ONC206 + Radiation Therapy for Brain Tumor
(PNOC023 Trial)
Recruiting in Palo Alto (17 mi)
+4 other locations
Age: < 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Sabine Mueller, MD, PhD
Must not be taking: Investigational drugs, Anti-cancer agents
Disqualifiers: Immune disorders, Uncontrolled infection, others
No Placebo Group
Trial Summary
What is the purpose of this trial?
This trial studies the effects of ONC206, a new drug that stresses out cancer cells to kill them, in children and young adults with difficult-to-treat brain tumors. The drug can be used alone or with radiation therapy. ONC206 is related to ONC201, which has shown promise in treating certain types of brain tumors.
Will I have to stop taking my current medications?
The trial requires that participants stop taking certain medications before starting the study. Specifically, you must wait a certain period after taking investigational agents, cytotoxic therapy, antibodies, and biologic or small molecule agents. If you are on strong inhibitors or inducers of specific enzymes (CYP3A4, 2D6, 1A2, 2C9, and 2C19), you must stop them at least 14 days before and throughout the study.
What data supports the effectiveness of the treatment ONC206 + Radiation Therapy for brain tumors?
How does the drug ONC206 differ from other treatments for brain tumors?
ONC206 is unique because it is combined with radiation therapy specifically for brain tumors, potentially offering a novel approach compared to standard treatments. While the exact mechanism of ONC206 is not detailed in the provided research, the combination with radiation therapy suggests a strategy to enhance treatment efficacy, similar to how other targeted therapies are used to improve outcomes in brain metastases from other cancers.678910
Eligibility Criteria
This trial is for children and adults with newly diagnosed or recurrent diffuse midline gliomas (DMG) and other malignant CNS tumors. Participants must have stable vital signs, not be pregnant or breastfeeding, agree to use contraception if applicable, and cannot be on certain medications that affect ONC206 absorption or immune system disorders.Inclusion Criteria
I have been on a stable or decreasing dose of steroids for at least 3 days before my baseline MRI scan.
Agreement to use adequate contraception for females of child-bearing potential and males
I have recovered from all side effects of my previous treatments.
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Exclusion Criteria
I have an immune system disorder like HIV, hepatitis B or C, or an autoimmune disease.
I do not have any infections that are currently uncontrolled.
Participants currently receiving another investigational drug
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Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive ONC206 orally up to six times per week, with cycles repeating every 28 days for up to 12 months. Radiation therapy is included for certain arms.
12-24 months
Follow-up
Participants are monitored for safety and effectiveness after treatment completion, with follow-ups at 30 days and then every 3 months for up to 5 years.
5 years
Treatment Details
Interventions
- ONC206 (Stress Response Inducer)
- Standard of Care Radiation Therapy (Radiation)
Trial OverviewThe trial is testing the effectiveness of a new drug called ONC206 alone or combined with standard radiation therapy. The goal is to find the best dose that can stop tumor growth by triggering a stress response in cancer cells without harming normal cells.
Participant Groups
4Treatment groups
Experimental Treatment
Group I: Arm D: ONC206 Therapy, Primary malignant CNS tumors with progressionExperimental Treatment2 Interventions
Patients receive ONC206 PO once a day (QD) up to six times per week. Cycles repeat every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity.
Group II: Arm C: ONC206 + radiation therapy, DMGs with evidence of first progression but previously untreatedExperimental Treatment3 Interventions
Patients undergo standard of care radiation therapy daily 5 days a week and receive ONC206 PO up to six times per week. Cycles repeat every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity.
Group III: Arm B: ONC206 + radiation therapy for newly diagnosed participantsExperimental Treatment3 Interventions
Patients undergo standard of care radiation therapy daily 5 days a week and receive ONC206 PO up to six times per week. Cycles repeat every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity.
Group IV: Arm A: ONC206 for participants with diffuse midline gliomas + prior therapyExperimental Treatment2 Interventions
Patients receive ONC206 orally (PO) up to six times per week. Cycles repeat every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Children's Hospital of PhiladelphiaPhiladelphia, PA
Emory UniversityAtlanta, GA
University of MichiganAnn Arbor, MI
University of California, San FranciscoSan Francisco, CA
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Who Is Running the Clinical Trial?
