Combination Therapy for Brain Cancer

(PNOC022 Trial)

Recruiting at 39 trial locations

Overseen By Kelly Hitchner

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: University of California, San Francisco

Must not be taking: CYP3A4/5 inhibitors, inducers

Disqualifiers: HIV, Hepatitis B/C, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 3

360 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial focuses on testing whether combining the drug ONC201 with either panobinostat or paxalisib can effectively treat diffuse midline gliomas (DMGs), a type of brain cancer with limited treatment options. The goal is to determine if these combinations can block enzymes that promote tumor cell growth. The trial seeks participants diagnosed with DMG who have either just completed radiation therapy or have experienced cancer progression. As a Phase 2 trial, the research measures the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that ONC201 is generally safe for people with certain types of brain tumors. In various studies, ONC201 did not raise safety concerns and has been approved for treating specific rare brain tumors, indicating it is well-tolerated by patients.

For paxalisib, studies indicate a consistent safety record with some common side effects, such as high blood sugar, mouth sores, and skin rash. Despite these side effects, paxalisib has been well-tolerated at the tested dose, even in people with newly diagnosed brain tumors.

Both ONC201 and paxalisib have demonstrated sufficient safety in past studies to warrant further testing. While side effects are always possible, these treatments have been tested in humans before and have not shown major safety issues. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they offer a fresh approach to tackling brain cancer. Unlike the standard therapies that typically involve surgical resection, chemotherapy, or radiation alone, this combination therapy targets cancer cells more precisely. ONC201, Panobinostat, and Paxalisib work together to disrupt cancer cell growth and survival pathways in unique ways. ONC201 targets the dopamine receptor pathway, Panobinostat inhibits histone deacetylases to affect gene expression, and Paxalisib targets the PI3K pathway, which is often overactive in brain cancers. This multi-faceted attack on tumor cells could potentially improve outcomes for patients with brain cancer, providing a new hope where conventional treatments may fall short.

What evidence suggests that this trial's treatments could be effective for diffuse midline gliomas?

Research has shown that ONC201, one of the treatments in this trial, may help treat brain tumors like glioblastoma. In studies, patients who received ONC201 lived longer than those who did not. Similarly, research on paxalisib, another treatment option in this trial, indicates it can extend the lives of patients with newly diagnosed glioblastoma. Specifically, patients treated with paxalisib lived longer than those who received standard treatment. Both ONC201 and paxalisib block certain enzymes that help tumor cells grow, which might be effective against hard-to-treat brain cancers like diffuse midline gliomas (DMGs). ^{2 4 6 7 8}

Who Is on the Research Team?

Sabine Mueller, MD, PhD, MAS

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

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.

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).

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• ONC201
• Panobinostat
• Paxalisib
• Radiation Therapy

Trial Overview The 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.

How Is the Trial Designed?

Group I: NOT CURRENTLY ENROLLING - ARM 6: Paxalisib (Day -1), Radiation+Paxalisib , Paxalisib+ONC201 Experimental Treatment 3 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+ONC201 Experimental Treatment 3 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+ONC201 Experimental Treatment 3 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 therapies Experimental Treatment 2 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 Treatment 2 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

Who Is Running the Clinical Trial?

University of California, San Francisco

Lead Sponsor

Trials

2,636

Recruited

19,080,000+

National Institute of Neurological Disorders and Stroke (NINDS)

Collaborator

Trials

1,403

Recruited

655,000+

Mithil Prasad Foundation

Collaborator

Trials

2

Recruited

570+

The Chad-Tough Defeat DIPG Foundation

Collaborator

Trials

1

Recruited

360+

Storm the Heavens Fund

Collaborator

Trials

2

Recruited

570+

Published Research Related to This Trial

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.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of Dovitinib in recurrent glioblastoma. Sharma, M., Schilero, C., Peereboom, DM., et al.[2020]

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.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Profile of panobinostat and its potential for treatment in solid tumors: an update. Anne, M., Sammartino, D., Barginear, MF., et al.[2023]

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.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Panobinostat: A histone deacetylase inhibitor for the treatment of relapsed or refractory multiple myeloma. Wahaib, K., Beggs, AE., Campbell, H., et al.[2022]

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.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brain Cancer Drug Discovery: Clinical Trials, Drug Classes, Targets, and Combinatorial Therapies. Sokolov, AV., Dostdar, SA., Attwood, MM., et al.[2022]

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.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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]

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.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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]

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.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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]

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.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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 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.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of oral panobinostat (LBH589) in Japanese patients with advanced solid tumors. Fukutomi, A., Hatake, K., Matsui, K., 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.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel anti-glioblastoma agents and therapeutic combinations identified from a collection of FDA approved drugs. Jiang, P., Mukthavaram, R., Chao, Y., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6108585/

TIC10/ONC201—a potential therapeutic in glioblastoma In this study, Allen et al. provided proof for the anti-neoplastic activity of TIC10/ONC201 in different cancer entities including data showing enhanced ...

2. ejcancer.com ejcancer.com/article/S0959-8049(24)01772-6/fulltext

Real life data of ONC201 (dordaviprone) in pediatric and ... Reirradiation was associated with significantly longer survival after ONC201 start only in children. Conclusion. While the efficacy of ONC201 ...

3. cancerletter.com cancerletter.com/clinical/20170629_9/

Efficacy results for ONC201 in recurrent glioblastoma ... Oncoceutics Inc. announced results from the first cohort of its phase II trial for patients with recurrent glioblastoma, which showed median overall survival ...

4. braintumor.org braintumor.org/news/first-treatment-approved-for-rare-pediatric-and-adult-brain-tumor-type-fda-grants-accelerated-approval-to-dordaviprone-modeyso/

First Treatment Approved for Rare Pediatric and Adult ... This approval was based on data from a pre-specified integrated efficacy analysis of 50 patients across five different open-label studies.

5. academic.oup.com academic.oup.com/noa/article/7/Supplement_3/iii1/8244874

6 ONC201 (DORDAVIPRONE) IN THE TREATMENT OF ... Median progression free survival (PFS) and median overall survival (OS) from initial diagnosis in the ONC201 vs. non-ONC201 patients was 9.05 ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11066921/

Safety and pharmacokinetics of ONC201 (dordaviprone ... Per preclinical data, sustained ONC201 exposure was associated with the death of newly diagnosed and recurrent glioblastoma cells. The present ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT02525692

Study Details | NCT02525692 | Oral ONC201 in Adult ... The decision to terminate the study was not related to any safety concerns with dordaviprone (ONC201). ... Dordaviprone (ONC201) is a brain-penetrant ...

8. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.10017

Efficacy and safety of dordaviprone (ONC201) in ... Dordaviprone (ONC201), a first in class imipridone, has demonstrated safety and efficacy in an integrated analysis of patients with recurrent H3 K27M-mutant ...