Combination Therapy for Brain Cancer
Recruiting in Ann Arbor (>99 mi)
+32 other locations
Age: < 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: University of California, San Francisco
Must not be taking: CYP3A4/5 inhibitors, inducers
Disqualifiers: HIV, Hepatitis B/C, others
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?
This trial is testing a combination of three drugs to treat a specific type of brain tumor called diffuse midline gliomas (DMGs). These drugs aim to stop the tumor from growing by blocking enzymes that the cancer cells need. The trial focuses on patients with DMGs because current treatments are not very effective for them.
Will I have to stop taking my current medications?
The trial does not specify if you must stop taking your current medications, but it does mention that you cannot use certain drugs like potent CYP3A4/5 inhibitors and inducers during the study. It's best to discuss your current medications with the study team to see if any adjustments are needed.
What data supports the effectiveness of the drug combination therapy for brain cancer?
Panobinostat, one of the drugs in the combination therapy, has shown potential in enhancing the effects of other cancer treatments in preclinical models, including glioma, by blocking cancer-related pathways and reversing cancer progression. Additionally, dovitinib, another drug in the combination, has been studied for its ability to target brain tumor pathways in glioblastoma, suggesting potential effectiveness in brain cancer treatment.12345
Is panobinostat generally safe for humans?
What makes the combination therapy for brain cancer unique?
This combination therapy for brain cancer is unique because it includes ONC201, Panobinostat, and Paxalisib, which are not commonly used together in existing treatments. These drugs target different pathways in cancer cells, potentially offering a more comprehensive approach to treatment compared to standard therapies that often focus on a single target.210111213
Eligibility Criteria
This trial is for patients aged 2 to 39 with diffuse midline gliomas, including those with spinal cord tumors. They must have completed standard radiation therapy and not be pregnant or breastfeeding. Participants need stable vital signs, controlled seizures if present, and agree to use contraception. Those with immune disorders or uncontrolled illnesses are excluded.Inclusion Criteria
I have taken temozolomide or dexamethasone at standard doses during radiation.
The effects of the study drugs on the developing human fetus are unknown. For this reason, females of child-bearing potential and males must agree to use adequate contraception. Adequate methods include: hormonal or barrier method of birth control; or abstinence prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while he or she is participating in this study, she should inform her treating physician immediately. Males treated or enrolled on this protocol must also agree to use adequate contraception prior to the study and for the duration of study participation.
My diarrhea is mild and not severe.
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Exclusion Criteria
My brain tumor is a thalamic H3K27M diffuse midline glioma.
My cancer has spread to the lining of my brain or spinal cord.
Female participants of childbearing potential must not be pregnant or breast-feeding. Female participants of childbearing potential must have a negative serum or urine pregnancy test prior to the start of therapy (as clinically indicated).
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Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Radiation/Re-irradiation
Participants undergo weekly radiation therapy and receive ONC201 weekly during radiation therapy
4 weeks
Weekly visits for radiation therapy
Maintenance
Participants receive ONC201 weekly and paxalisib daily. Cycles repeat every 28 days in the absence of adverse events or unacceptable toxicity
6 months
Monthly visits for treatment monitoring
Follow-up
Participants are monitored for safety and effectiveness after treatment
5 years
Every 3 months
Treatment Details
Interventions
- ONC201 (Enzyme Inhibitor)
- Panobinostat (Enzyme Inhibitor)
- Paxalisib (Enzyme Inhibitor)
- Radiation Therapy (Radiation)
Trial OverviewThe phase II trial tests ONC201 combined with panobinostat or paxalisib in treating diffuse midline gliomas (DMGs). These drugs inhibit enzymes that may stop tumor growth. The effectiveness of different drug combinations will be assessed for patients who've had little success with other treatments.
