TY - JOUR
T1 - Safety and clinical activity of MEDI0562, a humanized OX40 agonist monoclonal antibody, in adult patients with advanced solid tumors
AU - Glisson, Bonnie S.
AU - Leidner, Rom S.
AU - Ferris, Robert L.
AU - Powderly, John
AU - Rizvi, Naiyer A.
AU - Keam, Bhumsuk
AU - Schneider, Reva
AU - Goel, Sanjay
AU - Ohr, James P.
AU - Burton, Jennifer
AU - Zheng, Yanan
AU - Eck, Steven
AU - Gribbin, Matthew
AU - Streicher, Katie
AU - Townsley, Danielle M.
AU - Patel, Sandip Pravin
N1 - Funding Information:
The study (NCT02318394) was funded by MedImmune, the manufacturer of MEDI0562.
Funding Information:
B.S. Glisson reports grants from MedImmune (fees paid to institution to support this clinical trial) during the conduct of the study, as well as grants from Pfizer, ISA Pharmaceuticals, Turnstone Bio, and Cue Bio (fees to institution to support clinical research) outside the submitted work. R.S. Leidner reports other from MedImmune (institutional research support) during the conduct of the study and grants from MedImmune outside the submitted work. R.L. Ferris reports other from Aduro Biotech (consulting), Amgen (advisory board), Bain Capital Life Sciences (consulting), EMD Serono (advisory board), GlaxoSmithKline (advisory board), Iovance Biotherapeutics (consulting), Lilly (advisory board), MacroGenics (advisory board), Nanobiotix (consulting), Numab Therapeutics AG (advisory board), Oncorus (advisory board), Ono Pharmaceutical Co. (consulting), Pfizer (advisory board), PPD (advisory board), Regeneron Pharmaceuticals (advisory board), and Torque Therapeutics (consulting); grants and other from AstraZeneca/MedImmune (advisory board, clinical trial, research funding), Bristol-Myers Squibb (advisory board, clinical trial, research funding), Tesaro (advisory board, research funding), and TTMS (consulting, research funding); and grants from VentiRx Pharmaceuticals (research funding) outside the submitted work. J. Powderly reports other from AbbVie (clinical trial funding) during the conduct of the study; other from AstraZeneca (clinical trial funding, consultancy, advisory), Bristol-Myers Squibb (clinical trial funding, speakers bureau, consultancy), Merck (speakers bureau, advisory role, laboratory contract research), EMD Serono (clinical trial funding), Macrogenics (clinical trial funding), InCyte (clinical trial funding), RAPT Therapeutics (clinical trial funding), Alkermes (clinical trial funding), Tempest (clinical trial funding), Curis (clinical trial funding, consultancy, advisory role), Corvus (clinical trial funding), Top Alliance BioSciences (clinical trial funding), Precision for Medicine (clinical trial funding), MT Group (clinical trial funding), StemCell (clinical trial funding), Carolina BioOncology Institute, PLLC (founder, owner), and BioCytics, Inc. (founder, owner) outside the submitted work; additionally, Carolina BioOncology Institute PLLC and BioCytics Inc. are both developing intellectual property for personalized autologous cell therapies. N.A. Rizvi reports personal fees from AstraZeneca during the conduct of the study; personal fees from AbbVie, Boehringer Ingelheim, Calithera, Dracen, Editas, EMD Serono, G1 Therapeutics, Genentech, Gilead, GlaxoSmithKline, Merck, Novartis, Takeda; and personal fees and other from Arcus (stock options) and Gritstone (stock and stock options) outside the submitted work; and reports being listed as a coinventor on a pending patent regarding identifying determinants of cancer response to immunotherapy (PCT/US2015/062208) filed by Memorial Sloan Kettering Cancer Center and licensed to Personal Genome Diagnostics with royalties paid. Y. Zheng reports personal fees from AstraZeneca (employment and stock ownership) both during the conduct of the study and outside the submitted work. K. Streicher reports personal fees from AstraZeneca (employment and stock options) both during the conduct of the study and outside the submitted work. D.M. Townsley reports other from AstraZeneca/ MedImmune (employee) during the conduct of the study. S.P. Patel reports other from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Illumina, Rakuten, Paradigm, and Tempus (scientific advisory income), as well as research funding from Bristol-Myers Squibb, Eli Lilly, Incyte, AstraZeneca/MedImmune, Merck, Pfizer, Roche/ Genentech, Xcovery, Fate Therapeutics, Genocea, and Iovance (to institution). No conflicts of interest were disclosed by the other authors.
