2019 NCI-CONNECT and BTTC Meetings

June 3, 2019, by Kristin Odom, NCI-CONNECT Communications Editor

The 2019 NCI-CONNECT and Brain Tumor Trials Collaborative (BTTC) Annual Meetings were held on April 29 and 30 at NIH in Bethesda, Maryland. The meetings were hosted by NCI Center for Cancer Research (CCR) Neuro-Oncology Branch, and attended by over 100 leaders, health care providers, and researchers in neuro-oncology.

The meetings brought attendees across neuro-oncology specialties, including clinical care and research, basic science, and advocacy, together to discuss central nervous system (CNS) tumor clinical studies. Presentations and discussions included current studies and new clinical trial concepts that, in addition to measuring efficacy, incorporate patient quality of life and outcomes measures. The overall aim of each session was to ensure current and future studies will help effectively advance treatments for patients with gliomas and rare CNS cancers.

An overview of each meeting session and a summary of key findings are provided below.

Day 1: NCI-CONNECT

The NCI-CONNECT meeting focused on the program’s progress towards improving the lives of people with select rare CNS tumors. These include ATRT, choroid plexus tumors, diffuse midline gliomas, ependymoma, gliomatosis cerebri, gliosarcoma, medulloblastoma, meningioma, oligodendroglioma, pineal region tumors, PXA / APXA, and PNET. It also focused on the program’s plans for the coming year.

Tumor Board

The meeting began with a tumor board led by NCI Neuro-Oncologist Marta Penas-Prado, M.D.; Nurse Practitioner Christine Siegel; Genetic Counselor Margarita Raygada, Ph.D.; and Nurse Practitioner Lisa Boris. The team presented two cases to be reviewed and discussed by a panel of neuro-oncology specialists: Neuropathologist Kenneth Aldape, M.D.; Neurosurgeon Kareem Zaghloul, M.D.; Neuroradiologist Jim Smirniotopoulos, M.D.; and Radiation Oncologist Christine Tsien, M.D.

The first case was an anaplastic ependymoma. The second case was a patient with gliomatosis cerebri, a tumor that is challenging because the diagnosis is based on both pathology and imaging. Based on the information presented and thoughtful discussions, the tumor board panel provided treatment and management guidance.

Overview and Progress

After the tumor board, NCI-CONNECT Co-Directors Mark Gilbert, M.D., and Terri Armstrong, Ph.D., welcomed meeting attendees. Dr. Gilbert is also the principal investigator for the BTTC and chief of the Neuro-Oncology Branch. Dr. Armstrong is the deputy chief of the Neuro-Oncology Branch and co-leader of the BTTC.

Drs. Gilbert and Armstrong shared an overview of the NCI-CONNECT program and ways meeting participants can get involved to help the program reach its goals. To this end, investigators are collecting and analyzing patient-reported outcome and risk exposure, clinical and treatment history data, and biological specimens in clinical studies to enable a better understanding of rare CNS tumors. They intend to create a database, so all researchers have access to the data to develop future studies. Patients who visit NIH are also screened for open clinical trials and provided treatment advice. Patients are able to visit NIH free-of-charge so that much of the costs in seeking a consultation are eliminated. 

Drs. Gilbert and Armstrong then shared NCI-CONNECT accomplishments to date:

• Partnered with Central Brain Tumor Registry of the United States (CBTRUS) to report the incidence, prevalence, and survival of patients with select rare CNS tumors.
• Established partnerships with non-profit advocacy organizations. These include the American Brain Tumor Association (ABTA), Collaborative Ependymoma Research Network (CERN) Foundation, EndBrainCancer Initiative, International Brain Tumour Alliance (IBTA), National Brain Tumor Society (NBTS), and Oligo Nation.
• Established a network of centers for NCI-CONNECT studies using the BTTC infastructure—and additional collaborations with national cooperative groups (including NRG Oncology and Alliance) and international groups (including Peter Mac Cancer Center in Australia).
• Established disease-specific specialty clinics to enhance patient interactions and focus.
• Actively accrued patients to clinical studies.
• Expanded the online Outcomes and Risk Study to include all NCI-CONNECT tumor types.
• Began a series of disease-specific workshops to advance research.
• Launched the NCI-CONNECT website.

