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A Phase I, open-label, dose escalation study of MGA271 in combination with ipilimumab in patients with B7-H3-expressing melanoma, squamous cell cancer of the head and neck or non-small cell lung cancer

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Journal for ImmunoTherapy of Cancer20153 (Suppl 2) :P176

https://doi.org/10.1186/2051-1426-3-S2-P176

  • Published:

Keywords

  • Melanoma
  • Ipilimumab
  • Squamous Cell Cancer
  • Checkpoint Inhibitor
  • Cohort Expansion

Background

MGA271 is an Fc optimized, humanized IgG1 monoclonal antibody targeting B7-H3 (CD276), a member of the B7 family, and is currently undergoing Phase I testing. The Fc domain is engineered for enhanced binding to the activating FcγR, CD16A, and decreased binding to the inhibitory FcγR, CD32B. B7-H3 exhibits limited expression on normal tissues, but is highly expressed in a broad range of tumors, including melanoma (M), squamous cell cancer of the head and neck (SCCHN) and non-small cell lung cancer (NSCLC). The correlation between B7-H3 overexpression and poor prognosis in certain cancers suggests a role for B7-H3 in tumor immune escape. Although ipilimumab (anti-CTLA-4) is approved for the treatment of melanoma, only a minority of patients respond clinically. Combined targeting of CTLA-4 and PD-1, using ipilimumab and nivolumab (anti-PD-1), demonstrated synergistic antitumor activity, albeit with substantially increased toxicity over either agent alone. B7-H3 and CTLA-4 play distinct immunoregulatory roles and it appears that complementary mechanisms could be engaged by targeting these molecules. These include modulation of T-cell function, including the function of regulatory T-cells, and engagement of both innate and adaptive immunity. Further, B7-H3 expression in normal tissues is limited, suggesting that B7-H3 may not be a key driver in maintaining self-tolerance, thus reducing the potential for induction of immune-related AEs (irAEs) in patients treated with MGA271 compared to molecules such as anti-CTLA-4. Based on these observations, we hypothesized that MGA271 could potentiate the immunoregulatory and antitumor activity of ipilimumab, with a more favorable overall safety profile than other combinations such as anti-CTLA-4/anti-PD-1.

Methods

This multi-center, open-label trial (NCT02381314) enrolls patients with advanced B7-H3-expressing SCCHN, M, or NSCLC (squamous and non-squamous histology). Progression on previous checkpoint inhibitor therapy is allowed. To investigate whether B7H3 contributes to “immunologic escape” in patients treated with checkpoint inhibitors, M patients are required to have progressed on a checkpoint inhibitor within 12 weeks of enrollment. Using a 3+3 +3 dose escalation design, successive cohorts of patients will be treated with escalating doses of weekly IV MGA271 (starting dose 3 mg/kg) up to 1 year in combination with standard doses of IV ipilimumab (3 mg/kg) Q3 weeks x 4 doses. Cohort expansions will be enrolled at the maximum tolerated dose, and include patients with M, HNSC and NSCLC (16 patients/cohort). Major objectives for this study include characterization of safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of MGA271 in combination with ipilimumab.

Trial registration

ClinicalTrials.gov identifier NCT02381314.

Authors’ Affiliations

(1)
Earle A. Chiles Research Institute, Portland, OR, USA
(2)
Division of Hematology - Medical Oncology, UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA
(3)
MacroGenics, San Francisco, CA, USA
(4)
MacroGenics, Rockville, MD, USA
(5)
Columbia University Medical Center, New York, NY, USA

Copyright

© Urba et al. 2015

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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