A first-in-human (FIH) study of PF-04518600 (PF-8600) OX40 agonist in adult patients (pts) with select advanced malignancies

Background

Co-stimulation of activated T cells with agonistic monoclonal antibodies (mAb) against the tumor necrosis factor receptor superfamily member OX40 offers a novel immunotherapeutic approach to cancer. OX40 engagement may co-stimulate effector T cells and deplete regulatory T cells, resulting in enhanced tumor immunity. PF-8600 is a fully human agonist IgG2 mAb that targets OX40.

Methods

A Phase 1, open label, multicenter study is ongoing to evaluate safety, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity of PF-8600 in pts with advanced melanoma, head and neck squamous cell, renal cell, or hepatocellular carcinoma. PF-8600 was administered intravenously at increasing doses (0.01 – 3 mg/kg) every 2 weeks until disease progression or unacceptable toxicity. Additional biomarker cohorts (opened at each dose level except 0.01 mg/kg) enrolled pts who consented to baseline and on-treatment tumor biopsies for immune profiling by immunohistochemistry and RNAseq.

Results

As of 09 MAR 2016, 31 pts have enrolled in the dose-escalation phase of PF-8600 study: 0.01 mg/kg (2 pts), 0.1 mg/kg (10 pts), 0.3 mg/kg (8 pts), 1.5 mg/kg (7 pts) and 3 mg/kg (4 pts). 25.8% of patients received ≥ 4 prior therapies for advanced disease. No dose limiting toxicities, no drug-related or immune related grade (G) 3-5 adverse events (AEs) were observed. Drug-related AEs (DRAEs) were all G1/2 events and occurred in 21 pts (67.7%). The most common DRAEs were fatigue (29.0%) and decreased appetite (9.7%). Out of 25 pts evaluable for response, 1 pt experienced partial response (PR, -50%, confirmed), and 15 pts experienced stable disease (SD). 11 pts remain on treatment, and 5 patients continued treatment for >13 weeks. Assessment of peripheral blood lymphocyte indicated full OX40 receptor occupancy at ≥0.3 mg/kg, and maximal memory T cell proliferation at 0.1 and 0.3 mg/kg.

Conclusions

These preliminary results demonstrate that PF-8600 is safe up to 3 mg/kg. Updated safety, antitumor activity, and biomarker data will be presented.

Clinical trial identification

NCT02315066.

Legal entity responsible for the study

Pfizer, Inc.

Funding

Pfizer, Inc.

Disclosure

A. Diab: Advisory board for Nektar Therapeutics. A. El-Khoueiry: Grants:NCI/NIH, CTEP, SWOG Consultant: Genentech, Bayer, Astra-Zeneca, Medimmune, Celgene, BMS, Transgene Speakers Bureau: Merrimack Contracted. Research: Pfizer,CeloNova, Novartis, AstraZeneca, BMS, Genentech, Pfizer, Astex, Daiichi Sankyo, Nektar, Exelixis, Chiltern. F.A. Eskens: Adboard for Baxalta, Merck, AMGEN. C. Konto: Pfizer's employee and shareholder. C. Bermingham: I have Pfizer stock as part of my 401K. T. Joh: I am Pfizer employee, and stock owner. K. Liao: Currently, I am employed by Pfizer Inc. and own Pfizer stock. B. Ganguly: I am a Pfizer employee and that I own Pfizer stock. O. Hamid: Consulting: Amgen, Novartis, Roche, BMS. Speaker: Amgen, BMS, Genentech, Merck, Novartis. Contracted Research: Astra Zeneca, BMS, Celldex, Genentech, Immunocore, Incyte, Merck, Merck-Serano, MedImmune, Novartis, Pfizer, Rinat, Roche. All other authors have declared no conflicts of interest.