Drug Development of ONC392, a Novel CTLA-4 Inhibitor in Advanced Renal Cancer
Abstract
A clinical trial will be conducted in advanced (stage IV) clear cell kidney cancer patients after they have progressed on at least one previous therapy. The study utilizes a new medication called ONC392 that appears to be a more effective and less toxic immune therapy. Background: Immune checkpoint inhibitor therapy has demonstrated remarkable efficacy in advanced renal cancer and has become the standard of care. The combination of ipilimumab and nivolumab is one of the immunotherapies used. The regimen of ipilimumab+nivolumab was evaluated in the Checkmate-214 trial and showed robust efficacy with an average life expectancy of more than 4 years. Multiple other combination regimens of VEGFR-TKI and PD-1 inhibitor have been established in the frontline therapy of advanced renal cell carcinoma (RCC). Despite the promising responses, more than 50% of the patients progress on this regimen. The treatment of these patients is a large unmet need. Novel drug development is needed to improve the outcomes of metastatic RCC, a lethal disease. The toxicities of the combination of ipilimumab and nivolumab are also overwhelming with a high incidence of severe diarrhea requiring hospitalization and steroid therapy. Treatment-related adverse events led to discontinuation of therapy in 22% and severe (grade 3 and 4) toxicities were noted in 46% of patients. The toxicity led to limitations in drug delivery with the dose of ipilimumab being only 1 mg/kg and the number of doses being limited to a maximum of four. The mechanism of action of ipilimumab is inhibition of a receptor on immune cells called CTLA-4, which results in activation of immunity against cancer. We propose a clinical trial of a novel CTLA-4 inhibitor, ONC392 in advanced pretreated kidney cancer. ONC-392 is a highly selective, humanized monoclonal immunoglobulin G1 (IgG1)-kappa isotype antibody against CTLA-4. Laboratory research has shown that ONC392 is a more efficient CTLA-4 inhibitor than ipilimumab. It decreases the toxicity and improves immune cell activation making it an attractive agent for drug development in advanced RCC. A clinical study of ONC-392 (NCT04140526) has shown promising efficacy, tolerability and safety in patients with advanced solid tumors such as lung cancer, melanoma and ovarian cancer. Study Design: We propose a Phase 2 clinical trial testing ONC-392 as a monotherapy and in combination with tivozanib for advanced or metastatic kidney cancer patients who have progressed after at least one line of prior therapy. Eligible patients will be randomized to receive ONC-392 monotherapy or in combination with tivozanib. Tivozanib is a U.S. Food and Drug Administration-approved agent in advanced RCC for patients who have progressed after two prior therapies. A safety run in will be conducted within the first six patients enrolled on the combination. ONC-392 will be dosed at 10 mg/kg intravenously every 4 weeks; this dose and schedule has been well established. The patients will be continuously followed for tumor shrinkage or response, overall survival, and progression-free survival. A sample size of about 30 patients per arm will be planned. Applicability, Impact and Projected Timeline: The clinical trial grant proposes to add two cohorts in kidney cancer to the current ongoing ONC-392 trial (NCT04140526). The cohorts will be added as an amendment to the existing ongoing study and the RCC cohorts will be opened at selected sites, with investigators experienced in treating RCC and who have adequate volume of RCC patients to anticipate accrual. This strategy has multiple advantages: (1) The timing for regulatory submissions and approvals will be reduced; (2) The grant and contracting time will be expedited as the study is already open and active at these sites; (3) The drug delivery and processing to the sites is already established; (4) The participating investigators will have experience with the novel agent through their pri
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310926
Entities
People
- Ulka Vaishampayan
Organizations
- United States Army
- University of Michigan