Bringing Brigatinib to Neurofibromatosis Type-2 Patients:
From Promising Potential to Platform Clinical Trial
The Children’s Tumor Foundation today announced a significant advancement in care for neurofibromatosis type 2 patients with the launch of a new clinical trial called INTUITT-NF2, an innovative platform trial which will evaluate multiple treatments simultaneously in order to minimize potential negative impact on patients while at the same time maximize response opportunities to specific drugs within the same multi-arm trial. This initiative is a result of the landmark work of CTF’s visionary Synodos for NF2 research collaborative, its NF2 Accelerator Initiative, an investment from Takeda Pharmaceuticals, the participation of scientists at the National Center for Advancing Translational Sciences (NCATS) at the National Institutes of Health (NIH), and the vital Synodos NF2 leadership from Massachusetts General Hospital (MGH), Johns Hopkins University (JHU) and Indiana University (IU). The Principal Investigator of INTUITT NF2 is Scott Plotkin, MD, PhD from MGH and the five additional participating centers will be Johns Hopkins University (JHU), New York University (NYU), University of California at Los Angeles (UCLA), the Mayo Clinic in Minnesota (Mayo), and the University of Miami (UM). This alliance across the academic, pharma, and patient landscapes has shortened the time from initial research to active trial, thereby bringing promising treatment options to patients who need them.
The name INTUITT-NF2 stands for ‘Innovative Trial for Understanding the Impact of Targeted Therapies in NF2’, and its innovation is in responding to – and acting against – specific traits unique to NF2 patients. Neurofibromatosis causes tumors to grow on nerves throughout the body, with most NF2 patients affected by vestibular schwannomas on the eighth cranial nerve, which carries sound and balance information to the brain. NF2 affects 1 in 25,000 people of all populations equally, and in addition to schwannomas can develop meningiomas and ependymomas, with patients suffering hearing loss, severe balance problems, facial weakness/paralysis, and debilitating seizures, among other serious conditions. The INTUITT-NF2 trial will allow for the simultaneous study of the various tumor types, rather than waiting for studies on one tumor type alone, thereby accelerating the information gathering and results analysis processes.
This milestone development in NF2 research and care is the result of insights that came out of the Foundation’s Synodos for NF2 effort, which launched in 2014 and in collaboration with NCATS identified brigatinib as a high potential therapeutic for NF2 patients. The Synodos project brought together a multidisciplinary team of scientists from 12 world-class labs at academic and medical centers of excellence to address the confounding problem patients and researchers alike faced in that research results appeared to contradict each other – with some work showing positive results and others negative results. This siloed approach to the disease was hampering progress, and all agreed that an “audacious new way” was needed. Patients heeded that call and provided funding to the Children’s Tumor Foundation to launch a new, and for its time, a somewhat radical approach to the disease. In this model, called Synodos, researchers would work together on a Manhattan-project style approach to the disease, and they would share data and results in real-time. The funders behind that approach also ensured that patients be included in the research and clinical meetings that would define these methodologies.
The multidisciplinary Synodos team launched its work (Synodos stands for “on the same path, together”), and established the first-ever NF2 preclinical drug pipeline with cell and animal models connected to a sequencing enterprise so as to better understand the biology behind drug response and non-response. This information was shared among all members of the group for phase one of the project, and eventually made public available to any researcher through the establishment of natadataportal.org.
“The launch of the Synodos project was driven by our belief that by bringing all stakeholders together we could solve the medical problems that seemingly had no answers,” said Annette Bakker, PhD, President of the Children’s Tumor Foundation. “The patients and the medical and research experts all shared the same passion and purpose – to solve the mysteries of NF2 – but traditional approaches were getting in the way of needed solutions. Thanks to the persistence of the patients and the courageousness of the researchers, the group revealed new insights into NF2 biology and established a platform from which could spring high-potential therapies, which today has resulted in the establishment of this promising new clinical trial for NF2 patients.”
With a guarantee of shared data and a certainty of collaboration in hand, the Synodos team found that initial results remained insufficient to meet efficacy criteria, but that new and vast insights into NF2 biology had been generated. Scientists from NCATS, led by Marc Ferrer, PhD, offered high throughput capabilities to the Synodos team to potentially uncover new drug opportunities. In that process, Takeda’s Brigatinib (an approved drug for use in non-small cell lung cancer unrelated to NF) was discovered to show robust efficacy in both vestibular schwannomas and in meningiomas. This breakthrough meant that while more understanding was still needed to identify the exact mechanisms behind this finding, it appeared that Brigatinib shrinks NF2 tumors.
Leading the INTUITT-NF2 trial are Scott Plotkin, MD, PhD of Massachusetts General Hospital and Jaishri Blakely, MD, of Johns Hopkins University. The foundation of this new trial is to rapidly and efficiently screen multiple therapies simultaneously so as to enable faster approval studies that have the highest indication for success. The U.S. Food and Drug Administration (FDA) recently approved the initiation of this trial, and details on patient recruitment will be announced soon.
The INTUITT-NF2 trial will expand the possibilities for NF2 care in multiple ways. In a traditional clinical trial, patients are enrolled to test drug treatments that will measure response for one specific tumor type (even if patients have more than one type in their bodies, as is often the case for NF2 patients). If that tumor type does not respond to the treatment, then the trial potentially fails, and patients wait as the development process has to restart again, perhaps with a different drug, or with a new process that looks at a different tumor type. The “one tumor type at a time” approach slows down the development of treatments for NF2.
By contrast, the INTUITT-NF2 trial will monitor all tumors types of NF2 patients enrolled within the same trial. A patient may first be enrolled in the initial tumor arm of the trial, but then if a different tumor type is found to instead be responding, he/she will be moved to the more promising tumor arm. As a result, while each enrolled patient is being monitored for all of their tumors, the trial is maximizing opportunities to respond to a specific drug within the same trial while also minimizing the time it takes to collect these findings.
The Principal Investigators of the trial are Scott Plotkin of MGH and Jaishri Blakeley of JHU. Participating clinicians include Jeffrey Allen, MD (NYU); Leia Ngiemphu, MD (UCLA); Dusica Babovic-Vuksanovic (Mayo), and Christine Dinh, MD (UM).
Both the Children’s Tumor Foundation and Takeda Pharmaceuticals are supporting the financing of the INTUITT-NF2 trial. CTF’s investment is through its NF2 Accelerator Initiative.
To learn more about the INTUITT-NF2 trial, please visit https://clinicaltrials.gov/ct2/show/NCT04374305.
To learn about NF2 research and the progress being made against neurofibromatosis, please visit ctf.org.
Thank you to all who have supported the Synodos for NF2 and the NF2 Accelerator initiatives through donations, advocacy, awareness activity, and more. With special thanks to the lead funders for each project:
Synodos for NF2
Galloway Family
Carol and Steven Kalagher
Cynthia Henebry and Andrew Schoeneman
John and Beth Morris
Tony and Joan Nanci
Janet Shaver
Roland and Nicole Thoms
NF2 Accelerator
Thoms Family Fund at KBF Foundation Canada
Richard and Deborah Estabrook
Tracy Galloway
RB and Susan Harrison
Cynthia Henebry and Andrew Schoeneman
Carol and Steven Kalagher
Nicola Kean and Rob Brainin
John and Beth Morris
Alan and Jerye Robbins
Roland and Nicole Thoms
