PTC596 + Radiotherapy for Brain Tumor

Not currently recruiting at 10 trial locations

Overseen By Leonie Mikael, PhD

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Nationwide Children's Hospital

Must not be taking: Investigational drugs, Anticancer agents

Disqualifiers: Pregnancy, Oligodendroglioma, Uncontrolled infection, others

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

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety of a new drug, PTC596 (Unesbulin), combined with radiotherapy for children newly diagnosed with high-grade brain tumors, such as diffuse intrinsic pontine glioma (DIPG). The main goal is to determine a safe dosage of PTC596 and assess how much of the drug reaches the blood and tumor. Participants will take PTC596 twice a week while initially receiving daily radiotherapy, then continue with the drug alone. Children with newly diagnosed high-grade brain tumors who can swallow pills and have not received previous cancer treatments might be suitable for this trial. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Do I need to stop taking my current medications for the trial?

Yes, you may need to stop taking certain medications. The trial does not allow participants to take other anti-cancer agents, investigational drugs, enzyme-inducing anticonvulsants, rifampin, medications that prolong the QTc interval, CYP1A2 inhibitors like duloxetine, alosetron, or theophylline, beta-blockers, and therapeutic anticoagulants. Some SSRIs should be used with caution.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that PTC596, also known as Unesbulin, is generally well-tolerated. Most patients did not experience major side effects. In one study, only one patient experienced serious side effects, such as low white blood cell counts (neutropenia) and low platelet counts (thrombocytopenia), but these effects were reversible. Overall, safety data from previous studies suggest that PTC596 is safe when used alone or with treatments like radiotherapy. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for brain tumors, which often include surgery, chemotherapy, and radiotherapy, PTC596 is unique because it is a small molecule inhibitor that specifically targets cancer cell division. Researchers are excited about PTC596 because it disrupts the activity of a protein called BMI-1, which is involved in tumor growth and survival. This targeted approach could potentially enhance the effectiveness of radiotherapy, making the combined treatment more powerful than existing options. Additionally, PTC596 is administered orally, offering a more convenient option for patients compared to some traditional treatments that require injections or infusions.

What evidence suggests that PTC596 combined with radiotherapy might be an effective treatment for high-grade glioma?

Research has shown that PTC596, which participants in this trial may receive, has promising results in early studies. In mice, PTC596 slowed tumor growth, meaning tumors grew more slowly compared to those not given the drug. This treatment targets proteins that cancer cells need to grow and survive. PTC596 has also shown potential against different types of cancer. Additionally, when combined with other treatments, it may enhance their effectiveness. While more research is needed, these early findings suggest PTC596 could help treat high-grade gliomas in children. ^{3 4 6 7 8}

Who Is on the Research Team?

Maryam Fouladi, MD

Principal Investigator

Nationwide Children's Hospital

Patricia Baxter, MD

Principal Investigator

Baylor College of Medicine

Margot Lazow, MD

Principal Investigator

Nationwide Children's Hospital

Are You a Good Fit for This Trial?

This trial is for children and young adults aged between 1 and 21 with newly diagnosed high-grade gliomas, including DIPG. They must be able to swallow pills, have not had cancer treatment before, and their organs must function well. Those with certain other health issues or who can't follow the study rules are excluded.

Inclusion Criteria

I have been recently diagnosed with a high-grade glioma that is not in my brainstem.

I have a new diagnosis of DIPG and my doctor recommends a biopsy.

I have been diagnosed with a specific brain tumor called DIPG without needing a tissue sample.

Exclusion Criteria

Patients of childbearing or child fathering potential who have not agreed to use an effective contraceptive method

My cancer is related to HIV or a solid organ transplant.

Patients currently receiving another investigational drug

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment - Initial Cycle

Participants receive PTC596 orally twice weekly in combination with daily radiotherapy for 6-7 weeks

6-7 weeks

Daily visits for radiotherapy

Treatment - Maintenance Cycles

Participants continue with maintenance therapy receiving PTC596 orally twice weekly for up to 26 cycles

Up to 24 months

Surgical Cycle

For surgical cohort, PTC596 is administered prior to biopsy or re-resection, followed by radiotherapy and maintenance therapy

2 weeks before RT

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• PTC596
• Radiotherapy

Trial Overview

The safety of PTC596 (Unesbulin) combined with radiotherapy is being tested in pediatric patients with brain tumors like DIPG. The study aims to find a safe drug dose that doesn't cause serious side effects and to measure how much drug gets into the blood and tumor.

How Is the Trial Designed?

Group I: Treatment (PTC596) Experimental Treatment 2 Interventions

PTC596 administered orally twice weekly (M/Th or T/F schedule) concomitantly with RT for 6 -7 weeks. Each subsequent cycle is defined as 28 days. Post RT patients will continue to receive PTC596 twice weekly for up to 26 cycles at RP2D of 200mg/m2 with a maximum dose capped at 400mg for patients with BSA ≥2.0

Who Is Running the Clinical Trial?

Nationwide Children's Hospital

Lead Sponsor

Trials

354

Recruited

5,228,000+

PTC Therapeutics

Industry Sponsor

Trials

75

Recruited

6,300+

Dr. Matthew B. Klein

PTC Therapeutics

Chief Executive Officer since 2023

BA from the University of Pennsylvania, MD from Yale University School of Medicine, MS in Epidemiology from the University of Washington School of Public Health

Dr. Stuart W. Peltz

PTC Therapeutics

Chief Medical Officer since 2023

MD from Harvard Medical School

Published Research Related to This Trial

In a study of 23 patients with high-risk prostate cancer, stereotactic body radiation therapy (SBRT) was found to be feasible and well tolerated, with low rates of severe gastrointestinal (GI) and genitourinary (GU) toxicities.

