Savolitinib for Brain Tumors

Not currently recruiting at 12 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4 inducers, CYP3A4 inhibitors

Disqualifiers: Pregnancy, Serious infection, Uncontrolled hypertension, Cardiac diseases, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 1092 days (39 courses of 28 days each)

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called savolitinib (also known as Orpathys) for brain tumors that are recurring or not responding to other treatments. The main goal is to determine the safest dose and assess its effect on tumors, which can grow by using certain enzymes. The trial suits individuals with a primary central nervous system tumor, such as medulloblastoma, high-grade glioma, or diffuse intrinsic pontine glioma (DIPG), that has returned or is unresponsive to current treatments. Participants will receive savolitinib and undergo regular check-ups, including blood tests and scans, to monitor their response throughout the study. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot take certain medications that affect the liver enzyme CYP3A4 or herbal supplements like St. John's wort. It's best to discuss your current medications with the trial team.

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

Research has shown that savolitinib is generally safe across various studies. For instance, in treating certain lung cancers, most patients tolerated it well, though some experienced serious side effects, with 62% encountering significant issues like liver problems.

In studies involving brain treatments, combining savolitinib with local radiotherapy proved manageable, suggesting its potential suitability for brain tumors.

As this is a Phase 1 trial, the primary goal is to determine the optimal dose and monitor for side effects. While earlier studies are encouraging, this trial will further assess the safety of savolitinib for treating brain tumors. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Savolitinib is unique because it specifically targets a protein called MET, which is often overactive in certain brain tumors. Unlike traditional treatments like chemotherapy or radiation, which affect both cancerous and healthy cells, Savolitinib works by directly inhibiting this protein's activity, potentially leading to fewer side effects. Researchers are excited about Savolitinib as it offers a more targeted approach, which could improve outcomes for patients with fewer adverse effects compared to current therapies.

What evidence suggests that Savolitinib might be an effective treatment for brain tumors?

Research has shown that savolitinib, which participants in this trial will receive, may effectively treat certain cancers, including those that spread to the brain. In studies with patients whose cancer had metastasized to the brain, 31% lived for up to 15 months without disease progression. This suggests that savolitinib might help slow tumor growth. Additionally, patients with specific genetic changes in non-small cell lung cancer (NSCLC) experienced significant tumor shrinkage with savolitinib. This evidence indicates that savolitinib could be beneficial for brain tumors, especially when other treatments have failed. ^{1 2 3 6 7}

Who Is on the Research Team?

Ralph Salloum

Principal Investigator

Pediatric Brain Tumor Consortium

Are You a Good Fit for This Trial?

This trial is for young patients aged 5 to 21 with recurrent or stubborn primary CNS tumors, including medulloblastoma and gliomas. They must have tried standard treatments without success, be able to swallow tablets, and have stable neurological conditions. Pregnant women, nursing mothers, those with serious infections or other significant illnesses are excluded.

Inclusion Criteria

I can swallow whole tablets.

My blood, liver, kidney, and heart are functioning within normal ranges.

I recently completed a specific type of radiation therapy.

Exclusion Criteria

I do not have any major illnesses or organ problems unrelated to my cancer.

Patients with a history of allergic reactions attributed to compounds of similar composition

I am currently on other treatments.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive volitinib orally once daily. Treatment repeats every 28 days for up to 39 courses in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, X-ray imaging, and MRI scans throughout study.

Up to 1092 days (39 courses of 28 days each)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up at 30 days, then periodically for up to 2 years.

Up to 2 years

What Are the Treatments Tested in This Trial?

Interventions

• Savolitinib

Trial Overview The trial tests the safety and optimal dosage of volitinib on children and young adults with specific brain tumors that haven't responded to previous treatments. It involves biospecimen collection and imaging techniques like MRI alongside the administration of volitinib.

How Is the Trial Designed?

Group I: Treatment (volitinib) Experimental Treatment 4 Interventions

Patients receive volitinib PO QD. Treatment repeats every 28 days for up to 39 courses in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, X-ray imaging, and MRI scans throughout study.

Savolitinib is already approved in China for the following indications:

Approved in China as Orpathys for:

• Non-small cell lung cancer (NSCLC) with MET exon 14 skipping alterations

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In the phase 2 FIREFLY-1 trial, tovorafenib demonstrated a high overall response rate of 67% in treating pediatric low-grade glioma (pLGG) with BRAF alterations, with a median duration of response of 16.6 months.

While tovorafenib shows promise as an effective therapy, it is associated with notable treatment-related adverse events, including hair color changes (76%) and elevated creatine phosphokinase (56%), with 42% of patients experiencing grade ≥3 adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial. Kilburn, LB., Khuong-Quang, DA., Hansford, JR., et al.[2023]

The combination of the mTOR inhibitor TAK228 and the MEK inhibitor trametinib significantly suppressed the growth of pediatric low-grade glioma (pLGG) cells, leading to a 70% increase in median survival and reduced tumor volume compared to single treatments.

