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SummaryPurpose 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/m2. Three grade 3 DLTs occurred: hypotension (70 mg/m2), hyponatremia and neutropenia (both 90 mg/m2). The MTD for 48-h IV BAL101553 was 70 mg/m2. At this dose level, the AUC for BAL27862 was 8580 ng.h/mL and the Cmax 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.

Objectives This analysis evaluated the variability of isavuconazole plasma concentrations between subjects and between sampling times, and assessed their relationship to outcomes for subjects with invasive fungal disease (IFD) in the SECURE trial. Methods Isavuconazole-treated subjects received 372 mg of isavuconazonium sulphate (corresponding to 200 mg of isavuconazole) three times daily for 2 days, then once daily. Plasma samples were collected after day 4 and analysis sets were constructed as follows: analysis set 1 included all samples from subjects with proven/probable/possible IFD who received ≥1 dose of isavuconazole; analysis set 2 included samples from subjects in analysis set 1 who had provided >1 sample; and analysis set 3 included samples from subjects in analysis set 1 with proven/probable invasive aspergillosis. Assessments included overall distributions of plasma concentrations and variability between samples (analysis sets 1 and 2) as well as relationships to outcomes [all-cause mortality (day 42), overall response (end of treatment) and treatment-emergent adverse events; analysis sets 1 and 3]. Results Analysis sets 1, 2 and 3 included samples from 160, 97 and 98 subjects, respectively. Trough concentrations for each were distributed similarly [mean (SD): 3406.6 (1511.5), 3495.6 (1503.3) and 3368.1 (1523.2) ng/mL, respectively]. The mean coefficient of variation between samples in analysis set 2 was 23.2%; differences between concentrations in first samples and subsequent samples were

BackgroundBAL101553 (lisavanbulin), the lysine prodrug of BAL27862 (avanbulin), exhibits broad anti-proliferative activity in human cancer models refractory to clinically relevant microtubule-targeting agents.MethodsThis two-part, open-label, phase 1/2a study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of 2-h infusion of BAL101553 in adults with advanced or recurrent solid tumours. The MTD was determined using a modified accelerated titration design in phase I. Patients received BAL101553 at the MTD and at lower doses in the phase 2a expansion to characterise safety and efficacy and to determine the recommended phase 2 dose (RP2D).ResultsSeventy-three patients received BAL101553 at doses of 15–80 mg/m2(phase 1,n = 24; phase 2a,n = 49). The MTD was 60 mg/m2; DLTs observed at doses ≥60 mg/m2were reversible Grade 2–3 gait disturbance with Grade 2 peripheral sensory neuropathy. In phase 2a, asymptomatic myocardial injury was observed at doses ≥45 mg/m2. The RP2D for 2-h intravenous infusion was 30 mg/m2. The overall disease control rate was 26.3% in the efficacy population.ConclusionsThe RP2D for 2-h infusion of BAL101553 was well tolerated. Dose-limiting neurological and myocardial side effects were consistent with the agent’s vascular-disrupting properties.Clinical trial registrationEudraCT: 2010-024237-23.

3118 Background: EB1, a protein located on the plus-ends of microtubules is involved in microtubule function and has been associated with glioblastoma (GBM) stem-cell-ness and more aggressive disease. Lisavanbulin (BAL101553) is a prodrug of the lipophilic small molecule BAL27862, that promotes tumor cell death by modulating the spindle assembly checkpoint and has been shown in rodents to efficiently penetrate the brain. Data from GBM mouse models and recent phase 1 clinical data (Lopez et al. ESMO 2020) suggest that EB1 is a response-predictive marker for lisavanbulin in GBM. A phase 2 study is ongoing to confirm this hypothesis (NCT02490800). A proof-of-concept in GBM would support an expansion of EB1-directed lisavanbulin clinical development in non-GBM tumors, which requires prevalence estimates of EB1-positivity in non-GBM tumor types. Methods: Tissue samples from GBM and other tumor types were stained for EB1 using a CE-marked immunohistochemistry Clinical Trial Assay (Targos Molecular Pathology GmbH, Kassel Germany). EB1-positivity was assessed by a board-certified pathologist based on the percentage of tumor cells showing moderate or strong staining for EB1, using thresholds of ≥50%, ≥60% and ≥70% of tumor cells with EB1 positivity. Whole transcriptome sequencing (WTS) using RNAseq was performed in a subset of tissue samples to develop a potential RNA-based predictive response signature for lisavanbulin. Results: 73 GBM tissue samples and 333 tissue samples from 13 other cancer types were stained for EB1. The strongest overall signal for EB1-positivity was obtained for medulloblastoma, neuroblastoma and GBM. In addition, moderate or strong EB1-staining in ≥50% of tumor cells was observed in samples from colorectal cancer (CRC), non small-cell lung cancer (NSCLC), metastatic melanoma, small-cell lung cancer (SCLC) and triple-negative breast cancer (TNBC). An expanded staining campaign is ongoing in these cancer types. Initial results from the ongoing WTS analyses show marked differences in gene expression profiles between EB1-positive and -negative cases. Conclusions: Strong EB1-positivity is infrequent but occurs in a variety of tumor types, with the strongest signals in medulloblastoma, neuroblastoma and GBM. A phase 2 study is ongoing to assess prospectively whether EB1 is a response-predictive biomarker for lisavanbulin in GBM.[Table: see text]

