Phase 1b/2 Study of 177Lu Girentuximab Plus Cabozantinib and Nivolumab in Treatment-Naive Patients with Advanced Clear Cell RCC
Abstract
Objectives and Rationale: One of the most important unmet needs in the treatment of patients with metastatic renal cell carcinoma is access to therapy that can provide a cure. Currently available therapies accomplish this in a relatively small percentage of patients, a clear area for improvement. The first objective of this study is to increase the complete disappearance rate (also known as complete response) of metastatic tumors treated with a currently available combination of the blood vessel starving or antiangiogenic agent cabozantinib with the immune stimulating checkpoint antibody, nivolumab by adding a third, novel agent, 177Lu girentuximab. 177Lu girentuximab is a radiation-tagged antibody (a small protein that can bind to another protein in a highly selective manner) against a protein, carbonic anhydrase, that is nearly ubiquitously expressed in clear cell renal cell carcinoma. We hypothesize that 177Lu girentuximab will stimulate abnormal DNA repair in tumor cells, which will induce tumor cells to produce distress signals that attract immune cells to them, enhancing the ability of the immune system to eradicate cancer cells. The second objective of the study is to test two novel imaging modalities designed to measure the ratio of tumor to immune cells in the tumors being treated with our novel treatment combination, and to determine whether we can more effectively predict tumor eradication using these imaging modalities. The third objective is to analyze the impact of this novel treatment on the tumor cells and on the immune system by obtaining tissue samples from patients through biopsies and evaluating the levels of key biological factors involved in tumor cell and immune cell behavior. What are the potential clinical applications, benefits, and risks? This novel combination therapy can potentially be administered to individuals who have clear cell renal cell carcinoma that has spread to other organs in the body. The key benefit is the potential for cure. By increasing the percentage of patients who have complete disappearance of their disease, this regimen may increase the number of patients who can potentially completely stop their therapy after a period of time, and enjoy either period of time off therapy, or ideally, not need to get back on therapy at all for their renal cell carcinoma. The risks associated with this regimen are related to the radiation effects on normal body tissues, with prior studies showing that repeated, high doses of 177Lu can lower blood counts and platelet levels for a period of time. To minimize this risk, we will be using a relatively low dose of 177Lu girentuximab, which has been shown to be quite safe. Ultimate applicability: By improving the cure fraction of cabozantinib plus nivolumab, the addition of 177Lu girentuximab will be appropriate in most patients where the combination of cabozantinib plus nivolumab is being considered. If this study is successful, it will likely spur the investigation of other novel treatment combinations containing 177Lu girentuximab. The identification of better scanning or imaging modalities has the potential to more accurately identify individuals who are benefitting from cancer-fighting therapy. The analysis of biopsy tissues will allow us to precisely determine the effect of this novel regimen on tumor and immune cell function, which can lead to a further refinement of our treatment approach by either identifying people most likely to benefit from this regimen or to come up with additional therapeutic strategies that will further improve treatment for patients with metastatic renal cell carcinoma. What is the projected time it may take to achieve an impact on the standard of care for kidney cancer? We anticipate this study will take approximately four years to complete. If an interim analysis of the data shows a strong sign of effectiveness, this regimen could be launched in a randomized, registrational study designed to
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210456
Entities
People
- Eric Jonasch
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army