Human glioblastoma (GBM) is a highly aggressive, invasive and hypervascularised malignant brain cancer. Individual circulating tumour cells (CTCs) are sporadically found in GBM patients, yet it is unclear whether multicellular CTC clusters are generated in this disease and whether they can bypass the physical hurdle of the blood-brain barrier.  Here, we assessed CTC presence and composition at multiple time points in 13 patients with progressing GBM during an open-label phase 1/2a study with the microtubule inhibitor BAL101553. We observe CTC clusters ranging from 2 to 23 cells and present at multiple sampling time points in a GBM patient with pleomorphism and extensive necrosis, throughout disease progression. Exome sequencing of GBM CTC clusters highlights variants in 58 cancer-associated genes including ATM, PMS2, POLE, APC, XPO1, TFRC, JAK2, ERBB4 and ALK. Together, our findings represent the first evidence of the presence of CTC clusters in GBM.

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A dry-powder inhaled formulation of treprostinil (LIQ861) produced using PRINT^® technology offers a substantial advantage over current nebulized therapy. Treprostinil is a synthetic prostacyclin analogue that is currently approved for inhalation administration to patients with pulmonary arterial hypertension (PAH) via nebulized Tyvaso^® inhalation solution. LTI-101 was a phase 1, placebo-controlled, double-blind, randomized, single-center study that evaluated the ascending single-dose pharmacokinetics (PK) of LIQ861 in healthy subjects. Six sequential, escalating doses (25, 50, 75, 100, 125, and 150 mcg) were studied to investigate treprostinil exposure from LIQ861 inhalation. Subjects (n=57) were randomly assigned in a 3:1 ratio to receive a single dose of either LIQ861 (n=43) or placebo (n=14); 56 subjects completed all protocol-defined assessments. Following single-dose administration, treprostinil exposure from LIQ861 increased proportionally across the dose range studied, and the PK profile of treprostinil administered as LIQ861 was similar to prior reports of inhaled treprostinil. All doses of LIQ861 were generally well-tolerated with no deaths, serious adverse events, or dose-limiting toxicities. The most frequently reported treatment-emergent adverse events (TEAEs) related to study drug administration were coughing and throat irritation, which are common to dry-powder formulations. Treatment-related TEAEs were reported more frequently at higher dose levels; however, all were assessed as mild in severity. We conclude that the PK profile of treprostinil using a dry-powder inhaled formulation increased in proportion to dose as anticipated and was similar to earlier reports of inhaled, nebulized treprostinil (Tyvaso^®). Based on these results, a phase 3 study (INSPIRE; Clinicaltrials.gov Identifier NCT03399604) evaluating the long-term safety and tolerability of LIQ861 in patients with PAH was initiated.

Stereotaxic biopsy was performed in 17 pts (71%); 9 (53%) had grade II diffuse astrocytoma, and 3 (18%) pilocytic astrocytoma; glioblastoma (GBM) was found in 1 patient at diagnosis and in another at a late recurrence of a glial proliferation. Pons and bulb were the main sites of the tumor (N¼10/10). Among the 21 treated pts, all underwent radiotherapy (RT); 7 received sequential radiotherapy and chemotherapy (RT+CT). Median OS was 45.2 months and 5-y OS was 48.7% (95% CI 24.5-69.2%). No statistically significant association was found between OS and age, tmt modality, or MRI contrast enhancement. ECOG-PS 3-4 was identified as negative PF; although no statistically significant, there was a numerical difference of outcomes regarding histological grade (Table ).