Safety, PK and Efficacy of ONC-392 in Monotherapy and in Combination of Anti-PD-1 in Advanced Solid Tumors and NSCLC
Last updated on July 2021Recruitment
- Recruitment Status
- Recruiting
- Estimated Enrollment
- Same as current
Summary
- Conditions
- Metastatic Renal Cell Carcinoma
- Advanced Solid Tumor
- Metastatic Breast Cancer
- Metastatic Colorectal Cancer
- Metastatic Head and Neck Carcinoma
- Metastatic Melanoma
- Metastatic Prostate Cancer
- Non -Small Cell Lung Cancer
- Ovarian Cancer
- Sarcomas
- Small Cell Lung Cancer
- Type
- Interventional
- Phase
- Phase 1
- Design
- Allocation: Non-RandomizedIntervention Model: Sequential AssignmentIntervention Model Description: Open labelMasking: None (Open Label)Primary Purpose: Treatment
Participation Requirements
- Age
- Between 18 years and 125 years
- Gender
- Both males and females
Description
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), also known as CD152 (cluster of differentiation 152), is a cell surface protein receptor that interacts with B7-1 (CD80) and B7-2 (CD86) to ensure proper function of regulatory T cells and protect host against autoinflammatory diseases. Anti-CTLA...
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), also known as CD152 (cluster of differentiation 152), is a cell surface protein receptor that interacts with B7-1 (CD80) and B7-2 (CD86) to ensure proper function of regulatory T cells and protect host against autoinflammatory diseases. Anti-CTLA-4 monoclonal antibodies (mAbs) have demonstrated strong and broad cancer immunotherapeutic effects (CITE) in a variety of preclinical models and are used clinically both as monotherapy and as part of combination therapy with Nivolumab (anti-PD-1). However, CTLA-4 monotherapy has more immunotherapy-related adverse effects (irAEs) than anti-PD-1/PD-L1 therapy. In addition, the rate of severe irAE (Grades 3 and 4) reached 55% in melanoma patients receiving combination of Ipilimumab and Nivolumab. The strong irAEs further limit the doses tolerated by cancer patients. Nevertheless, combination with anti-PD-1 resulted in significantly improved response rates and patient survival in multiple types of cancer. Furthermore, anti-CTLA-4 antibodies induce long-lasting immunity in cancer patients. Therefore, CTLA-4 remains an important immunotherapy target, but major challenges remain in improving both safety and efficacy of anti-CTLA-4 mAbs. ONC-392 is a highly selective, humanized monoclonal IgG1-kappa isotype antibody against CTLA-4. The parental clone was identified through in vivo screening in humanized CTLA-4 mouse model for high anti-tumor efficacy and low autoimmune toxicity. We have recently demonstrated that ONC-392 is dissociation from CTLA-4 under low pH to allow its escape from lysosomal degradation and recycle to cell surface. We have provided several lines of evidence for the notion that a pH-sensitive antibody ONC-392 is not only safer but also more effective in Treg depletion and tumor rejection than the Ipilimumab, which is pH-insensitive. First, by preserving CTLA-4 on the cell surface, Onc-392 leaves higher ligand density for better ADCC. Second, Onc-392 is more efficient in Treg depletion in tumor microenvironment. Third, Onc-392 is significantly more potent in inducing rejection of large tumors. The study consists of two parts: The Part A study is a dose-finding rapid titration, Phase I trial of ONC-392 as a single agent in patients with advanced or metastatic solid tumors with various histology. The aim of this trial is to define the recommended Phase II dose for ONC-392 monotherapy (RP2D-M). The Part B study is a seamless Phase IA/IB trial of ONC-392 in combination with a standard dose of 200 mg pembrolizumab in patients with NSCLC. The trial consists of a dose-finding, dose de-escalation, Phase IA component aiming at defining the recommended phase II dose for ONC-392 in combination with a standard dose of pembrolizumab (RP2D-C), then progressing into two parallel, single arm, single stage Phase IB trials to test for efficacy in two cohorts of patients with NSCLC: Stage IV NSCLC anti-PD(L)-1 immunotherapy naïve with positive PD-L1 (TPS> or =1%); Stage IV NSCLC anti-PD(L)-1 refractory or resistant to immunotherapy. In the Par B Phase I component both immunotherapy naïve and refractory/resistant disease will be enrolled.
Tracking Information
- NCT #
- NCT04140526
- Collaborators
- National Cancer Institute (NCI)
- Investigators
- Principal Investigator: Tianhong Li, MD University of California, Davis