Jose Arganda Carrillo, Santosh Kesari, Jaya Mini Gill, Charles Redfern, Sean Carrick, Ivan Babic
Background: Pritumumab, a fully human IgG1 (kappa) monoclonal antibody (mAb), was originally isolated from a patient with cervical carcinoma. This classical example of a natural human anti-cancer antibody recognizes an altered form of the cytoskeletal protein vimentin, referred to as ectodomain vimentin (EDV). EDV is an ideal target for immunotherapy as it is expressed on the surface of tumor cells and is significantly overexpressed in glioblastomas (GBM). A multi-center phase 1 study was performed to assess the safety and pharmacokinetics of Pritumumab (NCT04396717). Methods: Eligible patients included age ≥18 years, histologically confirmed diagnosis of a central nervous system cancer, and have failed prior standard therapy. Exclusion criteria included insufficient time from prior therapy characterized as less than 28 days from cytotoxic therapy, less than 14 days from non-cytotoxic investigational agent, and less than 7 days for non-cytotoxic or immunotherapy agent. Dose Escalation Schema: Five cohort arms with up to 6 patients at each dose level included Cohort 1 (1.6 mg/kg), Cohort 2 (4.8 mg/kg), Cohort 3 (8.0 mg/kg), Cohort 4 (12.0 mg/kg), and Cohort 5 (16.2 mg/kg) on weekly 3+3 dosing schedule. Dose escalation was based on the dose-limiting toxicities (DLT) encountered through Day 28 of treatment. Pharmacokinetics:Blood and CSF samples were collected for pharmacokinetic (PK) analysis both pre- and post-dose. Results: 24 patients provided informed consent and 9 were excluded for not meeting eligibility. 15 patients received the investigational agent and were evaluable for safety and efficacy analyses. 12/15 patients had a diagnosis of glioblastoma and one patient each had anaplastic astrocytoma, oligodendroglioma, and non-small lung cancer with brain metastases. 13 patients discontinued treatment due to disease progression, one due to PI discretion for an unrelated CNS infection, and one withdrew for personal reasons. One partial response showed nearly a 98.0% and 40.8% reduction in 2 tumor lesions for 17 months on study. There were no dose-limiting toxicities to this natural human IgG mAb. The most common adverse events at least possibly attributed to Pritumumab were fatigue (53.3%) and constipation (33.3%). Other rare side effects, possibly related to Pritumumab, occurred at 6.7% were nausea, joint tenderness, dehydration, hypomagnesemia, neuropathy, pruritus, scalp dryness, dry skin (face), and depression. There were no Grade 3, 4, or 5 adverse events attributed to pritumumab. Preliminary pharmacokinetic (PK) data shows volume of distribution as 38.36 mL/kg and clearance of Pritumumab as 0.1305 mL/h/kg. The half-life of Pritumumab was found to be 12.5 days. Conclusions: Single agent Pritumumab is safe up to a dose of 16.2 mg/kg every 7 days in brain tumor patients. A phase 2 study is being planned as single agent and in combination with checkpoint inhibitors in both recurrent gliomas and upfront with chemoradiation in newly diagnosed gliomas. Clinical trial information: NCT04396717.