Abstract CT063: Preliminary findings of a Phase I safety and bioimaging trial of KB004 (ifabotuzumab) in patients with glioblastoma
Authors: Gan Hui , Cher Lawrence , Inglis Po , Lwin Zarnie , Lau Eddie , Wichmann Christian , Ackermann Uwe , Coombs Nicole , Remen Kirsten , Guo Nancy , Lee Sze Ting , Gong Sylvia , Palmer Jodie B. , Pathmaraj Kunthi , O'Keefe Graeme , Scott Fiona , Day Bryan W. , Boyd Andrew W. , Thomas Paul , Durrant Cameron , Scott Andrew M. 
Published: August 2019

Overview: Glioblastoma (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 38-40% of GBM and 100% of the tumor vasculature (2, 3). Ifabotuzumab is a non-fucosylated IgG1K antibody targeting 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 toxicity 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. Eligible pts had measurable tumors received a trace (5mg) dose of zirconium-89 labelled ifabotuzumab (89Zr-ifab) on day 1 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 was also undertaken. On Day 8, pts commenced weekly Ifabotuzumab infusions over 2 hours. Three cohorts are planned (3.5mg/kg, 5.25 mg/kg, 7.9 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: To date, 4 of 12 planned pts have enrolled. Their mean age is 53 years (±16.3) and 3 are male. Treatment emergent adverse events included infusion reactions in 4 patients, seizures in 3 pts, cerebral oedema in 1, rash in 1, headaches in 1, 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/CT scans showed rapid, specific targeting at all known tumor sites and in all pts, but no normal tissue uptake. MRI scans showed predominant T2/FLAIR changes, occasionally marked, which were consistent with treatment effect on tumor vasculature. The mean ± SD (n=4) PK parameters for first infusion 89Zr-ifab were T½α= 10.63 ± 3.14 hr, T½β = 106.85 ± 40.60 hr, V1 = 3.88 ± 0.88 L, CL= 94.11 ± 36.54 mL/hr.

Conclusions: 89Zr-Ifabotuzumab demonstrates sensitive, specific and reproducible targeting of the tumor microenvironment in GBM patients. The imaging changes suggest modulation of the tumor vasculature. Enrolment is on-going.

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 Gan, Lawrence Cher, Po Inglis, Zarnie Lwin, Eddie Lau, Christian Wichmann, Uwe Ackermann, Nicole Coombs, Kirsten Remen, Nancy Guo, Sze Ting Lee, Sylvia Gong, Jodie B. Palmer, Kunthi Pathmaraj, Graeme O'Keefe, Fiona Scott, Bryan W. Day, Andrew W. Boyd, Paul Thomas, Cameron Durrant, Andrew M. Scott. Preliminary findings of a Phase I safety and bioimaging trial of KB004 (ifabotuzumab) in patients with glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT063.