This is a study of drug KB004 in patients with recurrent glioblastoma (GBM). Eligible patients with measurable tumours will receive an initial trace (5mg) dose of zirconium labelled KB004 (89ZrKB004) on day 1 followed by sequential Positron emission tomography (PET) imaging over 1 week to determine its biodistribution into GBM and normal tissues. Safety assessments and pharmacokinetic (movement of drug) sampling will also be undertaken over this time. On Day 8, patients commence weekly KB004 infusions over 2 hours with standard premedications. Three cohorts are planned in this study (3.5mg/kg, 5.25 mg/kg, 7.9 mg/kg; additional dose levels may be explored based on toxicity, efficacy and biodistribution data as determined by the safety monitoring committee). On day 36, patients receive both 89ZrKB004 and KB004, allowing assessment of receptor occupancy to guide recommended phase two dose (RPTD) determination. Response rate (RANO) and survival data will be collected and patients benefiting may continue KB004 treatment until disease progression. Primary objective: to determine the toxicity and recommended phase two dose (RPTD) of KB004 in patients with advanced Glioblastoma (GBM).

Secondary objectives: to determine the biodistribution and pharmacokinetics of 89ZrKB004; to determine frequency of EphA3 (ephrin receptor A3) positive glioblastoma in archival specimens and by 89ZrKB004 scans, and correlate with known biomarkers; to describe response rates per RANO criteria (Response Assessment in Neuro-Oncology Criteria) and pharmacodynamics following KB004 infusion; Exploratory objectives: to perform exploratory analysis between clinical outcomes and biodistribution/Pharmacokinetics (PK)/pharmacodynamics (PD) data, including from matched biopsies.

Inclusion Criteria:

• Adults (greater than or equal to 18 years of age) with histologically proven glioblastoma
• Evidence of progressive glioblastoma (if within 3 months of radiotherapy, then progression outside of radiotherapy field is required)
• Measurable disease by RANO (Response Assessment in Neuro-Oncology Criteria)
• ECOG (Eastern Cooperative Oncology Group score) 0 to 1
• Expected survival more than 3 months
• Steroid dose less than 2.5 mg per day dexamethasone equivalents and stable or reducing for 1 week prior to day 1
• Archived (formalin fixed paraffin embedded) tissue or frozen tumour tissue or consent to obtain a fresh tumour biopsy at enrolment is required.
• Adequate organ function. Out of range values that are not clinically significant will be permitted, except for the following laboratory parameters which must be within the ranges specified
• Neutrophils greater than or equal to 1.5 x 109 per L
• Platelets greater than or equal to 100 x 109 per L
• International Normalised Ratio less than or equal to 1.4
• Serum Aspartate aminotransferase and Alanine aminotransferase less than or equal to 2.5 x ULN (upper limit of normal)
• Serum bilirubin less than or equal to 1.5 x ULN (upper limit of normal)

Exclusion Criteria:

• Evidence of infratentorial, extracranial or leptomeningeal disease
• More than one prior systemic therapy for progressive disease or prior Steriotactic radiosurgery (SRS) to sites of GB (glioblastoma).
• Prior treatment with bevacizumab or gliadel wafers
• Evidence of current or prior intracranial hemorrhage
• Need for anti-platelet or anti-coagulant drugs
• Use of anti-cancer therapy including craniotomy, chemotherapy, immunotherapy, radiotherapy, or any investigational therapy within 28 days prior to Study Day 1
• History of major immunologic reaction to any immunoglobulin G containing agent
• Medical conditions which place the subject at an unacceptably high risk
• Subject is pregnant, lactating or unwilling or unable to use adequate contraception