~58 spots leftby Dec 2025

Combination Therapy for Brain Cancer

Recruiting in Palo Alto (17 mi)
+32 other locations
Dr. Sabine Mueller | UCSF Benioff ...
Overseen bySabine Mueller, MD, PhD, MAS
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?

Panobinostat has been studied in various cancer types, including prostate cancer and solid tumors, to determine its safety. It has been evaluated for its maximum tolerated dose and potential toxicities, indicating that safety data exists for its use in humans.36789

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

Research Team

Dr. Sabine Mueller | UCSF Benioff ...

Sabine Mueller, MD, PhD, MAS

Principal Investigator

University of California, San Francisco

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.
See 27 more

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).
See 15 more

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 Francisco

Lead Sponsor

Trials
2636
Patients Recruited
19,080,000+

National Institute of Neurological Disorders and Stroke (NINDS)

Collaborator

Trials
1403
Patients Recruited
655,000+

Mithil Prasad Foundation

Collaborator

Trials
2
Patients Recruited
570+

The Chad-Tough Defeat DIPG Foundation

Collaborator

Trials
1
Patients Recruited
360+

Storm the Heavens Fund

Collaborator

Trials
2
Patients Recruited
570+

Findings from Research

Dovitinib, an oral multi-tyrosine kinase inhibitor, was found to be safe for patients with recurrent glioblastoma, with only 16.7% of adverse events classified as severe (grade 3) toxicity, primarily involving liver and blood-related issues.
The trial showed a progression-free survival rate of 16.7% at 6 months, indicating some efficacy, but this was not linked to the presence of the FGFR-TACC gene fusion in tumors, suggesting that further personalized trials are needed.
Phase I trial of dovitinib (TKI258) in recurrent glioblastoma.Schäfer, N., Gielen, GH., Kebir, S., et al.[2018]
Oral targeted agents, including BRAF inhibitors and various receptor inhibitors, show potential in treating brain metastases, but there is a lack of comprehensive data on their effectiveness in this specific area.
Many patients with brain metastases are excluded from clinical trials, leading to a significant gap in research and documentation of the intracranial activity of these therapies, highlighting the need for more focused investigations.
Oral Targeted Therapies and Central Nervous System (CNS) Metastases.Gabay, MP., Wirth, SM., Stachnik, JM., et al.[2022]
Panobinostat, a pan histone deacetylase inhibitor, shows time-dependent synergistic effects when combined with chemotherapy agents like docetaxel, doxorubicin, or gemcitabine in human breast cancer cell lines, indicating its potential to enhance treatment efficacy.
The combination of panobinostat with gemcitabine and bortezomib significantly increased cytotoxic effects, while no synergy was observed with anti-Her2 agents or metformin, suggesting that the effectiveness of panobinostat depends on the specific drugs used in combination.
Identification of unique synergistic drug combinations associated with downexpression of survivin in a preclinical breast cancer model system.Budman, DR., Calabro, A., Rosen, L., et al.[2022]
The combination of the HDAC inhibitor panobinostat with oncolytic herpes simplex virus (oHSV) significantly enhanced the virus's ability to replicate and kill cancer cells in vitro, particularly in human glioma and squamous cell carcinoma models.
In vivo studies demonstrated that this combination therapy not only improved therapeutic efficacy in mouse models of glioma and squamous cell carcinoma but also involved mechanisms like downregulation of antiviral genes and upregulation of PD-L1, suggesting a potential strategy for overcoming tumor resistance in cancer treatment.
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.Wu, Y., Chen, X., Wang, L., et al.[2023]
In a phase II study involving 33 patients with recurrent glioblastoma, dovitinib did not show efficacy in prolonging progression-free survival (PFS) at 6 months, with only 12% in the anti-angiogenic naïve group achieving this compared to 0% in the pretreated group.
The study revealed significant toxicity, with 67% of patients experiencing grade 3 toxicities and 15% experiencing grade 4 toxicities, indicating that while dovitinib was not effective, it did pose safety concerns for patients.
Phase II study of Dovitinib in recurrent glioblastoma.Sharma, M., Schilero, C., Peereboom, DM., et al.[2020]
In a study involving 13 adult patients with advanced solid tumors or cutaneous T-cell lymphoma, panobinostat was well tolerated at doses up to 20 mg, with no dose-limiting toxicity observed in 12 evaluable patients.
The most common side effects were diarrhea and nausea, experienced by 76.9% of patients, while thrombocytopenia occurred in 92.3%, indicating a need for monitoring blood cell levels during treatment.
A phase I study of oral panobinostat (LBH589) in Japanese patients with advanced solid tumors.Fukutomi, A., Hatake, K., Matsui, K., et al.[2022]
In a study involving 16 patients with castration-resistant prostate cancer (CRPC), oral panobinostat was found to be feasible but did not lead to significant disease control when used alone, as all patients experienced disease progression despite some biological activity.
However, when combined with docetaxel, 63% of patients showed a significant decline in prostate-specific antigen (PSA) levels, indicating potential efficacy of the combination treatment, which led researchers to consider focusing on an intravenous formulation for better results.
A phase I study of oral panobinostat alone and in combination with docetaxel in patients with castration-resistant prostate cancer.Rathkopf, D., Wong, BY., Ross, RW., et al.[2022]
Panobinostat, when used in combination with bortezomib and dexamethasone, significantly improves progression-free survival in patients with relapsed or refractory multiple myeloma, with a median survival of 11.99 months compared to 8.08 months for placebo.
While panobinostat shows promising efficacy, it is associated with serious side effects such as thrombocytopenia and peripheral neuropathy, which may limit its use in clinical practice.
Panobinostat: A histone deacetylase inhibitor for the treatment of relapsed or refractory multiple myeloma.Wahaib, K., Beggs, AE., Campbell, H., et al.[2022]
Panobinostat is a potent pan-histone deacetylase (HDAC) inhibitor that promotes the expression of repressed genes, leading to reduced cancer cell growth and increased cell death (apoptosis).
It has shown strong preclinical efficacy at nanomolar concentrations and is being tested in both intravenous and oral forms for various tumor types, indicating its potential as a novel cancer therapy.
Profile of panobinostat and its potential for treatment in solid tumors: an update.Anne, M., Sammartino, D., Barginear, MF., et al.[2023]
A comprehensive analysis of 981 clinical trials on brain tumors from 2010 to 2020 revealed a wide variety of therapeutic agents and targets, with 582 unique entities identified, highlighting the complexity of drug development in this area.
The most common classes of agents in these trials were kinase inhibitors, chemotherapeutic agents, and cancer vaccines, indicating a diverse approach to treatment, although certain agents like kinase inhibitors were less frequently used in combination therapies.
Brain Cancer Drug Discovery: Clinical Trials, Drug Classes, Targets, and Combinatorial Therapies.Sokolov, AV., Dostdar, SA., Attwood, MM., et al.[2022]
A screening of 446 FDA-approved drugs identified 22 with strong anti-glioblastoma (GBM) activity, including statins, which were found to inhibit GBM cell proliferation and induce autophagy.
Combining statins with irinotecan significantly enhanced the drug's pro-apoptotic effects while reducing toxicity compared to high-dose irinotecan alone, suggesting a safer and more effective treatment strategy for GBM.
Novel anti-glioblastoma agents and therapeutic combinations identified from a collection of FDA approved drugs.Jiang, P., Mukthavaram, R., Chao, Y., et al.[2021]
Temozolomide (TMZ) combined with the ribonucleotide reductase inhibitors Trimidox (TX) and Didox (DX) showed synergistic cytotoxic effects against human malignant glioma cell lines, indicating a promising approach for enhancing treatment efficacy in brain tumors.
The study found that these drug combinations could potentially reduce the required doses of each drug while maintaining effectiveness, although some combinations also exhibited additive or antagonistic effects depending on the specific cell line and drug ratios used.
Combined effects of temozolomide and the ribonucleotide reductase inhibitors didox and trimidox in malignant brain tumor cells.Figul, M., Söling, A., Dong, HJ., et al.[2018]
In a phase II study involving 53 patients with recurrent high-grade gliomas, the combination of procarbazine and high-dose tamoxifen achieved an overall response rate of 29.5%, indicating a reasonable level of efficacy in this heavily pretreated population.
While the treatment improved quality of life and performance status, it did not lead to significant increases in time to progression (TTP) or median survival time (MST), which were 13 weeks for glioblastoma multiforme and 27 weeks for anaplastic astrocytoma.
Procarbazine and high-dose tamoxifen as a second-line regimen in recurrent high-grade gliomas: a phase II study.Brandes, AA., Ermani, M., Turazzi, S., et al.[2022]

