Tchoghandjian

Honoré

et al. 2016

Molecular Cancer Therapeutics

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Glioblastoma patients have limited treatment options. Cancer stem-like cells (CSLC) contribute to glioblastoma invasiveness and repopulation; hence, they represent promising targets for novel therapies. BAL101553 is a prodrug of BAL27862, a novel microtubule-destabilizing agent inhibiting tumor cell proliferation through activation of the spindle assembly checkpoint, which is currently in phase I/II clinical development. Broad anticancer activity has been demonstrated against human cancer models, including tumors refractory to conventional treatments. We have shown that overexpression of microtubule + end-binding 1-protein (EB1) correlates with glioblastoma progression and poor survival. Here, we show that BAL27862 inhibits the growth of two glioblastoma CSLCs. As EB1 is overexpressed in the CSLC line GBM6, which displays a high tumorigenicity and infiltrative pattern of migration in vivo, we investigated drug activity on GBM6 according to EB1 expression. BAL27862 inhibited migration and colony formation at subcytotoxic concentrations in EB1-expressing control cells (GBM6-sh0) but only at cytotoxic concentrations in EB1-downregulated (GBM-shE1) cells. Three administrations of BAL101553 were sufficient to provoke an EB1-dependent survival benefit in tumor-bearing mice. Patterns of invasion and quantification of tumor cells in brain demonstrated that GBM6-sh0 cells were more invasive than GBM6-shEB1 cells, and that the antiproliferative and anti-invasive effects of BAL101553 were more potent in mice bearing control tumors than in EB1-downregulated tumors. This was associated with inhibition of stem cell properties in the GBM6-sh0 model. Finally, BAL27862 triggered astrocytic differentiation of GBM6 in an EB1-dependent manner. These results support the potential of BAL101553 for glioblastoma treatment, with EB1 expression as a predictive biomarker of response. Mol Cancer Ther; 15(11); 2740-9. ©2016 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Novel Tubulin-Binding Checkpoint Activator BAL101553 Inhibits EB1-Dependent Migration and Invasion and Promotes Differentiation of Glioblastoma Stem-like Cells

Bergès

Tchoghandjian

Honoré

et al. 2016

Molecular Cancer Therapeutics

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“…For each dose level, new patients were recruited and evaluated for safety, PK, pharmacodynamic (PD) effects, and for antitumor activity. The starting dose level of IV BAL101553 was 30 mg/ m 2 (based on the clinical experience and outcomes from study CDI-CS-001 in patients with advanced solid tumors who were administered BAL101553 as a 2-h IV infusion [25]). Dose increments of approximately 50% were planned from 30 mg/m 2 onwards until the occurrence of a DLT in any patient, after which all subsequent dose levels were to be incremented by 33%.…”

Section: Dose Escalationmentioning

confidence: 99%

“…A recent study looked at the dosing, safety and tolerability of IV BAL101553 in patients with advanced solid tumors (study CDI-CS-001) [25]. This was a two-part (dose escalation followed by dose expansion), open-label, Phase 1/2a study.…”

Section: Introductionmentioning

confidence: 99%

“…At doses ≥45 mg/m 2 , BAL101553 was associated with either fully or partially reversible, dose-limiting neurological and myocardial side effects, including gait disturbance and myocardial injury (grade 3 troponin elevation and electrocardiogram changes including T-wave inversions). However, the recommended Phase 2 dose level of 30 mg/m 2 was well-tolerated and showed signals of antitumor activity, including one patient with an ampullary carcinoma who had a partial response lasting for over 2 years [25].…”

Section: Introductionmentioning

confidence: 99%

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A Phase 1 study of BAL101553, a novel tumor checkpoint controller targeting microtubules, administered as 48-h infusion in adult patients with advanced solid tumors

et al. 2019

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Purpose BAL101553, the prodrug of the microtubule-destabilizer BAL27862, previously showed signs of antitumor activity when administered as a 2-h infusion, but its use was limited by vascular toxicity. We investigated an alternative dosing strategy aimed at improving the safety profile of BAL101553. Methods This multicenter, open-label, Phase 1 dose-escalation study used a 3 + 3 design to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics, and antitumor activity of BAL101553 administered as a 48-h IV infusion on Days 1, 8, and 15 of a 28-day cycle. Patients received oral BAL101553 on Days 15-21 of cycle 2 to assess oral bioavailability. Results BAL101553 was well tolerated at doses up to ≤70 mg/m 2. Three grade 3 DLTs occurred: hypotension (70 mg/m 2), hyponatremia and neutropenia (both 90 mg/m 2). The MTD for 48-h IV BAL101553 was 70 mg/m 2. At this dose level, the AUC for BAL27862 was 8580 ng.h/mL and the C max was 144 ng/ mL. No apparent dose-related effects on blood pressure were observed with 48-h BAL101553 IV infusion. BAL27862 oral bioavailability was >80%. Conclusions Continuous 48-h IV BAL101553 infusion achieved higher exposure of the BAL27862 active metabolite than a 2-h infusion at the RP2D and did not cause vascular toxicity. Clinicaltrials.gov registration: NCT02895360.

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Furazans in Medicinal Chemistry

et al. 2021

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Incorporation of heterocycles into drug molecules can enhance physical properties and biological activity. A variety of heterocyclic groups is available to medicinal chemists, many of which have been reviewed in detail elsewhere. Oxadiazoles are a class of heterocycle containing one oxygen and two nitrogen atoms, available in three isomeric forms. While the 1,2,4- and 1,3,4-oxadiazoles have seen widespread application in medicinal chemistry, 1,2,5-oxadiazoles (furazans) are less common. This Review provides a summary of the application of furazan-containing molecules in medicinal chemistry and drug development programs from analysis of both patent and academic literature. Emphasis is placed on programs that reached clinical or preclinical stages of development. The examples provided herein describe the pharmacology and biological activity of furazan derivatives with comparative data provided where possible for other heterocyclic groups and pharmacophores commonly used in medicinal chemistry.

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Phase 1/2a trial of intravenous BAL101553, a novel tumor checkpoint controller (TCC), in advanced solid tumors.

Cited by 3 publications

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The Novel Tubulin-Binding Checkpoint Activator BAL101553 Inhibits EB1-Dependent Migration and Invasion and Promotes Differentiation of Glioblastoma Stem-like Cells

The Novel Tubulin-Binding Checkpoint Activator BAL101553 Inhibits EB1-Dependent Migration and Invasion and Promotes Differentiation of Glioblastoma Stem-like Cells

A Phase 1 study of BAL101553, a novel tumor checkpoint controller targeting microtubules, administered as 48-h infusion in adult patients with advanced solid tumors

Furazans in Medicinal Chemistry

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