Then, Dr. Penas-Prado presented the newly launched NCI-CONNECT Clinic to improve the care of patients with rare CNS tumors. She shared the special services patients receive and ways the NCI-CONNECT network providers can refer patients. NCI providers want to work together with referring providers to ensure patients get the best treatment possible. 

Tissue Studies

The next meeting presentation and discussion focused on tumor tissue studies with Dr. Aldape, chief of NCI’s Laboratory of Pathology, and Dr. Penas-Prado. With roughly 12 percent of brain tumor patients misdiagnosed, Dr. Aldape discussed challenges and difficulty neuropathologists face classifying rare tumors. To provide an accurate diagnosis, Dr. Aldape performs an integrative analysis and uses methylation profiling. Patients who come to the NCI-CONNECT Clinic will have their tumor tissue analyzed to confirm their diagnosis.

To learn more about these tumors, Dr. Penas-Prado shared plans to collect clinical data and tumor tissue samples to create a tissue repository of rare CNS tumors to develop better treatments. The repository will allow researchers to study the clinical course of adult patients with rare tumors and help them predict effective drug therapies and outcomes. It will also enable researchers to more accurately classify CNS tumor types and predict which drugs, and combination of drugs, will respond. Included in the tissue repository will be samples from pregnant women with brain tumors. The retrospective study of pregnant women will study potential risks and changes in tumor biology that will help brain tumor patients make a more informed decision about pregnancy. 

Multi-Center Trials

CCR's Deputy Clinical Director Caryn Steakley shared a regulatory update on the BTTC multi-center trials in the NCI Intramural Research Program. CCR serves as the lead institution and coordinating center for the BTTC. It is developing a new study database, site payment process, and a process for using a single institutional review board for multi-center clinical research studies.

Michael Pollack, Ph.D., supervisory technology transfer manager at NCI, oversees the NCI-CONNECT and BTTC site agreements. Dr. Pollack is establishing agreements with the NCI-CONNECT network to provide clinical research studies to patients with rare CNS tumors. This will allow patients to access cutting-edge therapies at a center closer to their home.

Current Studies  

NCI-CONNECT has a number of treatment and assessment studies that are open for adult patients with rare CNS cancers. Dr. Armstrong gave an overview of the Outcomes and Risk Study that patients can participate in from home by completing an online survey and submitting a saliva sample to be used for genetic testing. This will help improve the understanding of outcomes and risk factors associated with the occurrence of rare CNS tumors. Second, she talked about the Natural History Study, which has enrolled more than 500 patients. The study collects patients’ biospecimens and information to improve the understanding of the disease over the full course of illness. Preliminary results showed over 50 percent of patients who have participated stated they have symptom and emotional impacts from their brain or spine tumor. There was interest throughout the BTTC sites to collect these data electronically at their centers.

Advocacy partners, including the ABTA, CERN Foundation, EndBrainCancer Initiative, IBTA, and Oligo Nation, as well as collaborators the Biden Cancer Initiative and Loglio, were an integral part of the conversation. They brought the patient perspective to help researchers and clinicians understand how to communicate their efforts to patients and their families.

Current Trials

Dr. Gilbert shared details on open clinical trials at NCI for patients with rare CNS tumors. This included a clinical trial investigating an immunotherapy drug called nivolumab for nine rare CNS cancers. Plans are underway to launch this as the first NCI-CONNECT multi-center trial across the research network in fall 2019.

Another open NCI-CONNECT clinical trial is investigating the drug sunitinib as a potential treatment for people with either a gliosarcoma or primary brain sarcoma. A gliosarcoma is a subtype of glioblastoma and is a very aggressive tumor. Dr. Gilbert also shared a newly opened clinical trial that is investigating the drug marizomib as a potential treatment for people with recurrent ependymoma. This trial will target pathways for treatment evaluating fairly aggressive RELA-fusion supratentorial ependymomas. If responses are seen, the study will be extended to include non RELA-fusion.