TPS2068 Background: Lisavanbulin (BAL101553, prodrug of BAL27862) is a novel tumor checkpoint controller that promotes tumor cell death by modulating the spindle assembly checkpoint. BAL27862 is a lipophilic, small molecule (MW 387) shown in rodents to penetrate the brain (1:1 plasma ratio) with promising antitumor activity in orthotopic models of glioblastoma (GB) as monotherapy or in combination with radiotherapy (RT) ± chemotherapy. In a completed phase 1 study (Lopez et al. ESMO 2020, NCT02490800) with daily oral lisavanbulin in patients with recurrent GB or high-grade glioma, the RP2D was determined at 25 mg/day. In this phase 1 study, two patients (out of 20 patients) with GB show a long-lasting (> 2 years) clinical benefit with improvement in clinical symptoms and in target and/or non-target GB lesions as per RANO criteria. Both patients show strong end-binding protein 1 (EB1) expression in their GB tissues as assessed by immunohistochemistry staining. EB1, a protein located on the plus-ends of microtubules, is involved in microtubule (MT) function and has been associated with stemness of glioma cells and a more aggressive disease. Data from GB mouse models suggest that EB1 is a predictive marker for response to lisavanbulin. The prevalence of EB1-positivity in GB is estimated at ̃5%. This ongoing phase 2 study is an extension of the completed Phase 1 study and is conducted to confirm prospectively whether EB1 is a response-predictive biomarker for lisavanbulin in GB. Methods: This is an ongoing multicenter, open-label, phase 2 study using a Simon Two-Stage design to assess the efficacy of lisavanbulin in patients with recurrent GB. The study is being performed in the UK, Switzerland and Germany. Patients with histologically-confirmed GB and recurrent disease after prior RT with alkylating chemotherapy (de-novo/primary GB) or after prior chemotherapy or RT (secondary GB), are eligible for enrollment if their GB archival tumor tissue is EB1-positive. EB1-positivity is defined as moderate to strong EB1-staining in at least 70% of GB tumor cells using a CE-marked immunohistochemistry Clinical Trial Assay (Targos Molecular Pathology GmbH). The primary study objective is the overall response rate by RANO, with MRI scans being performed every 8 weeks. Secondary endpoints include progression-free survival and overall survival. Adverse events are assessed using CTCAEv5. To develop a potential RNA-based response signature, molecular profiling of tumor tissue is performed using whole transcriptome sequencing (RNAseq) in each patient enrolled in the study to define the genomic expression profiles in patients with EB1-positive GB. Nine evaluable patients are to be enrolled in Stage 1, and an additional 10 patients will be enrolled in stage 2 if at least 2 objective responses per RANO criteria are observed in stage 1. Clinical trial information: 02490800.

Cancer cells react to CD95 activation with either apoptotic or tumorigenic responses. Yet, the determinants of these two antithetic reactions are fundamentally not understood. Here, we show that pre-confined CD95L molecules activate apoptosis of cancer cells in-vitro. For particular CD95L pre-confinement, apoptosis activation is most efficient. Surprisingly, in tumor models, the same pre-confinement yields enhanced proliferation of cancer cells. This shift is rooted in cell-cell interactions, as proliferation was also observed in tumorspheres in-vitro. Indeed, proliferation required death-domain tyrosine phosphorylation of CD95 that was facilitated by cell-cell contacts, whereas decreasing the levels of global tyrosine kinase activity favored apoptosis. Altogether, the response to CD95 activation is cell context-dependent and tunable by CD95L pre-confinement, thereby opening therapeutic opportunities in cancer.One Sentence SummaryCell-cell contact tunes tyrosine-kinase activity thereby dictating life or death upon CD95 activation by pre-confined CD95L.

