Crystal Shereen Denlinger

Supplementary Table 1. Characteristics of patients with prolonged SD ({greater than or equal to}24 weeks)

Patients receiving MEDI1873 at doses ranging from 7.5-25 mg or 75-250 mg were assessed for changes in the soluble factors interferon gamma (IFNy), IFNy-induced protein 10 (IP-10), interferon-inducible T cell alpha chemoattractant(I-TAC), and monokine induced by IFNy (MIG).

Patients receiving MEDI1873 at doses ranging from 7.5-25 mg or 75-250 mg were assessed for changes in the soluble factors interferon gamma (IFNy), IFNy-induced protein 10 (IP-10), interferon-inducible T cell alpha chemoattractant(I-TAC), and monokine induced by IFNy (MIG).

Supplementary Table 1. Characteristics of patients with prolonged SD ({greater than or equal to}24 weeks)

Changes in peripheral GITR+ effector memory T-cells from baseline were measured in the 25 mg, 75 mg, 250 mg, and 500 mg cohorts.

Visits after Day 57 were excluded for visual purposes. The excluded visits were: Days 71, 85, 99, 127, 155, 183, 211, 239, 267, 295, 323 and 351.

Changes in peripheral GITR+ effector memory T-cells from baseline were measured in the 25 mg, 75 mg, 250 mg, and 500 mg cohorts.

Purpose:The safety and preliminary efficacy of MEDI1873, an agonistic IgG1 fusion protein targeting glucocorticoid-induced TNF receptor–related protein (GITR), were evaluated in an open-label, first-in-human, phase I, dose escalation study in previously treated patients with advanced solid tumors.Patients and Methods:Two single-patient cohorts at 1.5 and 3 mg i.v. were followed by 3+3 dose escalation in six cohorts at 7.5, 25, 75, 250, 500, and 750 mg, all every 2 weeks, for up to 52 weeks. Primary endpoints were safety and tolerability, dose-limiting toxicities (DLT), and MTD. Secondary endpoints included antitumor activity, pharmacokinetics, immunogenicity, and pharmacodynamics.Results:Forty patients received MEDI1873. Three experienced DLTs: grade 3 worsening tumor pain (250 mg); grade 3 nausea, vomiting, and headache (500 mg); and grade 3 non-ST segment elevation myocardial infarction (750 mg). An MTD was not reached and treatment was well tolerated up to 500 mg. Most common treatment-related adverse events were headache (25%), infusion-related reaction (17.5%), and decreased appetite (17.5%). MEDI1873 exposure was dose proportional. Antidrug–antibody incidence was low. MEDI1873 increased peripheral CD4+ effector memory T-cell proliferation as well as cytokines associated with effector T-cell activation at dose levels ≥75 mg. The best response was stable disease (SD) in 17 patients (42.5%), including 1 unconfirmed partial response. Eight patients (20.0%) had SD ≥24 weeks.Conclusions:MEDI1873 showed acceptable safety up to 500 mg i.v. every 2 weeks with pharmacodynamics activity, and prolonged SD in some patients. However, further development is not planned because of lack of demonstrated tumor response.

Purpose:The safety and preliminary efficacy of MEDI1873, an agonistic IgG1 fusion protein targeting glucocorticoid-induced TNF receptor–related protein (GITR), were evaluated in an open-label, first-in-human, phase I, dose escalation study in previously treated patients with advanced solid tumors.Patients and Methods:Two single-patient cohorts at 1.5 and 3 mg i.v. were followed by 3+3 dose escalation in six cohorts at 7.5, 25, 75, 250, 500, and 750 mg, all every 2 weeks, for up to 52 weeks. Primary endpoints were safety and tolerability, dose-limiting toxicities (DLT), and MTD. Secondary endpoints included antitumor activity, pharmacokinetics, immunogenicity, and pharmacodynamics.Results:Forty patients received MEDI1873. Three experienced DLTs: grade 3 worsening tumor pain (250 mg); grade 3 nausea, vomiting, and headache (500 mg); and grade 3 non-ST segment elevation myocardial infarction (750 mg). An MTD was not reached and treatment was well tolerated up to 500 mg. Most common treatment-related adverse events were headache (25%), infusion-related reaction (17.5%), and decreased appetite (17.5%). MEDI1873 exposure was dose proportional. Antidrug–antibody incidence was low. MEDI1873 increased peripheral CD4+ effector memory T-cell proliferation as well as cytokines associated with effector T-cell activation at dose levels ≥75 mg. The best response was stable disease (SD) in 17 patients (42.5%), including 1 unconfirmed partial response. Eight patients (20.0%) had SD ≥24 weeks.Conclusions:MEDI1873 showed acceptable safety up to 500 mg i.v. every 2 weeks with pharmacodynamics activity, and prolonged SD in some patients. However, further development is not planned because of lack of demonstrated tumor response.

Visits after Day 57 were excluded for visual purposes. The excluded visits were: Days 71, 85, 99, 127, 155, 183, 211, 239, 267, 295, 323 and 351.