BO-112 is a synthetic dsRNA formulated with a cationic carrier, polyethylenimine, which prevents its degradation by nucleases. In melanoma (MEL) mouse models, systemic administration of BO-112 activates MDA-5 and NOXA, leading to anti-tumoral activity connected to a sustained and extended expression of interferon (IFN) response genes. IT BO-112 delivery demonstrated in transplanted mouse models a safer and enhanced local and systemic antitumor effects. Final toxicity and biological profile of the first in human clinical trial that explores IT BO112 as an immune-modulatory treatment is presented (NCT02828098).
Patients (pts) with solid malignant tumors and metastases ≥1 cm accessible to IT injection were treated in 3 cohorts (C) in a 3 + 3 phase I design: C1: single IT BO-112 dose of 0.6 mg; C2: 1mg IT BO112 qw x 2-3 doses. C3: 0.6 mg IT BO112 qw x 2-3 doses. Pre & post treatment biopsies from the injected lesion were obtained, analysing necrosis, apoptosis, immune infiltrate and (first time reported for this trial) IFN-gamma mRNA expression (nanostring). PKs, cytokines and circulating immune cells (CICs) were studied in pre and post BO-112 blood samples.
16 pts (12 more than the first report in ASCO 2017) were treated: 5 MEL, 3 sarcoma, 2 breast, 1 colorrectal, 1 neuroendocrine, 1 ovarian, 1 head & neck, 1 mesothelioma and 1 cystic adenoid. 50% pts had related AEs, being 94% G1-2 and 6% G3-4 (thrombocytopenia in 2 pts in C1 and C2, both considered DLT and recovered) BO112 was not detected in blood in any pts. Table summarizes the biological parameters that increase after BO112 treatment in tumor/blood samples.Table:
|TUMOR, N (%)||BLOOD, N (%)|
|COHORT (N)||NECROSIS- APOPTOSIS||CD8||CD4||IFN-gamma||CICs|
|1 (6)||4/5 (80)||2/5 (40)||4/5 (80)||3/5 (60)||6/6 (100)|
|2 (7)||4/5 (80)||2/5 (40)||4/5 (80)||1/1 (100)||6/6 (100)|
|3 (3)||3/3 (100)||0/3 (0)||0/2 (0)||NA||2/3 (67)|
BO112 demonstrated a manageable safety profile. Its biological activity is consistent with both a direct antitumor effect and with intratumoral and systemic immunity activation, driven by IFN-gamma pathway. 1mg qw x 2-3 doses in combination with anti-PD-1 is the chosen regimen for an expansion cohort in pts refractory to anti-PD-1 therapy.
Clinical trial identification
NCT02828098 Release date: June 23, 2016
Legal entity responsible for the study
I. Marquez Rodas: Advisory role form BMS, MSD, Novartis, Roche, Pierre Fabre, Amgen and Bioncotech S. Lopez-Tarruella Cobo: Advisory Role (Novartis, Pfizer, Celgene) y Honoraria/lecturer (Novartis, Pfizer, AZ, Celgene, Roche) L. Planelles, M. Quintero: Bioncotech (employment) S. Martin Algarra: Advisory role for BMS, MSD, Novartis, Roche, Amgen I. Melero: Advisory role/consulting AstraZeneca; Bristol-Myers Squibb; Pfizer; Roche/Genentech All other authors have declared no conflicts of interest.