Participant Groups
5Treatment groups
Experimental Treatment
Group I: NOT CURRENTLY ENROLLING - ARM 6: Paxalisib (Day -1), Radiation+Paxalisib , Paxalisib+ONC201Experimental Treatment3 Interventions
Participants may receive a safety lead in of ONC201. During trial validation phase, participants without prior biopsy receive paxalisib PO on day -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, participants without prior radiation therapy or have disease progression after radiation therapy undergo weekly radiation therapy and receive paxalisib PO daily during radiation therapy. During the maintenance phase, participants receive ONC201 PO weekly and paxalisib PO QD. Cycles repeat every 28 days (4 weeks) in the absence of adverse events of unacceptable toxicity
Group II: NOT CURRENTLY ENROLLING - ARM 4: ONC201 (Day -1,-2), Radiation+ONC201, Paxalisib+ONC201Experimental Treatment3 Interventions
Participants may receive a safety lead in of ONC201. During the trial validation phase, participants without prior biopsy receive ONC201 PO on days -2 and -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, participants may receive ONC201 PO weekly during radiation therapy. During the maintenance phase, participants receive ONC201 PO weekly and paxalisib PO QD. Cycles repeat every 28 days (4 weeks) in the absence of adverse events or unacceptable toxicity
Group III: NOT CURRENTLY ENROLLING - ARM 2: ONC201 (Day -1), Radiation+ONC201, Paxalisib+ONC201Experimental Treatment3 Interventions
Participants may receive a safety lead in of ONC201. During the trial validation phase, participants without prior biopsy receive ONC201 PO on day -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, participants without prior radiation therapy or have disease progression after radiation therapy undergo weekly radiation therapy and receive ONC201 PO weekly during radiation therapy. During the maintenance phase, participants receive ONC201 PO weekly and paxalisib PO daily (QD). Cycles repeat every 28 days (4 weeks) in the absence of adverse events of unacceptable toxicity
Group IV: Cohort 5 - ONC201 + Targeted therapiesExperimental Treatment2 Interventions
Participants will receive a starting dose of 625mg of ONC201 weekly on Day 1 and 2 during any non-interventional radiation/re-irradiation per standard of care treatment, and in combination with targeted agents to be selected from approved/available agents based on a rational therapy approach guided by molecular data from the tumor tissue or cerebral spinal fluid (CSF). Each individual targeted agent will be dosed at the recommended therapeutic dose, if a dose has been issued for the participant's age group. Observations and schedule of events will be issued based on the chosen agent determined to best fit the molecular profile (e.g. BRAFV600E, PDGFRA, FGFR1, NF1).
Group V: Cohort 4 - Dose Escalation, Starting Dose 2 (625mg ONC201)Experimental Treatment2 Interventions
Participants will receive a safety lead in of 625mg ONC201. During the trial validation phase, participants without prior biopsy receive ONC201 PO on days -2 and -1 prior to standard of care biopsy. During any non-interventional radiation/re-irradiation per standard of care treatment, participants will receive 625 mg as the starting dose of ONC201 Days 1 and 2 on a weekly basis. Cycles repeat every 28 days (4 weeks) in the absence of adverse events or unacceptable toxicity
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of California, San FranciscoSan Francisco, CA
Washington University in St. LouisSaint Louis, MO
Duke UniversityDurham, NC
University of UtahSalt Lake City, UT
More Trial Locations
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Who Is Running the Clinical Trial?
University of California, San FranciscoLead Sponsor
National Institute of Neurological Disorders and Stroke (NINDS)Collaborator
Mithil Prasad FoundationCollaborator
The Chad-Tough Defeat DIPG FoundationCollaborator
Storm the Heavens FundCollaborator
References
Phase I trial of dovitinib (TKI258) in recurrent glioblastoma. [2018]Dovitinib (TKI258) is an oral multi-tyrosine kinase inhibitor of FGFR, VEGFR, PDGFR β, and c-Kit. Since dovitinib is able to cross the blood-brain barrier and targets brain tumor-relevant pathways, we conducted a phase I trial to demonstrate its safety in recurrent glioblastoma (GBM).