Jing Wu, M.D., investigator in the CCR Neuro-Oncology Branch, presented and explained how there is no effective treatment for patients with hypermutated phenotype (HMP) tumors. NCI has developed a clinical trial that is investigating the immunotherapy drug nivolumab as an effective treatment for people with recurrent IDH-mutant gliomas with and without hypermutator phenotype, including oligodendrogliomas and gliomatosis cerebri.

Dr. Gilbert gave an update on two ependymoma trials. Interim data analysis is complete for the phase 2 carboplatin and bevacizumab clinical trial for recurrent low grade or anaplastic ependymomas. Plans are to continue with the trial to complete enrollment of patients. The other trial, a recently completed phase 2 study of temozolomide and lapatinib, was the first prospective adult clinical trial of chemotherapy in recurrent ependymoma. Dr. Gilbert shared results at the 2018 Society for Neuro-Oncology (SNO) Annual Meeting. Nearly 40 percent of patients had stable disease at one year, with improvement in disease-related symptoms. Results from the study were so impressive that the treatment is is now part of the National Comprehensive Cancer Network guidelines for adults with recurrent ependymoma. Plans are to conduct a confirmatory trial with the hope that confirmed results will result in regulatory approval.  

Neuro-oncology investigators proposed new trial ideas for attendees to review and discuss:

• A First in Human Phase 1 Single Agent Open Label Dose Escalation and Dose Expansion Study with Weekly Dosing of Oral ONC206 in Patients with Recurrent and Rare Primary CNS Neoplasms
  • Presented by Brett Theeler, M.D., Walter Reed National Military Medical Center
• Clinical Implications of Targeting Dopamine Receptor 2 (DRD2) or Personalized Brain Cancer Therapy
  • Presented by Jinkyu Jung, Ph.D., Neuro-Oncology Branch, CCR, NCI

Attendees showed enthusiasm for moving forward on the new proposed clinical trial ideas.  

Wrap Up

The NCI-CONNECT meeting concluded with a summary of the day and plans to further integrate the network investigators into the NCI-CONNECT program. The collaboration will allow NCI-CONNECT to reach more people with rare brain and spine tumors and improve care for patients.

Day 2: BTTC

The overall aim of the BTTC Annual Meeting was to discuss clinical trials for patients with malignant gliomas. Matt Anthony, Founder and Chairman of Head for the Cure (HFTC), kicked off the meeting with a moving presentation on the foundation’s accomplishments over the past year. He highlighted the HFTC Keeping the Faith program, which recognizes extraordinary patients and survivors at HFTC events. He also shared inspiring messages from the brain tumor community. Attendees were encouraged and motivated by HFTC’s community impact. 

Current Trial

Dr. Gilbert welcomed attendees and gave an update on the open study for patients with imaging studies that show a likely glioblastoma. This clinical trial combines an immune checkpoint inhibitor (pembrolizumab) plus an individualized tumor-specific vaccine made from the heat shock protein (HSPPC) plus standard radiation and temozolomide chemotherapy. The trial evaluates if the combination of HSPPC-96 vaccine made from the patient’s own tumor and pembrolizumab is more effective treatment than pembrolizumab. The combination of HSPCC-96 and pembrolizumab may synergistically result in an increase in tumor-specific immune response. This trial originally launched at NCI and is opening at 14 additional participating BTTC centers throughout the United States.

New Trial Ideas

A breakout session for BTTC investigators followed. Investigators discussed the following protocol concept ideas: 

• Phase 1/2 Study of Temozolomide + Eflornithine (DFMO) Versus Temozolomide Alone for Newly Diagnosed IDH Mutant Gliomas
  • Howard Colman, M.D., Huntsman Cancer Institute
• Pharmacodynamic Study of Larotrectinib in Surgically Accessible Recurrent Glioma Patients with NTRK Gene Fusions
  • Jacob Mandel, M.D., Baylor College of Medicine
• Phase 2 Trial of Checkpoint Inhibitor Therapy with or without BRAF/MEK Inhibitors in Newly Diagnosed or Recurrent Craniopharyngioma
  • Carlos Kamiya-Matsuoka, M.D., The University of Texas MD Anderson Cancer Center

The 33 BTTC investigators in attendance discussed the trial concepts and showed enthusiasm for moving forward on the proposed trial concepts. The plan is to continue discussions on these proposals with the expectation that several will be fully developed into BTTC clinical trials. More information will be shared as those trial concepts progress.