Sabine Mueller, MD, PhDLead Sponsor
Dana-Farber Cancer InstituteCollaborator
The ChadTough Defeat DIPG FoundationCollaborator
Storm the Heavens FundCollaborator
National Cancer Institute (NCI)Collaborator
ChimerixIndustry Sponsor
Mithil Prasad FoundationCollaborator
References
A systematic overview of radiation therapy effects in brain tumours. [2019]A systematic review of radiation therapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately (Acta Oncol 2003; 42: 357-365). This synthesis of the literature on radiation therapy for brain tumours is based on data from 9 randomized trials and 1 meta-analysis. Moreover, data from 2 prospective studies, 3 retrospective studies and 4 other articles were used. In total, 19 scientific articles are included, involving 4,266 patients. The results were compared with those of a similar overview from 1996 including 11,252 patients. The conclusions reached can be summarized as follows: The conclusion from SBU 129/2 that curative treatment is not available for patients with high-grade malignant glioma (grade III and IV) is still valid. The survival benefit from postoperative radiotherapy compared to supportive care only or chemotherapy is about 3-4 months, as demonstrated in earlier randomized studies. Quality of life is now currently estimated and considered to be of major importance when reporting the outcome of treatment for patients with brain tumours. There is no scientific evidence that radiotherapy using hyper- and hypofractionation leads to longer survival for patients with high-grade malignant glioma than conventional radiotherapy. There is large documentation, but only one randomized study. There is some documentation to support the view that patients with grade IV glioma and poor prognosis can be treated with hypofractionation and with an outcome similar to that after conventional fractionation. A shorter treatment time should be convenient for the patient. Documentation of the benefit of a radiotherapy boost with brachytherapy is limited and no conclusion can be drawn. There is no scientific evidence that radiotherapy prolongs life for patients with low-grade glioma. There are some data supporting that radiotherapy can be used to treat symptoms in patients with low-grade glioma. As no controlled studies have been reported, no firm conclusion can be drawn.
Use of monoclonal anti-EGFR antibody in the radioimmunotherapy of malignant gliomas in the context of EGFR expression in grade III and IV tumors. [2021]We investigated the putative benefits of simultaneous teleradiotherapy and anti-epidermal growth factor receptor (EGFR) 125I monoclonal antibody (MAb) 425 radioimmunotherapy, when applied after neurosurgery in high-grade gliomas, over teleradiotherapy alone. In comparison to previous studies which have reported good results with this type of radioimmunotherapy, we advanced the adjuvant radioimmunotherapy step, that is, gave it during, not after, teleradiotherapy. The randomized prospective study examined two groups: simultaneous postoperative teleradiotherapy and radioimmunotherapy (TRT + RIT; eight patients) versus teleradiotherapy alone (TRT; 10 patients). Patients who after primary operation of grade III (6 cases) or IV glioma (12 cases), showed no or less than 2 mL of remnant tumor on post-operative magnetic resonance (MR) study and were not treated postoperatively by chemotherapy were enrolled and randomized. Anti-EGFR 125IMAb 425 RIT was started during week 4 of radiotherapy, not later than 8 weeks after neurosurgery, and was repeated three times at 1-week intervals. Total activity given was 5026 + 739 MBq/patient. The tolerance of TRT was good. No immediate side effects of concomitant anti-EGRF 125I RIT were observed. Observation showed a median total survival (as evaluated from the primary neurosurgical treatment) of 14 months (range 3.5-28 months). There was no improvement in disease-free or total survival in the group of patients treated by TRT + RIT after neurosurgery. In addition, an immunohistochemical analysis of EGFR expression in gliomas was performed in a group of 100 cases and was distinctly positive in 50% grade IV gliomas and 68% grade III gliomas. We conclude that simultaneous radiotherapy and radioimmunotherapy with anti-EGFR 125I-MAb 425 is not beneficial over radiotherapy alone in adjuvant treatment of high-grade gliomas after neurosurgery. We also recommend individual confirmation of EGFR expression in further anti-EGFR radioimmunotherapy trials.
Radiation therapy of brain tumors. [2019]Results of radiation therapy obtained at the University of California, San Francisco, over approximately the past 20 years for various histologic types of brain tumors are presented. Included are astrocytomas, malignant gliomas, medulloblastomas, ependymomas, oligodendrogliomas, and brain stem tumors. Degree of malignancy and tendency to disseminate within the central nervous system are also reviewed. For each tumor type and grade considered, the survival rate appeared improved when incomplete resection was followed by irradiation. The increase in survival rate for glioblastomas was only evident for 1-2 years, but for the remainder the improvement extends to 5-10 years. Since many patients were still alive at the time of review, it is possible that permanent control of many intracranial neoplasms may be induced by radiation therapy.
Radiosurgery alone or in combination with whole-brain radiotherapy for brain metastases. [2022]Evaluation of the treatment outcome after radiosurgery (RS) alone or in combination with whole-brain radiotherapy (WBRT) with special attention to prescribed dose and its influence on local control and survival.
Fractionated stereotactic radiation therapy in the management of primary oligodendroglioma and oligoastrocytoma. [2018]To retrospectively analyze the outcomes and benefits from radiation therapy (RT) as a component of multimodal treatment for oligodendroglioma and oligoastrocytoma, assessing local control and survival rates and evaluating prognostic factors.
