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

Abstract : Purpose - In this phase I study (NCT01307267), we evaluated safety, pharmacokinetics, clinical activity, and pharmacodynamics of treatment with utomilumab plus rituximab in patients with relapsed/refractory follicular lymphoma (FL) and other CD20 non-Hodgkin lymphomas (NHL). Patients and methods - Primary objectives were to assess treatment safety and tolerability for estimating the MTD, using a modified time-to-event continual reassessment method, and selecting the recommended phase II dose (RP2D). Results - Sixty-seven patients received utomilumab (0.03-10.0 mg/kg every 4 weeks) and rituximab (375 mg/m weekly) in the dose-escalation groups or utomilumab (1.2 mg/kg every 4 weeks) plus rituximab in the dose-expansion cohort. No patient experienced dose-limiting toxicity. The MTD for utomilumab in combination with rituximab was not reached and estimated to be ≥10 mg/kg every 4 weeks. The majority of the utomilumab treatment-related adverse events (AE) were grade 1 to 2; the most common AE was fatigue (16.4%). The pharmacokinetics of utomilumab in combination with rituximab was linear in the 0.03 to 10 mg/kg dose range. A low incidence (1.5%) of treatment-induced antidrug antibodies against utomilumab was observed. The objective response rate was 21.2% (95% CI, 12.1%-33.0%) in all patients with NHL, including four complete and 10 partial responses. Analysis of paired biopsies from a relapsed/refractory FL patient with complete response showed increased T-cell infiltration and cytotoxic activity in tumors. Biomarker correlations with outcomes suggested that clinical benefit may be contingent on patient immune function. Conclusions - Utomilumab in combination with rituximab demonstrated clinical activity and a favorable safety profile in patients with CD20 NHLs.
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https://hal-univ-rennes1.archives-ouvertes.fr/hal-02563360
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Submitted on : Tuesday, May 5, 2020 - 11:51:28 AM
Last modification on : Tuesday, September 1, 2020 - 10:03:42 AM

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Ajay K Gopal, Ronald Levy, Roch Houot, Sandip P Patel, Leslie Popplewell, et al.. First-in-Human Study of Utomilumab, a 4-1BB/CD137 Agonist, in Combination with Rituximab in Patients with Follicular and Other CD20 Non-Hodgkin Lymphomas. Clinical Cancer Research, American Association for Cancer Research, 2020, 26 (11), pp.2524-2534. ⟨10.1158/1078-0432.CCR-19-2973⟩. ⟨hal-02563360⟩

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