City of Hope, one of the largest cancer research and treatment organizations in the U.S., has launched a groundbreaking phase 1 clinical trial that could revolutionize treatment for rectal cancer patients. The DINOMITE trial (NCT06834126) is testing papaverine, an investigational drug designed to make rectal cancer more responsive to radiation therapy, potentially eliminating the need for surgery in many patients.
Novel Approach to Radiation Sensitization
The trial represents a significant departure from traditional rectal cancer treatment approaches. "The research that we were doing was focused on understanding how to improve the effects of radiation tumor cells while sparing the normal cells that surround the tumor," explained Terence Williams, M.D., Ph.D., chair of the Department of Radiation Oncology at City of Hope and principal investigator of the clinical trial.
Papaverine works through a unique mechanism that addresses a fundamental challenge in radiation oncology. The drug has been found in both preclinical and ongoing clinical trials to sensitize tumor cells to radiation therapy by blocking oxygen consumption in tumor cells. This approach aims to turn off oxygen consumption in the tumor cell and raise oxygen content, as radiation works better when oxygen is present.
Addressing Treatment Limitations
Rectal cancer, which constitutes about a third of colorectal cancer cases, is commonly treated with a combination of chemotherapy, radiation, and surgery when localized in the pelvis area. However, current treatment approaches often fall short of optimal outcomes.
"Sometimes surgery is required, or the type of surgery that is required is such that that leaves a patient with a permanent colostomy...and they are forced to have that for the rest of their lives," Williams noted. For patients who are eligible for a watch-and-wait approach, improving the efficacy of radiation and avoiding the need for surgery may improve quality of life, particularly if patients receiving surgery will need a permanent colostomy and require stool to be collected in an external bag.
Trial Design and Objectives
The DINOMITE trial has a primary goal of determining the side effect profile and most effective dose of papaverine when given with radiation therapy to patients with rectal cancer that has spread to nearby tissue or lymph nodes (locally advanced) but that has not spread beyond the pelvis. The phase 1 trial will test the combination of papaverine and radiation therapy, aiming to determine the maximum tolerated dose and the recommended phase 2 dose, while also establishing the safety and tolerability of the combination.
Scientific Rationale
The therapeutic strategy is based on fundamental differences between tumor and normal tissue oxygenation. "We believe that this strategy is a new way to effectively improve radiation effects on tumors, more so than normal tissues, because normal tissue have well oxygenated already, but tumors have areas of hypoxia, which is low oxygen content. So, this drug is designed to elevate the oxygen levels within tumors," Williams explained.
This approach could transform rectal cancer from a mostly radiation-resistant disease to one that can be cured using radiation and chemotherapy. The ultimate goal is to improve radiation therapy in a way that sensitizes tumors, but not normal organs and tissues, to radiation therapy and prevent patients with localized rectal cancer from needing surgery.
Translational Medicine Approach
City of Hope experts are leveraging a discovery made in the laboratory, building upon recent work in Dr. Williams' lab and prior work at a colleague's lab. The institution is known for its "bench to bedside" approach to translational medicine, rapidly moving research from the lab to clinical trials and patient care.
Surgery would be reserved for patients whose tumors recur in the pelvis after radiation and chemotherapy, representing a significant shift in treatment paradigm. Innovations in radiation oncology to make radiation work more effectively, such as the approach being tested in this trial, could prevent the need for patients to undergo life-changing surgery.
