No treatment-related deaths were observed
No treatment-related deaths were observed. Table 2 Safety summary in the as-treated population Pipequaline hydrochloride adverse event aPatients were counted once for each category Plat regardless of the number of events Table 3 Any-grade treatment-related AEs occurring in 10% of total population and all grade??3 treatment-related AEs adverse event aPatients were counted once for each category regardless of the number of events AEs of special interest Grade 3 treatment-related AESIs occurred in 4/58 patients (7%): ALT and AST increases and autoimmune hepatitis (mutations) and 5 had kidney cancer, including 1 who had a CR. allogeneic dendritic cellCT cell mixed lymphocyte reactions. (b) Cellular cytotoxicity mediated by EBV-reactive CD8 T cells over time, as determined by noninvasive electrical impedance measurement in an xCelligence RTCA MP instrument as a surrogate for cell death. Physique S5. Representative examples of flow cytometry of peripheral blood from patients treated with MEDI0680. (a) Ki67 staining in CD4+ and CD8+ T cells at cycle 1 day 1 pre-treatment (C1D1) and at cycle 1 day 8 post-treatment, as indicated. (b) HLA-DR and CD38 co-staining on CD4+ effector memory T cells (CD4+ TEM) at the same time points. Figure S6. Lack of correlation between changes in peripheral pharmacodynamic markers and objective clinical response. (a) Fold change in the indicated cytokine and chemokine markers in all cohorts or (b) only in the 10 and 20mg/kg cohorts or (c) the fold change in T-cell proliferation and CD4+ TEM CD38high HLA-DRhigh (activated) T cells with respect to objective clinical responses are shown. Table S1. Key eligibility criteria. Table S2. Patient characteristics Pipequaline hydrochloride and samples evaluated for pharmacodynamic analysis. Table S3. In silico identification of PD-1 paralogs using the protein Basic Local Alignment Search Tool BLASTp. Table S4. Study disposition (as-treated populace). (ZIP 5.02 mb) 40425_2019_665_MOESM1_ESM.zip (5.0M) GUID:?EA697658-613B-49D5-B0DB-2512C947592C Data Availability StatementThe clinical dataset analyzed during the current study is available at clinicaltrials.gov, https://clinicaltrials.gov/ct2/show/results/NCT02013804. Other datasets used and/or analyzed during the current study are available and may be obtained in accordance with AstraZenecas data sharing policy, which is usually described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Abstract Background The safety, efficacy, pharmacokinetics, and pharmacodynamics of the anti-programmed cell death-1 antibody MEDI0680 were evaluated in a phase I, multicenter, dose-escalation study in advanced solid malignancies. Methods MEDI0680 was administered intravenously once every 2 weeks (Q2W) or once every 3 weeks at 0.1, 0.5, 2.5, 10 or 20?mg/kg. Two cohorts received 20?mg/kg once a week for 2 or 4?weeks, then 20?mg/kg Q2W. All were treated for 12?months or until progression. The primary endpoint was safety. Secondary endpoints were efficacy and pharmacokinetics. Exploratory endpoints included pharmacodynamics. Results Fifty-eight patients were treated. Median age was 62.5?years and 81% were male. Most had kidney cancer (Eastern Cooperative Oncology Group, fragment crystallizable, non-small cell lung cancer, programmed cell death ligand-2 aData unavailable for 1 patient bAll tumors harboring mutations had mutations except for 1 with mutation cIncludes adenoma of unknown primary, cellular uterine leiomyoma, and fallopian tube carcinoma dIncludes 1 patient enrolled before the May 2014 amendment who received prior AMP-224 PD-L2 Fc fusion protein and 1 patient who received prior pegylated interferon alfa-2b, recorded as an immunotherapy by the investigator eIncludes 1 patient who received the therapeutic anticancer vaccine, rocapuldencel-T, plus sunitinib The study design is shown in Additional file 1: Physique S1a, including dose levels and administration frequency for Pipequaline hydrochloride each dose cohort. Eligible patients had advanced solid malignancies that were refractory to standard therapy or for which no standard therapy existed. They were enrolled if they had 1 measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1), had not received previous anti-PD-1/PD-L1 antibodies (expanded in a protocol amendment in May 2014 to exclude any immunotherapy except therapeutic cancer vaccines), had sufficient organ function, and had an Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1. Based on accumulating evidence of response to PD-1 inhibition in kidney cancer and melanoma [31C35], the study protocol was amended to enroll only patients with these tumor types in cohorts 5C9. Therefore, the majority of patients had kidney cancer (62%) or melanoma (16%). Patients received MEDI0680 for 12?months or until progressive disease; those maintaining disease control were followed for an additional 12?months. All patients were followed long-term for survival. Retreatment was permitted in cases of progression during the 12-month follow-up period. Endpoints and assessments Primary The primary endpoint was safety, assessed by evaluating dose-limiting toxicities Pipequaline hydrochloride (DLTs), adverse events (AEs), serious adverse events (SAEs), laboratory evaluations, vital signs, physical examinations, and electrocardiograms. The National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 was used to classify and grade AEs and SAEs. Laboratory abnormalities were monitored from the start of the study until 12?months after the last dose of study Pipequaline hydrochloride drug, or until the patient withdrew from follow-up. Adverse events of special interest (AESIs) included AEs of hepatic function.