A first-in-human study of BLZ-100 (tozuleristide) demonstrates tolerability and safety in skin cancer patients

Miko Yamada, Dennis M Miller, Melinda Lowe, Casey Rowe, Dominic Wood, H Peter Soyer, Kelly Byrnes-Blake, Julia Parrish-Novak, Laura Ishak, James M Olson, Gordon Brandt, Paul Griffin, Lynda Spelman, Tarl W Prow, Miko Yamada, Dennis M Miller, Melinda Lowe, Casey Rowe, Dominic Wood, H Peter Soyer, Kelly Byrnes-Blake, Julia Parrish-Novak, Laura Ishak, James M Olson, Gordon Brandt, Paul Griffin, Lynda Spelman, Tarl W Prow

Abstract

BLZ-100 (tozuleristide) is an intraoperative fluorescent imaging agent that selectively detects malignant tissue and can be used in real time to guide tumor resection. The purpose of this study was to assess the safety, tolerability, and pharmacokinetics of BLZ-100 and to explore the pharmacodynamics of fluorescence imaging of skin tumors. In this first-in-human study, BLZ-100 was administered intravenously to 21 adult patients 2 days before excising known or suspected skin cancers. Doses were 1, 3, 6, 12, and 18 mg, with 3-6 patients/cohort. Fluorescence imaging was conducted before and up to 48 h after dosing. BLZ-100 was well tolerated. There were no serious adverse events, deaths, or discontinuations due to adverse events, and no maximum tolerated dose (MTD) was identified. Headache (n = 2) and nausea (n = 2) were the only BLZ-100 treatment-related adverse events reported for >1 patient. Median time to maximal serum concentration was <0.5 h. Exposure based on maximal serum concentrations increased in a greater than dose-proportional manner. For intermediate dose-levels (3-12 mg), 4 of 5 basal cell carcinomas and 4 of 4 melanomas were considered positive for BLZ-100 fluorescence. BLZ-100 was well tolerated at all dose levels tested and these results support further clinical testing of this imaging agent in surgical oncology settings. Clinicaltrials.gov: NCT02097875.

Keywords: CTX, chlorotoxin; Cystine-knot miniproteins; Fluorescent dyes; NCI CTCAE, National Cancer Institute's Common Terminology Criteria for Adverse Events; NMSC, non-melanoma skin cancer; PK, pharmacokinetic(s); Skin neoplasms.

Conflict of interest statement

DMM, JPN, and LI are employees or former employees of and hold equity in Blaze Bioscience, Inc. ML, KBB, and GB are consultants for Blaze Bioscience, Inc. and Blaze Bioscience Australia Pty Ltd. JMO is a co-founder of and holds equity in Blaze Bioscience, Inc. LS was a paid clinical investigator on the trial. HPS is a shareholder of MoleMap NZ Limited and e-derm consult GmbH and undertakes regular teledermatological reporting for both companies. HPS is a Medical Consultant for Canfield Scientific Inc., MetaOptima and Revenio Research Oy and also a Medical Advisor for First Derm.

© 2021 The Authors.

Figures

Fig. 1
Fig. 1
Mean (SD) Serum BLZ-100 Concentration vs Time Profiles after a Single IV Infusion of BLZ-100.
Fig. 2
Fig. 2
NIR imaging of a basal cell carcinoma from the 3 mg cohort (top row) and an amelanotic melanoma in situ from the 6 mg cohort (bottom row). (A, D) Clinical photographs. The image in panel A was adjusted for color balance and brightness. (B, E) NIR images taken before BLZ-100 administration. The arrows are paper pointers with fluorescing pigment indicating the clinically identified lesion. (C, F) NIR images (500 msec exposures) acquired 2 h after dosing with BLZ-100. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

