Phase 1 Study of HLX10, a Monoclonal Antibody Targeting Programmed Death-1 (PD-1) in Patients With Advanced Solid Tumors

Overview

The purpose of this study is to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of humanized anti-PD-1 monoclonal antibody, HLX10, in patients with advanced or metastatic tumors refractory to standard therapy. This study will also evaluate the pharmacokinetics, pharmacodynamics, immunogenicity and anti-tumor effect of HLX10 and explore the potential prognostic and predictive biomarkers.

The lack of immunologic control is currently recognized as one of the hallmarks of cancer. The cancer immunoediting concept has been proposed as a mechanism by which tumors escape control. The concept involves three phases: elimination (tumor cell eradication), equilibrium (when editing of surviving tumor cells occurs) and escape (when the altered tumor cells progress through the shield of the activated immune response). When the TCR of a T cell recognizes antigens expressed in the context of the MHC, the immune checkpoint modulates signaling: co-stimulatory molecules such as CD28 on T cells enhance the signal, whereas co-inhibitory molecules suppress it. Recent research has implicated the expression of immunoinhibitory checkpoints such as CTL antigen 4 (CTLA-4) and programmed death protein 1 (PD-1) as potential mediators of the equilibrium and escape phases of cancer immunoediting described above. These molecules are expressed on activated T cells, but when they bind to ligands either on antigen-presenting cells (CTLA-4 binding to CD80/CD86) or tumor cells (PD-1 binding to PD-L1), they tend to shut down the anti-tumor response. Efforts to use antibodies to target and block these immuno-inhibitory interactions have ushered in a new era of immunotherapy. Tumors display a wide variety of antigens that can potentially be exploited by harnessing the adaptive immune response. The T-cell response to these antigens can be dysregulated by tumor cells seeking to evade immunologic detection and destruction by hijacking physiological homeostatic immune-checkpoint signaling pathways. In addition to a variety of mechanisms that can create an immunosuppressive microenvironment (e.g. secretion of inhibitory cytokines, presence of regulatory T cells), many tumor types also express PD-L1. Nivolumab and pembrolizumab are the two anti-PD1 monoclonal antibodies currently approved for multiple cancers. The application of nivolumab or pembrolizumab alone or in combination with chemotherapy has completely changed cancer management. HLX10 is a new monoclonal antibody targeting PD1 on T cells, developed from mouse hybridoma technology. In vitro studies have demonstrated the growth inhibition of multiple cancer cell lines, and shown growth inhibition of tumors in murine xenogeneic studies. Nonclinical studies dosing up to 50 mg/kg HLX10 weekly in cynomolgus monkeys for 13 weeks have shown good tolerability without evident toxicities (please refer to Investigator's Brochure). HLX10 shows cross-reactivity to both monkey and human PD1, but does not bind rodent PD1. Based on the pharmacology studies and pharmacokinetic and toxicokinetic studies in cynomolgus monkeys, this study is a phase-1 study to address the safety and tolerability of HLX10 in patients with metastatic or recurrent cancer. HLX10 has not yet been tested in human. Therefore, the investigators propose this first-in-human phase 1 study. In this study, the investigators intend to investigate the safety, and tolerability of HLX10 in humans, and hope to identify the maximum tolerated dose (MTD), and determine the recommended phase 2 dose in future study. At the same time, the investigators would like to gain information of the pharmacokinetics and pharmacodynamics of this drug and its potential immunogenicity. To minimize the risk of patients who volunteer to receive this experimental drug, the investigators will choose 0.1 mg/kg as the initial starting dose. The selection of starting dose is based on the repeat-dose toxicology study on monkey, at 1/166 of the human equivalent dose of No-Observed Adverse Effect Level (NOAEL) in cynomolgus studies. To investigate the dose required to reach maximal effect, the investigators propose a dose escalation sequence. The purpose of the dose escalation is to obtain the pharmacokinetics and pharmacodynamics of HLX10 at different dose levels, and investigate its relationship with adverse reactions. The investigators also intend to identify the MTD. The information from the dose escalation is crucial to determine the optimal dose in future studies and potential indications for HLX10.

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