Oral Targeted Therapies and Central Nervous System (CNS) Metastases. [2022]The purpose of our review is to summarize the clinical activity of oral targeted agents against brain metastases. This includes BRAF inhibitors (dabrafenib and vemurafenib), human epidermal growth factor receptor inhibitors (lapatinib, gefitinib, erlotinib, and afatinib), multi-kinase angiogenesis inhibitors (sorafenib, sunitinib, pazopanib, and vandetanib), and ALK/c-MET (crizotinib) and ALK/IGF-1 (ceritinib) inhibitors. Effective systemic therapies are needed for long-term benefit in brain metastases and documentation of intracranial activity for many therapies is poor. Our review provides a summary of the literature with pertinent data for clinicians. This is needed as subjects with brain metastases are often prevented from enrolling in clinical trials and investigations focused on systemic therapies for brain metastases are rare.
Identification of unique synergistic drug combinations associated with downexpression of survivin in a preclinical breast cancer model system. [2022]An in-vitro 72-h assay using median effect analysis and curve shift analysis was used to evaluate the utility of potentially clinically useful combinations of agents for synergism or antagonism. Six human breast cancer cell lines, both receptor rich and receptor poor, were studied.Panobinostat (LBH-589), a pan histone deacetylase inhibitor with a multitude of biological effects, exhibits time-dependent synergistic effects in breast cancer cell lines with docetaxel, doxorubicin, or gemcitabine in clinically relevant concentrations. Survivin expression was markedly downregulated in the presence of panobinostat with gemcitabine. Bortezomib, a proteasome inhibitor,markedly enhanced the cytotoxic effects of panobinostat combined with gemcitabine. Panobinostat did not demonstrate universal enhancement of cytotoxic drugs,and therefore, synergy was dependent on the second agent selected. No synergy was noted with anti-Her2 agents in Her2 overexpressing cell lines. Metformin combined with panobinostat demonstrated no synergy in this test system. These effects were confirmed by an apoptosis assay and caspase-3 production. A positive drug interaction was identified. The triplet of panobinostat with either doxorubicin/carboplatin or gemcitabine/carboplatin was especially potent in all cell lines. As all these agents are clinically available, further studies of the potent combinations are warranted.
Histone Deacetylase Inhibitor Panobinostat Benefits the Therapeutic Efficacy of Oncolytic Herpes Simplex Virus Combined with PD-1/PD-L1 Blocking in Glioma and Squamous Cell Carcinoma Models. [2023]Combination therapy has been widely explored for oncolytic virus (OV), as it can be met with tumor resistance. The HDAC inhibitor (HDACi) panobinostat is a potent pan-deacetylase inhibitor which blocks multiple cancer-related pathways and reverses epigenetic events in cancer progression.
Phase II study of Dovitinib in recurrent glioblastoma. [2020]Dovitinib is an oral, potent inhibitor of FGFR and VEGFR, and can be a promising strategy in patients with recurrent or progressive glioblastoma (GBM).
A phase I study of oral panobinostat (LBH589) in Japanese patients with advanced solid tumors. [2022]The objective was to determine the maximum tolerated dose and the dose-limiting toxicity of panobinostat (LBH589) when administered as a single agent to adult patients with advanced solid tumors or cutaneous T-cell lymphoma whose disease had progressed despite standard therapy or for whom no standard therapy existed.
A phase I study of oral panobinostat alone and in combination with docetaxel in patients with castration-resistant prostate cancer. [2022]Histone deacetylase inhibitors have demonstrated anticancer activity against a range of tumors. We aimed to define the maximum tolerated dose, toxicity, activity, and pharmacokinetics of oral panobinostat, a pan-deacetylase inhibitor, alone and in combination with docetaxel for the treatment of castration-resistant prostate cancer (CRPC).