References

    1. Harmsen S., Teraphongphom N., Tweedle M.F., Basilion J.P., Rosenthal E.L. Optical surgical navigation for precision in tumor resections. Mol. Imag. Biol. 2017;19:357–362.
    1. Alander J.T., Kaartinen I., Laakso A., Pätilä T., Spillmann T., Tuchin V.V., Venermo M., Välisuo P. A review of indocyanine green fluorescent imaging in surgery. Int. J. Biomed. Imag. 2012:940585. 2012.
    1. Tummers Q.R., Verbeek F.P., Schaafsma B.E., Boonstra M.C., van der Vorst J.R., Liefers G.J., van de Velde C.J., Frangioni J.V., Vahrmeijer A.L. Real-time intraoperative detection of breast cancer using near-infrared fluorescence imaging and Methylene Blue. Eur. J. Surg. Oncol. 2014;40:850–858.
    1. Schucht P., Murek M., Jilch A., Seidel K., Hewer E., Wiest R., Raabe A., Beck J. Early re-do surgery for glioblastoma is a feasible and safe strategy to achieve complete resection of enhancing tumor. PloS One. 2013;8
    1. Khanyile S., Masamba P., Oyinloye B.E., Mbatha L.S., Kappo A.P. Current biochemical applications and future prospects of chlorotoxin in cancer diagnostics and therapeutics. Adv. Pharmaceut. Bull. 2019;9:510–520.
    1. Baik F.M., Hansen S., Knoblaugh S.E., Sahetya D., Mitchell R.M., Xu C., Olson J.M., Parrish-Novak J., Mendez E. Fluorescence identification of head and neck squamous cell carcinoma and high-risk oral dysplasia with BLZ-100, a chlorotoxin-indocyanine green conjugate. JAMA Otolaryngol. Head Neck Surg. 2016;142:330–338.
    1. Fidel J., Kennedy K.C., Dernell W.S., Hansen S., Wiss V., Stroud M.R., Molho J.I., Knoblaugh S.E., Meganck J., Olson J.M., Rice B., Parrish-Novak J. Preclinical validation of the utility of BLZ-100 in providing fluorescence contrast for imaging spontaneous solid tumors. Canc. Res. 2015;75:4283–4291.
    1. Butte P.V., Mamelak A., Parrish-Novak J., Drazin D., Shweikeh F., Gangalum P.R., Chesnokova A., Ljubimova J.Y., Black K. Near-infrared imaging of brain tumors using the Tumor Paint BLZ-100 to achieve near-complete resection of brain tumors. Neurosurg. Focus. 2014;36:E1.
    1. Parrish-Novak J., Byrnes-Blake K., Lalayeva N., Burleson S., Fidel J., Gilmore R., Gayheart-Walsten P., Bricker G.A., Crumb W.J., Jr., Tarlo K.S., Hansen S., Wiss V., Malta E., Dernell W.S., Olson J.M., Miller D.M. Nonclinical profile of BLZ-100, a tumor-targeting fluorescent imaging agent. Int. J. Toxicol. 2017;36:104–112.
    1. Dintzis S.M., Hansen S., Harrington K.M., Tan L.C., Miller D.M., Ishak L., Parrish-Novak J., Kittle D., Perry J., Gombotz C., Fortney T., Porenta S., Hales L., Calhoun K.E., Anderson B.O., Javid S.H., Byrd D.R. Real-time visualization of breast carcinoma in pathology specimens from patients receiving fluorescent tumor-marking agent tozuleristide. Arch. Pathol. Lab Med. 2019;143:1076–1083.
    1. Patil C.G., Walker D.G., Miller D.M., Butte P., Morrison B., Kittle D.S., Hansen S.J., Nufer K.L., Byrnes-Blake K.A., Yamada M., Lin L.L., Pham K., Perry J., Parrish-Novak J., Ishak L., Prow T., Black K., Mamelak A.N. Phase 1 safety, pharmacokinetics, and fluorescence imaging study of tozuleristide (BLZ-100) in adults with newly diagnosed or recurrent gliomas. Neurosurgery. 2019;85:E641–E649.
    1. Azari F., Kennedy G., Bernstein E., Hadjipanayis C., Vahrmeijer A., Smith B., Rosenthal E., Sumer B., Tian J., Henderson E., Lee A., Nguyen Q., Gibbs S., Pogue B., Orringer D., Charalampaki C., Martin L., Tanyi J., Lee M., Lee J.Y., Singhal S. Intraoperative molecular imaging clinical trials: a review of 2020 conference proceedings. J. Biomed. Opt. 2021;26
    1. Debie P., Hernot S. Emerging fluorescent molecular tracers to guide intra-operative surgical decision-making. Front. Pharmacol. 2019;10:510.
    1. Liu R., Xu Y., Xu K., Dai Z. Current trends and key considerations in the clinical translation of targeted fluorescent probes for intraoperative navigation. Aggregate. 2021:1–23. 2021.
    1. Lee Y.J., Krishnan G., Nishio N., van den Berg N.S., Lu G., Martin B.A., van Keulen S., Colevas A.D., Kapoor S., Liu J.T.C., Rosenthal E.L. Intraoperative fluorescence-guided surgery in head and neck squamous cell carcinoma. Laryngoscope. 2021;131:529–534.
    1. Belykh E., Martirosyan N.L., Yagmurlu K., Miller E.J., Eschbacher J.M., Izadyyazdanabadi M., Bardonova L.A., Byvaltsev V.A., Nakaji P., Preul M.C. Intraoperative fluorescence imaging for personalized brain tumor resection: current state and future directions. Front Surg. 2016;3:55.
    1. Schupper A.J., Yong R.L., Hadjipanayis C.G. The neurosurgeon's armamentarium for gliomas: an update on intraoperative technologies to improve extent of resection. J. Clin. Med. 2021;10:236.
    1. Hoogstins C.E., Tummers Q.R., Gaarenstroom K.N., de Kroon C.D., Trimbos J.B., Bosse T., Smit V.T., Vuyk J., van de Velde C.J., Cohen A.F., Low P.S., Burggraaf J., Vahrmeijer A.L. A novel tumor-specific agent for intraoperative near-infrared fluorescence imaging: a translational study in healthy volunteers and patients with ovarian cancer. Clin. Canc. Res. 2016;22:2929–2938.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner