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BackgroundT cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) is an inhibitory receptor expressed on T cells, including regulatory T cells (Tregs) and natural killer (NK) cells. In the tumor microenvironment, TIGIT is often overexpressed and directly inhibits both T cell and NK cell effector function and proliferation. TIGIT is also involved in regulating Treg function. Therefore, inhibiting the TIGIT-related immunosuppressive pathway may result in antitumor activity. M6223 is an intravenously (IV) administered, human, antagonistic, immunoglobulin G1 (IgG1) anti-TIGIT antibody with an Fc mediated effector region. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the human transforming growth factor β receptor II (a TGFβ ”trap”) fused to a human IgG1 monoclonal antibody blocking programed death ligand 1 (PD-L1). As TIGIT and programed death receptor 1 (PD-1) are co-expressed on T cells, dual inhibition of both immune checkpoints may enhance antitumor activity. This phase Ia study (NCT04457778) aims to determine the safety, tolerability, maximum tolerated dose and recommended dose for expansion of M6223 monotherapy and M6223 (both the once every 2 weeks [Q2W] and once every 3 weeks [Q3W] regimens) in combination with bintrafusp alfa. Secondary objectives include the evaluation of pharmacokinetics and clinical activity of M6223 with and without bintrafusp alfa.MethodsEligible patients include those aged ≥18 years with: an Eastern Cooperative Oncology Group performance status ≤1; adequate baseline hematological, renal and hepatic function; and histologically or cytologically proven locally advanced or advanced solid tumors, for which no effective standard therapy is available. Patients previously treated with a TIGIT targeting agent or bintrafusp alfa are excluded. Patients with brain metastases are also excluded, except those without neurological symptoms ≥4 weeks before start of treatment and those receiving either a stable or decreasing dose of steroids AcknowledgementsThe authors would like to thank Daniel Holland of the healthcare business of Merck KGaA, Darmstadt, Germany for his involvement and contribution to the design and conduct of this study. Medical writing assistance was provided by David Lester of Bioscript Stirling Ltd, Macclesfield, UK, and funded by the healthcare business of Merck KGaA, Darmstadt, Germany [CrossRef Funder ID: 10.13039/100009945].Funding: The healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945).Trial RegistrationNCT04457778Ethics ApprovalThe study and the protocol were approved by the Institutional Review Board or ethics committee at each site. All patients provided written informed consent before any study procedures were performed.

Introduction Recombinant human luteinizing hormone (r-hLH) is used in a fixed-ratio combination with recombinant human follicle-stimulating hormone (r-hFSH) for the stimulation of follicular development. Objective The objective of this article was to conduct a review of safety data to evaluate the risks of r-hFSH/r-hLH treatment. Methods Data were retrieved from the Global Safety Database (Merck KGaA, Darmstadt, Germany) including reports from healthcare professionals, patients, health authorities, clinical trials, non-interventional studies, and the literature. Reports of important risks (identified and potential) as per the risk management plan applicable at the time of data retrieval were obtained up to December 2017. The estimated patient exposure to r-hFSH/r-hLH in the post-marketing setting was 427,012 treatment cycles. Nine hundred patients received r-hFSH/r-hLH during company-sponsored clinical trials (pre- and post-marketing). Results We identified 72 case reports describing important risks related to r-hFSH/r-hLH use, including 46 cases of ovarian hyperstimulation syndrome (10.8 per 100,000 treatment cycles) and 24 of hypersensitivity reaction (5.6 per 100,000 treatment cycles). No thromboembolic events were reported. One congenital anomaly, not suspected to be related to r-hFSH/r-hLH use, was reported during a clinical trial; the event was resolved by corrective surgery. Two fatal cases were identified; one case of recurrent malignant melanoma (suspected to be related to r-hFSH/r-hLH use) and one case resulting from complications of ovarian hyperstimulation syndrome. Conclusion Cumulative reporting rates of important identified and potential risks of r-hFSH/r-hLH during a 10-year surveillance period demonstrate the benefit–risk balance is positive. This post-marketing surveillance and continued surveillance of safety events should provide reassurance about the use of r-hFSH/r-hLH in clinical practice. Electronic supplementary material The online version of this article (10.1007/s40264-018-0742-3) contains supplementary material, which is available to authorized users.

ispartof: Reproductive Biomedicine Online vol:35 issue:4 pages:433-433 ispartof: location:Netherlands status: published