Recruitment

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