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First-In-Human Study of Utomilumab, a 4-1BB/CD137 Agonist, in Combination with Rituximab in Patients with Þ Follicular and Other CD20 Non-Hodgkin Lymphomas a C Ajay K

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First-In-Human Study of Utomilumab, a 4-1BB/CD137 Agonist, in Combination with Rituximab in Patients with Þ Follicular and Other CD20 Non-Hodgkin Lymphomas a C Ajay K Published OnlineFirst March 6, 2020; DOI: 10.1158/1078-0432.CCR-19-2973 CLINICAL CANCER RESEARCH | CLINICAL TRIALS: IMMUNOTHERAPY First-in-Human Study of Utomilumab, a 4-1BB/CD137 Agonist, in Combination with Rituximab in Patients with þ Follicular and Other CD20 Non-Hodgkin Lymphomas A C Ajay K. Gopal1, Ronald Levy2, Roch Houot3,4,5, Sandip P. Patel6, Leslie Popplewell7, Caron Jacobson8, Xinmeng J. Mu9, Shibing Deng9, Keith A. Ching9, Ying Chen9, Craig B. Davis9, Bo Huang10, Kolette D. Fly10, Aron Thall9, Adrian Woolfson11, and Nancy L. Bartlett12 ABSTRACT ◥ Purpose: In this phase I study (NCT01307267), we evaluated the utomilumab treatment-related adverse events (AE) were safety, pharmacokinetics, clinical activity, and pharmacodynamics grade 1 to 2; the most common AE was fatigue (16.4%). The of treatment with utomilumab plus rituximab in patients with pharmacokinetics of utomilumab in combination with rituximab þ relapsed/refractory follicular lymphoma (FL) and other CD20 was linear in the 0.03 to 10 mg/kg dose range. A low incidence non-Hodgkin lymphomas (NHL). (1.5%) of treatment-induced antidrug antibodies against Patients and Methods: Primary objectives were to assess treat- utomilumab was observed. The objective response rate was ment safety and tolerability for estimating the MTD, using a 21.2% (95% CI, 12.1%–33.0%) in all patients with NHL, includ- modified time-to-event continual reassessment method, and select- ing four complete and 10 partial responses. Analysis of paired ing the recommended phase II dose (RP2D). biopsies from a relapsed/refractory FL patient with complete Results: Sixty-seven patients received utomilumab (0.03– response showed increased T-cell infiltration and cytotoxic 10.0 mg/kg every 4 weeks) and rituximab (375 mg/m2 weekly) activity in tumors. Biomarker correlations with outcomes in the dose-escalation groups or utomilumab (1.2 mg/kg every suggested that clinical benefit may be contingent on patient 4 weeks) plus rituximab in the dose-expansion cohort. No immune function. patient experienced dose-limiting toxicity. The MTD for Conclusions: Utomilumab in combination with rituximab utomilumab in combination with rituximab was not reached demonstrated clinical activity and a favorable safety profile in þ and estimated to be ≥10mg/kgevery4weeks.Themajorityof patients with CD20 NHLs. Introduction immunotherapeutic approaches including 4-1BB/CD137, pro- grammed death 1 (PD-1), and PD-ligand 1 (PD-L1) targeted anti- Treatment with anti-CD20 antibodies, such as rituximab, induces þ bodies, as well as bispecific antibodies and chimeric antigen receptor responses in most patients with CD20 non-Hodgkin lymphoma (CAR) T cells are currently under investigation in patients with NHL (NHL) and results in a significant reduction in the risk of death (1). and other hematologic malignancies (4–14). The antitumor activity of rituximab is believed to be mediated in part The anti-epidermal growth factor receptor (EGFR) antibody cetuxi- by antibody-dependent cellular cytotoxicity (ADCC; ref. 1). However, mab has been reported to enable cross-presentation of tumor antigens a substantial proportion of patients develop resistance to treatment, by dendritic cells and enhance EGFR-targeted cytotoxic T lymphocyte underscoring the need for more effective strategies (1–3). A variety of (CTL) responses in patients with head and neck squamous cell carcinoma (HNSCC; ref. 15). Treatment of patients with HNSCC with a combination of cetuximab and the 4-1BB/CD137 agonist 1University of Washington, Fred Hutchinson Cancer Research Center, Seattle antibody urelumab was associated with elevated levels of activated Cancer Care Alliance, Seattle, Washington. 2Stanford Cancer Center, Stanford, California. 31 CHU Rennes, Service Hematologie Clinique Rennes, France. 4Uni- natural killer (NK) cells, myeloid cells, and T cells in circulation (16). versity of Rennes, EFS, Microenvironment, Cell Differentiation, Immunology and These data support the hypothesis that 4-1BB/CD137 agonist anti- Cancer Rennes, France. 5INSERM 0203, Unite d'Investigation Clinique, Rennes, bodies can increase innate and adaptive immune responses arising France. 6University of California at San Diego Moores Cancer Center, San Diego, after treatment with ADCC-competent antibodies. 7 8 California. City of Hope National Medical Center, Duarte, California. Dana- Utomilumab (PF-05082566) is a fully-human IgG2 agonist mAb 9 fi Farber Cancer Institute, Boston, Massachusetts. P zer Oncology, San Diego, that selectively binds human 4-1BB/CD137, resulting in NF-kB California. 