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

  • 1,
  • 1,
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  • 2,
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Journal for ImmunoTherapy of Cancer20153 (Suppl 2) :P177

https://doi.org/10.1186/2051-1426-3-S2-P177

  • Published:

Keywords

  • Melanoma
  • Dose Escalation
  • Squamous Cell Cancer
  • Checkpoint Inhibitor
  • IgG1 Monoclonal Antibody

Background

MGA271 is an Fc optimized humanized IgG1 monoclonal antibody that binds to B7-H3 (CD276), a member of the B7 family, 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 has limited expression in normal tissue and high expression in multiple 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 escape. Despite the clinical success of agents including anti-CTLA-4, anti-PD-1 and anti-PD-L1 antibodies, the majority of patients with M, SCCHN or NSCLC progress nonetheless, and substantial unmet need exists for these patients. The underlying hypotheses for combining MGA-271 (anti-B7-H3) with pembrolizumab (anti-PD-1) are: 1) combining immune-modulating agents may mediate additive or synergistic antitumor activity (e.g. anti-CTLA-4+anti-PD-1), and can do so where neither single agent has pronounced antitumor activity (e.g. anti-PD-1+anti-LAG-3), 2) coordinate engagement of both innate and adaptive immunity, 3) both agents may enhance the immune response against tumors via modulation of T cell immunosuppression, and 4) limited expression of B7-H3 on normal tissues may help focus an immune attack on tumors, limiting the risk of immune-related adverse events (irAEs) resulting from the disruption of self-tolerance, allowing MGA271 to be combined more readily with other immune-modulating agents, including anti-CTLA-4 and anti-PD-1 antibodies. /PD-1 /PD-L1.

Methods

This US, multi-center, open-label trial (NCT02475213) enrolls patients with advanced B7-H3-expressing SCCHN, M, or squamous NSCLC. Progression on previous checkpoint inhibitor is allowed. Following a 3+3 +3 dose escalation scheme, successive cohorts of patients will receive escalating doses of weekly IV MGA271 beginning at 3 mg/kg, and a fixed dose of IV pembrolizumab (2 mg/kg) administered every three weeks. Both study drugs will be administered starting on Day 1 of the study and given for up to one year. A three-cohort expansion phase will open at the established MTD with 16 patients each with M, SCCHN and NSCLC. The primary objective of this study is to determine the safety, dose-limiting toxicity and maximum tolerated dose of the MGA271/pembrolizumab combination. Secondary objectives include evaluation of pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity of this combination. This novel study will provide the first clinical assessment of coordinated targeting of both the B7-H3 and PD-1/PD-L1 axes in patients with advanced cancer.

Trial registration

ClinicalTrials.gov identifier NCT02475213.

Authors’ Affiliations

(1)
MacroGenics, San Francisco, CA, USA
(2)
MacroGenics, Rockville, MD, USA
(3)
University of Pennsylvania, Philadelphia, PA, USA

Copyright

© Baughman 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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