ctHPVDNA Response-Adapted Chemoradiation +/- Retifanlimab Treatment in Locally-Advanced Anal Cancer

This study is for people who have anal cancer and have not yet had treatment. The regular treatment for people who have anal cancer is chemoradiation therapy (CRT). CRT is when chemotherapy and radiation therapy are given at the same time. Studies show that CRT works well to treat anal cancer and prevents many people from needing surgery which may require a colostomy bag. Doctors know that CRT is an effective way to treat anal cancer. But, they are doing studies to find out how much dose of radiation and chemotherapy should be given during the CRT. Higher doses of chemotherapy and radiation could increase the risk of side effects, but lowering the dose of chemoradiation has the risk of not being as effective to treat the cancer. One way to predict whether participants need higher or lower doses of radiation therapy is to do a blood test called ctDNA (circulating tumor DNA) to test for the presence of human papillomavirus (HPV). This test is done at certain times while participants are getting CRT. This has been shown to be a marker for the presence of anal cancer. In this study, doctors will tailor lower versus higher doses of CRT based on the tumor response that is measured by ctDNA. The purpose of this study is to see if customizing the dose of chemoradiation based on the amount of ctDNA will increase survival in participants with anal cancer and/or decrease the risk of side effects. Some participants in this study whose cancer does not respond as well to the CRT may have the opportunity to receive a drug called Retifanlimab that stimulates the body's immune system. Retifanlimab is approved by the Federal Drug Administration (FDA) for treating anal cancer that is recurrent or metastatic since there is proven benefit in these situations.