Panobinostat: A histone deacetylase inhibitor for the treatment of relapsed or refractory multiple myeloma. [2022]The mechanism of action, pharmacodynamics, pharmacokinetics, clinical efficacy, interaction potential, adverse effects, and place in therapy of panobinostat are reviewed.
Profile of panobinostat and its potential for treatment in solid tumors: an update. [2023]The histone deacetylase (HDAC) inhibitors have emerged as novel therapies for cancer. Panobinostat (LBH 589, Novartis Pharmaceuticals) is a pan-deacetylase inhibitor that is being evaluated in both intravenous and oral formulations across multiple tumor types. Comparable to the other HDACs, panobinostat leads to hyperacetylation of histones and other intracellular proteins, allowing for the expression of otherwise repressed genes, leading to inhibition of cellular proliferation and induction of apoptosis in malignant cells. Panobinostat, analogous to other HDAC inhibitors, also induces apoptosis by directly activating cellular death receptor pathways. Preclinical data suggests that panobinostat has inhibitory activity at nanomolar concentrations and appears to be the most potent clinically available HDAC inhibitor. Here we review the current status of panobinostat and discuss its role in the treatment of solid tumors.
Brain Cancer Drug Discovery: Clinical Trials, Drug Classes, Targets, and Combinatorial Therapies. [2022]Brain cancer is a formidable challenge for drug development, and drugs derived from many cutting-edge technologies are being tested in clinical trials. We manually characterized 981 clinical trials on brain tumors that were registered in ClinicalTrials.gov from 2010 to 2020. We identified 582 unique therapeutic entities targeting 581 unique drug targets and 557 unique treatment combinations involving drugs. We performed the classification of both the drugs and drug targets based on pharmacological and structural classifications. Our analysis demonstrates a large diversity of agents and targets. Currently, we identified 32 different pharmacological directions for therapies that are based on 42 structural classes of agents. Our analysis shows that kinase inhibitors, chemotherapeutic agents, and cancer vaccines are the three most common classes of agents identified in trials. Agents in clinical trials demonstrated uneven distribution in combination approaches; chemotherapy agents, proteasome inhibitors, and immune modulators frequently appeared in combinations, whereas kinase inhibitors, modified immune effector cells did not as was shown by combination networks and descriptive statistics. This analysis provides an extensive overview of the drug discovery field in brain cancer, shifts that have been happening in recent years, and challenges that are likely to come. SIGNIFICANCE STATEMENT: This review provides comprehensive quantitative analysis and discussion of the brain cancer drug discovery field, including classification of drug, targets, and therapies.
Novel anti-glioblastoma agents and therapeutic combinations identified from a collection of FDA approved drugs. [2021]Glioblastoma (GBM) is a therapeutic challenge, associated with high mortality. More effective GBM therapeutic options are urgently needed. Hence, we screened a large multi-class drug panel comprising the NIH clinical collection (NCC) that includes 446 FDA-approved drugs, with the goal of identifying new GBM therapeutics for rapid entry into clinical trials for GBM.
Combined effects of temozolomide and the ribonucleotide reductase inhibitors didox and trimidox in malignant brain tumor cells. [2018]Temozolomide (TMZ), an oral alkylating agent with good penetration of the blood-brain barrier, has shown efficacy in the treatment of malignant brain tumors. Ribonucleotide reductase (RR), the rate-limiting enzyme of DNA synthesis, seems to be a complementary target for combination chemotherapy of brain tumors. Trimidox (TX) and didox (DX) are two recently synthesized specific inhibitors of RR. The combinations of TMZ with TX or DX as a basis for synergistic chemotherapy protocols were tested in this study.
Procarbazine and high-dose tamoxifen as a second-line regimen in recurrent high-grade gliomas: a phase II study. [2022]A phase II study was conducted in patients with high-grade gliomas that recurred after surgery plus radiotherapy and a first-line nitrosourea-based regimen. Our aim was to investigate the efficacy of procarbazine (PCB) combined with high-dose tamoxifen in relation to tumor control, toxicity, and time to progression (TTP).