The treatment resulted in acute grade 1 GI toxicities in only 9.1% of patients and grade 3 GU toxicities in 4.5%, indicating that serious side effects were uncommon, but further long-term follow-up is needed to assess ongoing safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early Tolerance Outcomes of Stereotactic Hypofractionated Accelerated Radiation Therapy Concomitant with Pelvic Node Irradiation in High-risk Prostate Cancer. Pinitpatcharalert, A., Happersett, L., Kollmeier, M., et al.[2022]

Motexafin gadolinium (MGd) is a novel radiation sensitizer that may improve the effectiveness of whole brain radiation therapy (WBRT) for patients with brain metastases from non-small cell lung cancer (NSCLC).

Current outcomes for NSCLC patients undergoing WBRT are poor, with median survival times only in months, highlighting the need for effective treatments like MGd to enhance therapeutic results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Motexafin gadolinium injection for the treatment of brain metastases in patients with non-small cell lung cancer. Thomas, SR., Khuntia, D.[2019]

In a phase II trial involving 14 patients with brain metastases, the combination of pentoxifylline (PTX) and standard whole-brain radiation treatment (WBRT) showed a median survival time of 33 days, which aligns with historical control data.

The study indicated that PTX was well-tolerated, as toxicity was not a common reason for patients dropping out, suggesting that higher doses of PTX could be explored in future research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II evaluation of pentoxifylline combined with radiation in the treatment of brain metastases. Johnson, FE., Harrison, BR., McKirgan, LW., et al.[2013]

In a phase I/II trial involving 75 patients with brain metastases, the combination of whole-brain radiotherapy (WBRT) and the chemotherapy drug topotecan showed a promising overall response rate of 72%, indicating potential effectiveness in this challenging patient population.

The study found that the recommended dosage of topotecan was 0.4 mg/m²/day due to higher toxicity at 0.5 mg/m²/day, with moderate side effects occurring in 19% of patients, suggesting that while the treatment is effective, careful monitoring of toxicity is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I/II trial of topotecan and radiation therapy for brain metastases in patients with solid tumors. Hedde, JP., Neuhaus, T., Schüller, H., et al.[2013]

In early phase I studies, patients undergoing 252Cf brachytherapy combined with whole brain photon beam therapy tolerated the treatment well and showed improvements in performance status and reductions in tumor size as evaluated by CT scans.

The study highlighted the need for individualized treatment plans due to the large size of tumors and significant brain edema, indicating that high-dose external beam irradiation is necessary for effective responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interstitial 252Cf neutron therapy for glioblastoma multiforme. Maruyama, Y., Chin, HW., Young, AB., et al.[2019]

In a study of 260 patients treated for brain and skull base tumors with photon and particle therapies, no unexpected severe toxicities were reported, indicating a favorable safety profile for these treatments.

The use of particle therapy, particularly protons and carbon ions, shows promise in potentially reducing the risk of secondary malignancies and improving neurocognitive outcomes, although longer follow-up is needed to confirm these benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Proton and carbon ion radiotherapy for primary brain tumors and tumors of the skull base. Combs, SE., Kessel, K., Habermehl, D., et al.[2016]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC9398121/

Preclinical and Early Clinical Development of PTC596, a ...

The median time for tumors to reach 1,000 mm3 in vehicle dosed mice was 18.6 days. In mice dosed with PTC596 monotherapy [12.5 mg/kg, twice weekly for 6 weeks ( ...

2.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC6944693/

Off-target effect of the BMI1 inhibitor PTC596 drives epithelial ...

When compared to A1016 or BMI1 knockout, the PTC596 molecule presented additional effects, including inhibition of EZH2, SOX2, and FOXG1.

3.

clinicaltrials.gov

clinicaltrials.gov/study/NCT03605550

A Phase 1b Study of PTC596 in Children With Newly ...

The goal of this study is to evaluate the safety of the study drug PTC596 (Unesbulin) taken in combination with radiotherapy (RT) when given to pediatric ...

4.

researchgate.net

researchgate.net/publication/353486834_Preclinical_and_Early_Clinical_Development_of_PTC596_a_Novel_Small-Molecule_Tubulin-Binding_Agent

Preclinical and Early Clinical Development of PTC596, a ...

PTC596 exhibited broad-spectrum anticancer activity. PTC596 showed efficacy as monotherapy and additive or synergistic efficacy in combinations ...

5.

clinicaltrials.gov

clinicaltrials.gov/study/NCT03605550?intr=PTC596&rank=1

A Phase 1b Study of PTC596 in Children With Newly ...

The goal of this study is to evaluate the safety of the study drug PTC596 (Unesbulin) taken in combination with radiotherapy (RT) when given to pediatric ...

6.

accp1.onlinelibrary.wiley.com

accp1.onlinelibrary.wiley.com/doi/10.1002/cpdd.904

Pharmacokinetics and Safety of PTC596, a Novel Tubulin ...

Although due to the small population the safety data are limited, the available data suggest that PTC596 was well tolerated with manageable side ...

7.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/33440067/

Pharmacokinetics and Safety of PTC596, a Novel Tubulin- ...

Only 1 patient treated with 10.4 mg/kg experienced dose-limiting toxicity of neutropenia and thrombocytopenia, both of which were reversible.

8.

researchgate.net

researchgate.net/publication/348524275_Pharmacokinetics_and_Safety_of_PTC596_a_Novel_Tubulin-Binding_Agent_in_Subjects_With_Advanced_Solid_Tumors

Pharmacokinetics and Safety of PTC596, a Novel Tubulin‐ ...

... Moreover, PTC596 (Unesbulin), a small molecule inhibitor of Bmi-1, showed satisfactory safety profiles in phase I trials [29] . For instance ...