Tozuleristide is a conjugate of an indocyanine green (ICG; a near-infrared fluorescent dye) and a tumor homing peptide that enables selective targeting and cell internalization for multiple tumor types, including low and high grade CNS tumors and breast cancer, and is in development as an adjunct for intraoperative identification of tumor tissue.  Two Phase 1 studies in subjects with pediatric and adult CNS tumors provided favorable safety and dose-response data and established clinical proof of concept, with 81% sensitivity and 93% positive predictive value in pediatric tumors.  Extensive discussions were held with FDA on the design of the pivotal Phase 2/3 trial Study BB-006, which had 4 co-primary endpoints: the sensitivity and specificity of tozuleristide fluorescence, and demonstration of superiority to surgeon designation of tumor or non-tumor, via ratios for both sensitivity and specificity (tozuleristide/surgeon) >1.  These endpoints were based on “equivocal tissues” that the surgeons identified under white light (only) and considered ambiguous as tumor or normal tissue, but nonetheless assigned a surgeon designation as more or less likely tumor.  Fluorescence assessment by an Imaging Operator not involved in the conduct of the surgery, but viewing fluorescence on a monitor in real-time, and surgeon designation for each equivocal tissue were compared to histopathology, with tumor cellularity >1% considered tumor positive.

Study BB-006 enrolled 118 subjects between November 2018 and March 2022, of whom 105 on the treatment arm received 15 mg/m² tozuleristide by IV bolus injection between 1 to 36 hrs prior to surgery.  Tozuleristide was safe and well tolerated with only 5 (all Grade 1 or 2) of 1291 treatment emergent adverse events considered potentially related to tozuleristide.  Tozuleristide fluorescence had sensitivity of 79.8% (95% CI 70.2, 90.2%) for identifying tumor in equivocal tissues, which exceeded the pre-defined success criterion of 60%.  The ratio (tozuleristide/surgeon) for sensitivity was ~1.1 but the 95% CI did not exclude 1, therefore the success criteria for the ratio was not met.  Specificity depends entirely on normal tissue collection and therefore its robust estimation would have required resecting a markedly greater number than the ~50 obtained in the trial.  Specificity is therefore considered poorly estimated in the study for both tozuleristide and surgeon designation and the success criteria for tozuleristide specificity (threshold and ratio to surgeon designation) were not met.  In hindsight, sufficient power for the specificity and ratio endpoints would have likely required the collection of perhaps thousands of normal brain tissues and ~3- to 4-fold the number of subjects enrolled, which are not ethical or feasible in this rare patient population.

Study BB-006 was designed and conducted as an apparent shift in the US regulatory landscape for fluorescence guided surgery agents began with the approval of 5-ALA in adult high grade glioma (2017), continuing through the approvals of pafolacianine in ovarian and lung cancer (2021, 2022) and pegulicianine in breast cancer (2024).  Differences between Study BB-006 and the pivotal trials for the approved agents will be discussed, as will the outcome of ongoing discussions with FDA on a new pivotal trial for tozuleristide in patients with pediatric primary CNS tumors.

Presenter Biography:
Graham Jang is Executive Vice President, Head of Research & Development at Blaze Bioscience, and has over 25 years industry experience in all phases of drug discovery and development, with key individual and team leadership roles for dozens of INDs or other development phase transitions and numerous BLA or NDA submissions and approvals. Prior to joining Blaze in 2022, Graham gained this experience through roles with increasing levels of responsibility at Bristol Myers-Squibb, Amgen, Seattle Genetics, Regulus and Silverback Therapeutics.

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