In preclinical studies, OX40 agonists have been shown to stimulate immune effector and memory T cell function while attenuating immunosuppressive function of regulatory T cells, leading to anti-tumor activity.
This is a Phase 1 study evaluating MEDI0562, a humanized OX40 agonist mAb, in adult pts with advanced solid tumors. The study has 2 phases: dose escalation and dose expansion. Dose escalation follows 3 + 3 design with pts enrolled in sequential cohorts of up to 6 dose levels of MEDI0562 (0.03, 0.1, 0.3, 1.0, 3.0, or 10 mg/kg, via intravenous infusion). Tumor assessments are performed every 8 weeks. Selected pts have mandatory pre- and on-treatment tumor biopsies to explore the relationship between drug exposure and pharmacodynamics. We report the preliminary results of safety, tumor response, pharmacokinetics, and pharmacodynamics in the dose escalation phase.
As of April 01 2016, 27 pts were treated (n = 7, 9, 7, 4 received 0.03, 0.1, 0.3, and 1 mg/kg MEDI0562, respectively). Adverse events (AEs) and treatment-related AEs were seen in 24 (88.9%) and 16 (59.3%) pts, respectively; the only related AE occurring in ≥ 10% of pts was fatigue (8/27, 29.6%). Most pts experienced AEs of Grade 1 and 2 in severity. Serious AEs (SAEs) were seen in 12 (44.4%) pts; no treatment-related or immune-related SAEs were observed. No related treatment discontinuations, deaths or dose limiting toxicities have occurred. Of 19 evaluable pts, 1 pt (0.03 mg/kg) with squamous cell carcinoma of the larynx had partial response at first tumor assessment and maintained for 3.7+ months (ongoing); 4 pts had stable disease. Serum exposure of MEDI0562 increased approximately dose proportionally. A 2-3-fold mean increase in peripheral Ki67+ CD4+ memory T cells was observed. Paired tumor biopsies showed induction of PD-L1 expression and increased CD8+ T cell infiltration in 2 of 3 evaluated pts, including 1 pt at 0.03 mg/kg. Updated clinical data will be presented at the meeting.
Preliminary data showed that MEDI0562 is generally well tolerated in adult pts with advanced solid tumors and exhibits clinical and pharmacological activity. A maximum tolerated dose has not been determined.
Clinical trial identification
Legal entity responsible for the study
B.S. Glisson: Research funding for Clinical Trials from Pfizer, Bristol Myers Squibb, Oncomed, Stemcentrx, and Medimmune provided for MD Anderson. I am a PI on these grants. R. Leidner: Research is being supported by: Medimmune/ Astra Zeneca and Bristol-Myers Squibb R.L. Ferris: Paid member of Advisory Board (Ad-Hoc)- Merck, Celgene, Bristol Myers Squibb, AZ/Medimmune Research/Grant Funding- VentiRx, Bristol Myers Squibb AZ/Medimmune. J. Powderly: Lion BioTechnologies, Juno Therapeutics, BlueBird Bio, Kite Pharma, ZioPharm Oncology, BMS, Genentech, EMD, Serono, AstraZeneca, InCyte, Macrogenics, Sequenom, Corvus, Carolina BioOncology Institute, PLLC, BioCytics Inc., Human Applications Lab, Merck. N. Rizvi: Consulting for AstraZeneca, Merck, Roche, Novartis, Lilly. Co-founder and shareholder, Gritstone Oncology. J.D. Norton: I am an employee of MedImmune LLC, a subsidiary of AstraZeneca, and hold restricted AstraZeneca stock shares. J. Burton: Employee of MedImmune Ltd. M.C. Lanasa: Employee of MedImmune LLC / AstraZeneca. S.P. Patel: Dr. Patel receives research funding from: MedImmune, Genentech, Pfizer, Amgen, Xcovery, Lilly, Bristol-Myers Squibb. He receives consulting fees from: Lilly, Pfizer. He receives speaking fees from: Boehringer Ingelheim, Merck.