Survival advantage combining a BRAF inhibitor and radiation in BRAF V600E-mutant glioma. [2019]Radiation (RT) is critical to the treatment of high-grade gliomas (HGGs) but cures remain elusive. The BRAF mutation V600E is critical to the pathogenesis of 10-20% of pediatric gliomas, and a small proportion of adult HGGs. Here we aim to determine whether PLX4720, a specific BRAF V600E inhibitor, enhances the activity of RT in human HGGs in vitro and in vivo. Patient-derived HGG lines harboring wild-type BRAF or BRAF V600E were assessed in vitro to determine IC50 values, cell cycle arrest, apoptosis and senescence and elucidate mechanisms of combinatorial activity. A BRAF V600E HGG intracranial xenograft mouse model was used to evaluate in vivo combinatorial efficacy of PLX4720+RT. Tumors were harvested for immunohistochemistry to quantify cell cycle arrest and apoptosis. RT+PLX4720 exhibited greater anti-tumor effects than either monotherapy in BRAF V600E but not in BRAF WT lines. In vitro studies showed increased Annexin V and decreased S phase cells in BRAF V600E gliomas treated with PLX4720+RT, but no significant changes in β-galactosidase levels. In vivo, concurrent and sequential PLX4720+RT each significantly prolonged survival compared to monotherapies, in the BRAF V600E HGG model. Immunohistochemistry of in vivo tumors demonstrated that PLX4720+RT decreased Ki-67 and phospho-MAPK, and increased γH2AX and p21 compared to control mice. BRAF V600E inhibition enhances radiation-induced cytotoxicity in BRAF V600E-mutated HGGs, in vitro and in vivo, effects likely mediated by apoptosis and cell cycle, but not senescence. These studies provide the pre-clinical rationale for clinical trials of concurrent radiotherapy and BRAF V600E inhibitors.
A Phase II Multi-institutional Clinical Trial Assessing Fractionated Simultaneous In-Field Boost Radiotherapy for Brain Oligometastases. [2020]Purpose/Objective Published preclinical and phase I clinical trial data suggest that fractionated lesional radiotherapy with 60 Gy in 10 fractions can serve as an alternative approach to single fraction radiosurgical boost for brain oligometastases. Methods and Materials A phase II clinical trial (NCT01543542) of a total of 60 Gy in 10 fractions of lesional (one to three) radiotherapy (given simultaneously with whole-brain helical tomotherapy with 30 Gy in 10 fractions) was conducted at five institutions. We hypothesized that fractionated radiotherapy would be considered unsuitable if the median overall survival (OS) was degraded by two months or if six-month intracranial control (ICC) and intracranial lesion (ILC) were inferior by 10% compared with the published RTOG 9508 results. Results A total of 87 patients were enrolled over a 4.5-year accrual period. Radiological lesion and extralesional central nervous system progression were documented in 15/87 (17%) and 11/87 (13%) patients, respectively. Median OS for all patients was 5.4 months. Six-month actuarial estimates of ICC and ILC were 78% and 89%, respectively. However, only the ILC estimate achieved statistical significance (p=0.02), demonstrating non-inferiority to the a priori historical controls (OS: p=0.09, ICC=0.31). Two patients developed suspected asymptomatic radionecrosis. Conclusions The phase II estimates of ILC were demonstrated to be non-inferior to the results of the RTOG 9508.
[Brain metastasis in breast cancer]. [2018]Brain metastasis is an important issue in modern neurooncology. Our results of combined treatment of brain metastases are presented and available approaches to brain irradiation and chemotherapy are discussed. There is strong evidence to suggest that maximum combinations of approaches might improve treatment efficacy and extend median overall survival to as long as 6 months (p
Brain Metastases from NSCLC: Radiation Therapy in the Era of Targeted Therapies. [2022]Brain metastases (BMs) will develop in a large proportion of patients with NSCLC throughout the course of their disease. Among patients with NSCLC with oncogenic drivers, mainly EGFR activating mutations and anaplastic lymphoma receptor tyrosine kinase gene (ALK) rearrangements, the presence of BM is a common secondary localization of disease both at the time of diagnosis and at relapse. Because of the limited penetration of a wide range of drugs across the blood-brain barrier, radiotherapy is considered the cornerstone of treatment of BMs. However, evidence of dramatic intracranial response rates has been reported in recent years with targeted therapies such as tyrosine kinase inhibitors and has been supported by new insights into pharmacokinetics to increase rates of tyrosine kinase inhibitors' penetration of the cerebrospinal fluid (CSF). In this context, the combination of brain radiotherapy and targeted therapies seems relevant, and there is a strong radiobiological rationale to harness the radiosentizing effect of the drugs. Nevertheless, to date, there is a paucity of high-level clinical evidence supporting the combination of brain radiotherapy and targeted therapies in patients with NSCLC and BMs, and there are often methodological biases in reported studies, such as the lack of stratification by mutation status. Moreover, among asymptomatic patients not suitable for ablative treatment, this strategy is challenged by the promising results associated with the administration of targeted therapies alone. Herein, we review the biological rationale to combine targeted therapies and brain radiotherapy for patients with NSCLC and BMs, report the clinical data available to date, and discuss future directions to improve outcome in this group of patients.
Interstitial 252Cf neutron therapy for glioblastoma multiforme. [2019]252Cf brachytherapy has been combined with whole brain photon beam therapy to 6000 rads in 5-7 weeks. In early phase I studies, all patients selected for study tolerated the procedure and the subsequent photon beam therapy. All showed improvement in performance status and decreased tumor size by CT scan evaluation, but it became clear that these tumors are of large size and bulk, produce marked adjacent brain edema, and require individualized implant therapy as well as high-dose external beam irradiation if response is to occur.