10Pfizer Oncology, Groton, Connecticut. 11Pfizer Oncology, New York, New York. 12Washington University School of Medicine, Siteman Cancer Center, activation and downstream cytokine production in cell lines and St Louis, Missouri. primary lymphocytes (17). Utomilumab can induce human leukocyte proliferation and has demonstrated significant antitumor activity as a Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). single agent in human peripheral blood lymphocyte (PBL) SCID xenograft tumor models (17). Corresponding Author: Ajay K. Gopal, University of Washington/Seattle Cancer Utomilumab was well tolerated and active both as a single agent and Care Alliance, SCCA, 825 Eastlake Avenue East, CE3-300, Seattle, WA 98109. – Phone: 206-606-2037; Fax: 206-606-1130; E-mail: [email protected] in combination with the anti PD-1 antibody pembrolizumab, in patients with advanced solid tumors (18, 19). Durable responses Clin Cancer Res 2020;XX:XX–XX (duration >6 months) have been observed following single-agent or doi: 10.1158/1078-0432.CCR-19-2973 combination treatment in patients with Merkel cell carcinoma, non– Ó2020 American Association for Cancer Research. small cell cancer and small cell lung cancer, renal cell carcinoma, AACRJournals.org | OF1 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst March 6, 2020; DOI: 10.1158/1078-0432.CCR-19-2973 Gopal et al. product of the diameters >2.25 cm2; Eastern Cooperative Oncology Translational Relevance Group (ECOG) performance status ≤1; absolute neutrophil count Prior studies have shown that 4-1BB/CD137 agonistic antibo- ≥1.0 Â 109/L; platelet count ≥75 Â 109/L; hemoglobin ≥8.0 g/dL; and dies can deliver costimulatory signals, enhancing antibody- adequate renal, hepatic, and cardiac functions. dependent cellular cytotoxicity and potentially eliciting T-cell– Exclusion criteria included prior allogeneic hematopoietic stem cell mediated antitumor immune responses. To evaluate new treatment transplant, any anticancer therapy or hematopoietic growth factors strategies for relapsed/refractory disease after rituximab therapy, within 28 days or systemic corticosteroid therapy or radiation therapy þ patients with follicular lymphoma (FL) and other CD20 relapsed/ within 14 days prior to the first dose of study treatment, prior refractory non-Hodgkin lymphomas (NHL) were treated with the treatment with a 4-1BB/CD137 agonist, an autoimmune disorder or anti–4-1BB/CD137 antibody utomilumab and rituximab. Utomi- an active clinically significant infection, a severe allergic or anaphy- lumab has previously demonstrated a well-tolerated safety profile lactic reaction to antibodies or infused therapeutic proteins, and and antitumor activity as monotherapy or in combination with the known utomilumab and/or rituximab antidrug antibodies (ADA). anti-programmed death 1 (PD-1) antibody pembrolizumab in Furthermore, patients were not included if they had symptomatic patients with advanced solid tumors. In this phase I study, com- brain metastases requiring steroid therapy. Patients were eligible if bined treatment with utomilumab plus rituximab showed a favor- they had completed treatment for their brain metastases and recovered able safety profile and clinical activity in patients with relapsed/ from the acute effects of radiation therapy or surgery, had discontinued þ refractory FL and other CD20 NHLs. corticosteroids for ≥4 weeks, and were neurologically stable. The study was approved by the institutional review board or independent ethics committee of the participating institutions and followed the Declaration of Helsinki and the International Conference squamous cell carcinoma of the head and neck, and thyroid on Harmonization Good Clinical Practice guidelines. All subjects cancer (18, 19). Treatment with utomilumab was associated with a provided written informed consent. The study was sponsored by Pfizer favorable safety profile, with no dose-limiting toxicities (DLT) and no and registered at ClinicalTrials.gov (NCT01307267). treatment-related deaths at the doses evaluated. Treatment-emergent adverse events (AE) were mostly mild or moderate in severity (18, 19). Treatment In this phase I, dose-finding study, we assessed the safety, tolera- Utomilumab was administered as a 1-hour intravenous infusion bility, pharmacokinetics, preliminary clinical activity, and pharmaco- every 4 weeks. In dose escalation, patients were assigned to receive dynamics of treatment with utomilumab in combination with rituxi- utomilumab at a starting dose of 0.03 mg/kg, with the dose being mab in patients with relapsed or refractory follicular lymphoma (FL) escalated/de-escalated in subsequent dose cohorts to: 0.06, 0.12, 0.18, þ and other CD20 NHLs. Potential associations between clinical out- 0.24, 0.30, 0.60, 1.2, 2.4, 5.0, and 10 mg/kg, using
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