Abstract CT101: Phase I safety and bioimaging trial of ifabotuzumab in patients with glioblastoma

Abstract

Overview Glioblastoma multiforme (GBM) is the most frequent and lethal primary brain neoplasm, with only 10% of patients surviving 5 years.1 EphA3 is a tumor restricted antigen expressed in various solid tumors and the tumor vasculature of 100% of GBM.2,3 Ifabotuzumab is a non-fucosylated IgG1κ humaneered antibody targeting the EphA3 receptor.4 A Phase I study of ifabotuzumab in haematological malignancies showed it was well tolerated and clinically active.5 Here we report on a Phase I dose escalation and biodistribution study of ifabotuzumab in recurrent GBM. Study Design The primary objective is to determine the safety and recommended Phase II dose of ifabotuzumab in GBM patients (pts). Secondary objectives are to determine the biodistribution and pharmacokinetics (PK) of 89Zr- ifabotuzumab, the frequency of EphA3 positive GBM and response rates. On day 1, eligible pts with measurable tumors received a trace (5mg) dose of zirconium labelled ifabotuzumab (89Zr-ifab) followed by sequential PET imaging over 1 week to determine its biodistribution, frequency of in situ EphA3 expression and quantitative tumor uptake. Safety assessments and PK sampling were also undertaken. On day 8, pts commenced weekly ifabotuzumab infusions over 2 hours in one of two cohorts (3.5mg/kg, 5.25 mg/kg). On day 36, pts received both 89Zr-ifab and ifabotuzumab, allowing assessment of receptor occupancy. Response rate (RANO) and survival data were collected. Pts then continued on ifabotuzumab until progression. Results In total, 12 pts have been enrolled, including 6 in the 3.5mg/kg and 6 in the 5.25 mg/kg dose cohorts. Mean age was 51.6 years (±14.24) and 7/12 pts were male. Treatment emergent adverse events included infusion reactions in 4 pts, seizures in 3 pts, cerebral oedema in 1, rash in 1, headaches in 8, eye disorder in 1. Most were considered related to study drug except seizure in 2 pts, headaches and eye disorder. Seizures and infusion reactions were readily managed with increased premedications after the first occurrence. The best response was stable disease for 23 weeks. 89Zr-ifab-PET scans showed rapid, tumor-specific targeting at all known tumor sites and in all pts, but with no normal tissue uptake. MRI scans showed predominant T2/FLAIR changes, occasionally marked, which were consistent with treatment effect of ifabotuzumab on tumor vasculature. The mean ± SD (n=12) PK parameters for first infusion 89Zr-ifab were T½α= 9.03 ± 4.45 hr, T½β = 92.50 ± 65.65 hr, V1 = 3.75 ± 0.67 L, CL= 132.11 ± 70.16 mL/hr. Conclusions: Ifabotuzumab demonstrates highly sensitive, specific and reproducible targeting of the tumor and tumor microenvironment in all patients in this study. The imaging changes suggest direct modulation of the tumor vasculature. Additional studies are planned to evaluate ifabotuzumab as part of an antibody-drug conjugate in various solid tumor types. References: 1. Stupp R, et al, Lancet Oncology 10:459-66, 2009 2. Day BW, et al. Cancer Cell 23:238-48, 2013 3. Vail ME, et al. Cancer Research 74:4470-81, 2014 4. Tomasevic N, et al. Growth Factors 32:223-35, 2014 5. Swords RT, et al. Leukemia Research 50:123-131, 2016 Citation Format: Hui K. Gan, Lawrence Cher, Po Inglis, Zarnie Lwin, Eddie Lau, Christian Wichmann, Alex McDonald, Ashray Gunjur, Uwe Ackermann, Kirsten Remen, Kate Fluck, Gel Bolarnos, Nancy Guo, Sze Ting Lee, Sylvia Gong, Jodie B. Palmer, Kunthi Pathmaraj, Graeme J. O'Keefe, Fiona E. Scott, Bryan W. Day, Andrew W. Boyd, Paul Thomas, Omar Ahmed, Dale Chappell, Cameron Durrant, Andrew M. Scott. Phase I safety and bioimaging trial of ifabotuzumab in patients with glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT101.

Antibody-Based Formats to Target Glioblastoma: Overcoming Barriers to Protein Drug Delivery

“…Marin et al ascribed nonuniform distribution across the BBB as the possible reason for limited efficacy of the candidate ADC . Nonetheless, other tumor-associated antigens (TAAs) like IL-13RA2, glypican-1 (GPC-1), , and the ephrin receptor family ,− are currently being considered as alternative GB targets for novel ADC engineering.…”