David Munn, MD

They have now enrolled 15 patients, completed the dose-finding phase using the initial chemotherapy regimen, and opened a second arm testing a less-toxic chemotherapy option that will provide important flexibility as this therapy moves toward multi-center studies. Enrollment has remained steady, including younger children now that the age restriction for ibrutinib has been lifted, and early laboratory findings show that many children are mounting very strong immune responses, confirming that the treatment is working as intended.

In parallel, the team is preparing to transition to an improved formulation of indoximod. This “pro-drug” version of indoximod is absorbed by the body more easily, allowing higher drug levels and potentially greater effectiveness, without increasing side effects. Their interactions with the FDA have been encouraging, with the agency granting Rare Disease designation for the pro-drug, engaging in early discussions about a future approval-focused trial, and agreeing to let them use all pediatric data obtained from the original version of indoximod, including in this trial.

In their phase I trial, they are testing a combination of standard oral chemotherapy with two immunotherapy drugs- indoximod, previously developed in their own lab, and ibrutinib, an FDA- approved drug-that work together to stimulate the immune system. With 14 patients enrolled so far, the team has identified the likely optimal dose of ibrutinib and is finalizing the dose finding portion of the trial. Early results are promising, with several children showing partial responses, disease stabilization, and prolonged survival. One child has even achieved a complete response, a remarkable case in which a patient with widespread brain cancer regained function, returned to high school, and graduated while still receiving treatment.

While results have been encouraging, the team found that the current chemotherapy regimen is more toxic than necessary, making it harder for patients to tolerate treatment and slowing enrollment. They are now working with the drug manufacturer and FDA to amend the trial protocol to incorporate a less toxic, well-established chemotherapy regimen with fewer side effects. With this change, and as a separate indoximod-only trial is concluding, they expect enrollment to accelerate in the months ahead.

Importantly, their recent lab data show that this treatment approach is triggering strong immune responses in children, similar to or better than responses seen in adults treated with immunotherapy. This breakthrough finding supports the idea that children can benefit from immune-based treatments, especially when those treatments are designed specifically for them.

At 18 months into the Catapult Award period, they have enrolled 14 out of the planned 31 patients. Initially, the trial was limited to patients over 12 years old due to a restriction based on limited safety data of ibrutinib for younger children when the trial first began. This restriction caused the investigators to be forced to turn away many patients under the age of 12 who may have been able to participate otherwise. As ibrutinib has since been approved for use in younger children, Drs. Munn and Johnson were able to successfully negotiate with the drug company to lower the minimum age for enrollment to 3 years old, as well as to provide a pediatric liquid version of the drug for use in the clinical trial. These changes, incorporated in November 2024, are expected to increase enrollment and allow younger children desperately in need of novel treatment options to participate in the trial. The treatment has produced notable side effects, all of which have been manageable and are consistent with multi-drug treatment approaches. Importantly, molecular analyses of patient blood samples during the trial and archival tumor biopsies from before treatment have shown robust T cell activation in both the blood and tumors – this suggests that the therapy is achieving its intended immune-targeting effects, offering promising early results.

The outcome for these patients is dismal, and has changed little in 20 years. Thus, better therapies are urgently needed. Dr. Munn’s current clinical trial uses a new immunotherapy drug called indoximod, developed in their laboratory, that is combined with conventional chemotherapy, plus the approved drug ibrutinib, to offer an additional treament option for pediatric brain tumor patients.

In his Catapult-funded clinical trial, Dr. Munn and his team are trying to determine if adding the ibrutinib drug, which they recently showed works together with indoximod, will enhance and extend the therapeutic response in these desperately ill patients who do not benefit from indoximod alone. During the first 6 months of funding, Dr. Munn and his team have set up the fully functioning infrastructure for the phase 1 clinical trial, and enrolled 8 patients and counting.

An important scientific component of the trial is the collection of serial blood samples that they are able to obtain from each patient. The samples are analyzed for immune activation, and stored away in a frozen archive for detailed molecular analysis of immune response. The results of these laboratory studies are showing a large immune response in the responding patients, which supports their hypothesis that treating patients with ibrutinib plus indoximod and chemotherapy mav provide a new treatment option for children with brain tumor which were previously untreatable. This level of detailed molecular analysis has never been performed on a pediatric chemoimmuno- therapy trial before, thus the initial results are extremely exciting and also have a high potential to impact the entire field of pediatric oncology.