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/10/15
Y1 - 2020/10/15
N2 - Purpose: Immune checkpoint blockade has demonstrated clinical benefits across multiple solid tumor types; however, resistance and relapse often occur. New immunomodulatory targets, which are highly expressed in activated immune cells, are needed. MEDI0562, an agonistic humanized mAb, specifically binds to the costimulatory molecule OX40. This first-inhuman study evaluated MEDI0562 in adults with advanced solid tumors. Patients and Methods: In this phase I, multicenter, open-label, single-arm, dose-escalation (3þ3 design) study, patients received 0.03, 0.1, 0.3, 1.0, 3.0, or 10 mg/kg MEDI0562 through intravenous infusion every 2 weeks, until confirmed disease progression or unacceptable toxicity. The primary objective evaluated safety and tolerability. Secondary endpoints included antitumor activity, pharmacokinetics, immunogenicity, and pharmacodynamics. Results: In total, 55 patients received ≥1 dose of MEDI0562 and were included in the analysis. The most common tumor type was squamous cell carcinoma of the head and neck (47%). Median duration of treatment was 10 weeks (range, 2-48 weeks). Treatment-related adverse events (TRAEs) occurred in 67% of patients, most commonly fatigue (31%) and infusion-related reactions (14%). Grade 3 TRAEs occurred in 14% of patients with no apparent dose relationship; no TRAEs resulted in death. Two patients had immune-related partial responses per protocol and 44% had stable disease. MEDI0562 induced increased Ki67þ CD4þ and CD8þ memory T-cell proliferation in the periphery and decreased intratumoral OX40þ FOXP3þ cells. Conclusions: MEDI0562 was safely administered at doses up to 10 mg/kg in heavily pretreated patients. On-target pharmacodynamic effects were suggested in this setting. Further evaluation with immune checkpoint inhibitors is ongoing.
AB - Purpose: Immune checkpoint blockade has demonstrated clinical benefits across multiple solid tumor types; however, resistance and relapse often occur. New immunomodulatory targets, which are highly expressed in activated immune cells, are needed. MEDI0562, an agonistic humanized mAb, specifically binds to the costimulatory molecule OX40. This first-inhuman study evaluated MEDI0562 in adults with advanced solid tumors. Patients and Methods: In this phase I, multicenter, open-label, single-arm, dose-escalation (3þ3 design) study, patients received 0.03, 0.1, 0.3, 1.0, 3.0, or 10 mg/kg MEDI0562 through intravenous infusion every 2 weeks, until confirmed disease progression or unacceptable toxicity. The primary objective evaluated safety and tolerability. Secondary endpoints included antitumor activity, pharmacokinetics, immunogenicity, and pharmacodynamics. Results: In total, 55 patients received ≥1 dose of MEDI0562 and were included in the analysis. The most common tumor type was squamous cell carcinoma of the head and neck (47%). Median duration of treatment was 10 weeks (range, 2-48 weeks). Treatment-related adverse events (TRAEs) occurred in 67% of patients, most commonly fatigue (31%) and infusion-related reactions (14%). Grade 3 TRAEs occurred in 14% of patients with no apparent dose relationship; no TRAEs resulted in death. Two patients had immune-related partial responses per protocol and 44% had stable disease. MEDI0562 induced increased Ki67þ CD4þ and CD8þ memory T-cell proliferation in the periphery and decreased intratumoral OX40þ FOXP3þ cells. Conclusions: MEDI0562 was safely administered at doses up to 10 mg/kg in heavily pretreated patients. On-target pharmacodynamic effects were suggested in this setting. Further evaluation with immune checkpoint inhibitors is ongoing.
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U2 - 10.1158/1078-0432.CCR-19-3070
DO - 10.1158/1078-0432.CCR-19-3070
M3 - Article
C2 - 32816951
AN - SCOPUS:85096057790
VL - 26
SP - 5358
EP - 5367
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 20
ER -