Abstract
1562
Objectives: Glioblastoma multiforme (GBM) is the most frequent and lethal primary brain neoplasm, with only 10% of patients surviving 5 years from diagnosis. EphA3 is a tumor restricted antigen expressed in 100% of the tumor vasculature as well as on some stromal cells in GBM, and other solid tumors. Ifabotuzumab is a non-fucosylated IgG1κ antibody targeting EphA3. A Phase I study of ifabotuzumab in hematological malignancies showed it to be well tolerated and clinically active. Here we report on a Phase I dose escalation and biodistribution study of ifabotuzumab in patients with recurrent GBM.
Methods: Eligible patients 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 and quantitative tumor uptake. Safety assessments and PK sampling were also undertaken. The primary objective is to determine the safety and recommended Phase II dose of ifabotuzumab in GBM patients. Secondary objectives are to determine the biodistribution and pharmacokinetics (PK) of 89Zr-ifabotuzumab, the frequency of EphA3-positive GBM, and response rates. On day 8, patients commenced weekly ifabotuzumab infusions over 2 hours in one of three cohorts 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. Patients then continued on ifabotuzumab until disease progression.
Results: To date, 8 of 12 planned patients have enrolled (6 at 3.5 mg/kg, 2 at 5.25 mg/kg). Mean age is 51 years (range 24-71 yrs) and 5 patients are male. Treatment emergent adverse events included infusion reactions in 3 patients, seizures in 2 patients, cerebral oedema in 2 patients, rash in 1 patient, pruritis in 1 patient, headaches in 7 patients and eye disorder in 2 patients. Most were considered related to study drug except seizure in 1 patient, headaches and eye disorder. Seizures and infusion reactions were readily managed with increased premedications after the first occurrence. The best response in cohort 1 (to date) is stable disease for 23 weeks. 89Zr-ifab PET/CT scans showed rapid, specific targeting at all known tumor sites and in all patients, and no specific normal tissue uptake. No saturation of uptake of 89Zr-ifab in tumor was seen with unlabelled ifabotuzumab co-infusion. MRI scans showed predominant T2/FLAIR changes, occasionally marked, which were consistent with treatment effect on tumor vasculature. The mean ± SD PK parameters for first infusion of 89Zr-ifab were T½α 10.54 ± 4.52 hr, T½β = 101.51 ± 54.08 hr, V1 = 3.89 ± 0.66 L, CL= 108.37 ± 46.43 mL/hr.
Conclusions: 89Zr-ifab demonstrates sensitive, specific and reproducible targeting of the tumor microenvironment in GBM patients. The imaging changes suggest modulation of the tumor vasculature and treatment effect. Enrolment is on-going.