References

Phase I trial of dovitinib (TKI258) in recurrent glioblastoma. [2018]
Oral Targeted Therapies and Central Nervous System (CNS) Metastases. [2022]
Identification of unique synergistic drug combinations associated with downexpression of survivin in a preclinical breast cancer model system. [2022]
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]
Phase II study of Dovitinib in recurrent glioblastoma. [2020]
A phase I study of oral panobinostat (LBH589) in Japanese patients with advanced solid tumors. [2022]
A phase I study of oral panobinostat alone and in combination with docetaxel in patients with castration-resistant prostate cancer. [2022]
Panobinostat: A histone deacetylase inhibitor for the treatment of relapsed or refractory multiple myeloma. [2022]
Profile of panobinostat and its potential for treatment in solid tumors: an update. [2023]
10.United Statespubmed.ncbi.nlm.nih.gov
Brain Cancer Drug Discovery: Clinical Trials, Drug Classes, Targets, and Combinatorial Therapies. [2022]
Novel anti-glioblastoma agents and therapeutic combinations identified from a collection of FDA approved drugs. [2021]
Combined effects of temozolomide and the ribonucleotide reductase inhibitors didox and trimidox in malignant brain tumor cells. [2018]
13.United Statespubmed.ncbi.nlm.nih.gov
Procarbazine and high-dose tamoxifen as a second-line regimen in recurrent high-grade gliomas: a phase II study. [2022]