Research Staff Session

BTTC coordinating center team members at NCI led a session for research staff to learn more about clinical care for the multi-center clinical trials. Dr. Armstrong welcomed and thanked the research staff for their hard work. NCI Research Nurse Lisa Chamberlain gave an overview of the NCI-CONNECT program and BTTC network and the roles of the coordinating center staff. NCI Nurse Practitioners Christine Seigel and Lisa Boris shared information about brain tumors, current treatments, and available clinical trials. 

Next, a panel discussion was held. It included Chamberlain; Research Associate Alvina Acquaye of NCI; Seigel; Research Nurses Sonja Crandon of NCI and Patricia Lada of NorthShore University HealthSystem; and Protocol Coordinator Jennifer Reyes of NCI. The panelists asked the participants questions on multiple topics including clinical care, regulatory activities, operations, and patient-reported outcomes. Their questions prompted lively and informative discussions.

Patient-reported Outcomes and Virtual Reality

After the breakout sessions, Dr. Armstrong presented results from her patient-reported outcomes surveys on how brain and spine tumors affect patients. Of patients surveyed, 40 percent reported at least three symptoms as moderate to severe. Distress is one of the most severe symptoms and other common symptoms are fatigue, drowsiness, difficulty remembering, and disturbed sleep. Twenty percent of patients have significant anxiety or depression.  

NCI is developing interventions to help treat these issues. These include:

• Developing an app for patients to monitor their symptoms and send reports to their physician
• Empowering the patient to manage their care and live meaningfully through the CALM program
• Using virtual reality (VR) to manage anxiety and distress

A special presentation from AppliedVR©, Joe Powers, Ph.D., and Jeannette Tsuei, shared the value of using VR to manage and lessen depressive symptoms. Tsuei shared studies that have shown effective results and the application that the company uses. During the break, attendees were given the opportunity to test the VR application. Attendees enjoyed the opportunity. 

Plans are to study these interventions throughout the BTTC network in the future.

New Targeted Therapy Approach and Clinical Trial

Dr. Gilbert presented the challenges to successful targeted therapeutic approaches to treating brain tumors. The challenge for most primary brain tumors is that there is not a clear molecular or gene target. Dr. Gilbert proposed a new targeted approach called synthetic lethality. Synthetic lethality is when a combination of deficiencies in the expression of two or more genes leads to cell death, whereas a deficiency in only one of these genes does not. Therefore, the discovery of a synthetic lethal pair where one of the two genes is already lost means that targeting the other should be lethal to the tumor cell. Orieta Celiku, Ph.D., staff scientist at NCI, presented the concept of synthetic rescue interactions, where the same system to detect synthetic lethality identification can be used to predict resistance mediators in patients with primary brain tumors. Dr. Gilbert proposed developing synthetic lethality for a clinical trial.

In summary, synthetic lethality can:

• Predict drug response and resistance based on the molecular profile of the tumor pre-treatment
• Predict selective therapies that exploit tumor vulnerabilities based on whole genome context
• Increase coverage of patient cohorts eligible for targeted and combination therapies

Dr. Wu shared information about an open phase 1 trial of TG02 plus dose-dense or metronomic temozolomide in high-grade astrocytoma and glioblastoma. Plans are to finish the phase 1 trial and later open the phase 1 trial through the BTTC network to determine whether the combination of TG02 and temozolomide prolongs survival and improves patients’ quality of life.

Wrap Up

In conclusion, the NCI-CONNECT and BTTC Annual Meetings were a great success. Attendees learned from other neuro-oncology experts and advocates; participated in invigorating discussions on current disease treatments and advances in the pipeline; reviewed proposed clinical trials; and discussed new clinical trial ideas and concepts. All attendees were gathered for the same ultimate goal: to improve therapies and outcomes for adult patients with brain and spine tumors.