2025 Background: BAL101553 (prodrug of BAL27862) is a novel TCC that promotes tumor cell death by modulating the spindle assembly checkpoint. BAL27862 is a lipophilic, small molecule shown in rodents to penetrate the brain (brain/plasma ratio around unity), with promising antitumor activity in orthotopic preclinical GBM models as monotherapy or in combination with radiotherapy (RT) with or without temozolomide. In this ongoing study (NCT02490800, CDI-CS-002), daily oral BAL101553 was initially examined in solid-tumor patients, with an MTD of 16 mg/d and DLTs of G4 hyponatremia and G2 hallucinations (Lopez 2018, JCO 36, 2018, suppl. A2530). Subsequently the study was expanded by including a separate cohort of patients with progressive or recurrent GBM or high-grade glioma (Ingles Garces 2017, JCO 35, 2018, suppl. TPS2601). Methods: Patients with histologically-confirmed GBM or high-grade glioma, with progressive or recurrent disease after prior RT with/without chemotherapy, received once-daily oral BAL101553 (28-day cycles) in a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD). Adverse events were assessed by CTCAE v4.03 grade (G), and tumor response by RANO every two cycles. Pharmacokinetics (PK) were evaluated on Day 1 of Cycles 1 and 2. Results: In the ongoing study, 23 pts (13M/10F; median age 50 y), median (min–max) number of prior regimens = 2 (1–5), received doses of 8, 15, 20, 25 or 30 mg oral BAL101553 once daily. One DLT of reversible G2 depression and fatigue occurred at 20 mg. Both mean Cmax and AUC increased with dose between 8 and 30 mg. The PK exposure in GBM patients was lower than for solid tumor patients, in particular at 20 and 25 mg. At 25 mg/d (n = 3), one patient with IDH-mutated GBM had a partial response (63% area reduction per RANO) and continues on study > 8 months, and another patient had stable disease for 5 months. At 15–20 mg/d, stable disease was observed in 3/10 patients. Conclusions: The current data in patients with GBM or high-grade glioma suggest that BAL101553 is well tolerated at dose levels above the MTD established in patients with advanced solid tumors, and shows indications of clinical activity. Clinical trial information: 02490800.

2530Background: BAL101553 is the prodrug of BAL27862, a small molecule TCC that binds microtubules and promotes tumor cell death by activation of the spindle assembly checkpoint. In a study of BAL1...

2529Background: BAL101553 is the prodrug of BAL27862, a small molecule TCC that binds microtubules and promotes tumor cell death by activation of the spindle assembly checkpoint. In a study of BAL1...

Despite the fact that the knowledge about the structure and the function of the supplementary motor area (SMA) is steadily increasing, the role of the SMA in the human brain, e.g., the contribution of the SMA to the Bereitschaftspotential, still remains unclear and controversial. The goal of this study was to contribute further to this discussion by taking advantage of the increased spatial information of a whole-scalp magnetoencephalography (MEG) system enabling us to record the magnetic equivalent of the Bereitschaftspotential 1, the Bereitschaftsfeld 1 (BF 1) or readiness field 1. Five subjects performed a complex, and one subject a simple, finger-tapping task. It was possible to record the BF 1 for all subjects. The first appearance of the BF 1 was in the range of −1.9 to −1.7 s prior to movement onset, except for the subject performing the simple task (−1 s). Analysis of the development of the magnetic field distribution and the channel waveforms showed the beginning of the Bereitschaftsfeld 2 (BF 2) or readiness field 2 at about −0.5 s prior to movement onset. In the time range of BF 1, dipole source analysis localized the source in the SMA only, whereas dipole source analysis containing also the time range of BF 2 resulted in dipole models, including dipoles in the primary motor area. In summary, with a whole-head MEG system, it was possible for the first time to detect SMA activity in healthy subjects with MEG.

In this paper, we designed a quantitative model of biological membranes by the deposition of planar lipid membranes on solid substrates (called supported membranes), and immobilized biotinylated oligomers of hyaluronic acid (oligo-HA, 6–8 disaccharide units in length) to the membrane surface via neutravidin cross-linkers. By controlling the self-assembly of biotinylated lipid anchors, the mean distance between the oligo-HA molecules on the membrane could be controlled to nm accuracy. The adhesion and motility of pancreatic adenocarcinoma cells expressing different splice variants of the HA-binding cell surface receptor CD44 on these surfaces were investigated quantitatively. The combination of label-free, time-lapse imaging of living cells and statistical analysis suggests that the static morphology (global shape and cytoskeleton remodeling) of cells, their stochastic morphological dynamics, and the probability of directed motion reflect the metastatic behaviour of the cancer cells.