This combination therapy also decreased tumor vascularization and inhibited endothelial cell migration by blocking key signaling pathways, suggesting a promising strategy for treating unresectable or recurrent pLGG.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synergistic activity of mTORC1/2 kinase and MEK inhibitors suppresses pediatric low-grade glioma tumorigenicity and vascularity. Arnold, A., Yuan, M., Price, A., et al.[2021]

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]

Targeted therapies, such as receptor tyrosine kinase inhibitors and farnesyl transferase inhibitors, are being investigated to address the abnormal growth factor signaling pathways that contribute to brain tumor development, which are often resistant to traditional treatments.

Clinical trials are currently testing several of these targeted agents, including imatinib mesylate and gefitinib, in patients with high-grade gliomas, aiming to improve survival and quality of life for those affected by these aggressive tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular neuro-oncology and development of targeted therapeutic strategies for brain tumors. Part 1: Growth factor and Ras signaling pathways. Newton, HB.[2007]

The combination of sorafenib and lapatinib was found to work synergistically to kill various CNS tumor cells, including those resistant to lapatinib, suggesting a promising treatment strategy for glioblastoma.

This drug combination not only enhanced the effectiveness of radiation therapy but also altered cellular mechanisms related to autophagy, indicating a complex interaction that could be leveraged for improved cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sorafenib/regorafenib and lapatinib interact to kill CNS tumor cells. Hamed, HA., Tavallai, S., Grant, S., et al.[2021]

A nine-year-old male patient with anaplastic astrocytoma progressed to an epithelioid glioblastoma, and mutational analysis revealed a BRAF V600E mutation, suggesting this mutation as a potential therapeutic target in glioma.

Treatment with the BRAF inhibitor dabrafenib resulted in clinical stability and 'Stable Disease' for ten months, indicating that targeted therapy may be a promising salvage option for younger patients with gliomas harboring this mutation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib Treatment in a Patient with an Epithelioid Glioblastoma and BRAF V600E Mutation. Ceccon, G., Werner, JM., Dunkl, V., et al.[2022]

In a study of 10 patients with recurrent malignant glioma, the combination of apatinib and irinotecan resulted in a 55% objective response rate and a 78% disease control rate, indicating promising efficacy for this treatment approach.

The treatment was generally well-tolerated, with the most common side effects being gastrointestinal reactions, hypertension, and myelosuppression, suggesting that while there are some risks, the safety profile is manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pilot clinical study of apatinib plus irinotecan in patients with recurrent high-grade glioma: Clinical Trial/Experimental Study. Wang, L., Liang, L., Yang, T., et al.[2022]

In a phase II trial involving 49 patients with recurrent glioblastoma and EGFR amplification, dacomitinib showed limited efficacy, with a 6-month progression-free survival rate of only 10.6%.

The treatment was associated with significant adverse effects, as 40.8% of patients experienced grade 3-4 drug-related side effects, primarily diarrhea and rash, highlighting the need for careful patient selection based on molecular characteristics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of dacomitinib, a pan-human EGFR tyrosine kinase inhibitor, in recurrent glioblastoma patients with EGFR amplification. Sepúlveda-Sánchez, JM., Vaz, MÁ., Balañá, C., et al.[2022]

The study found that pediatric low-grade astrocytoma and ependymoma cells express multiple receptor tyrosine kinases (RTKs), making them potential targets for treatment with inhibitors like sorafenib and dasatinib, which decreased cell viability and increased apoptosis.

However, growth factors present in the tumor environment can rescue these cells from treatment, particularly with dasatinib, indicating that combination therapies may be necessary to overcome this resistance and improve treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Growth-factor-driven rescue to receptor tyrosine kinase (RTK) inhibitors through Akt and Erk phosphorylation in pediatric low grade astrocytoma and ependymoma. Sie, M., den Dunnen, WF., Lourens, HJ., et al.[2018]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9547292/

Long-Term Efficacy, Safety, and Subgroup Analysis of ... In patients with brain metastases, 12- and 15-month PFS rates were 31% (95% CI: 9.5–55.4) and 31% (95% CI: 9.5–55.4), respectively. The tumor response outcomes ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.8513

Efficacy and CNS results from a randomized subset of the ... Efficacy and CNS results from a randomized subset of the phase 2 SAVANNAH study comparing savolitinib (savo) + osimertinib (osi) combination ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1556086424021063

EP.12D.07 Efficacy and Safety of Savolitinib for MET- ... MET-altered EGFRw NSCLCs treated with savolitinib in the first-line setting showed promising primary tumor shrinkage and a durable response, regardless of brain ...

4. hutch-med.com hutch-med.com/elcc25/

HUTCHMED Highlights Savolitinib SAVANNAH Phase II ... In 87 treatment-naïve patients, median overall survival (“OS”) was 28.3 months (95% CI: 17.5–not evaluable), and the 36-month OS rate was 44.7%. In 79 ...

5. pbtc.org pbtc.org/public/Summaries/PBTC-049/PBTC-049_Abstract%20for%20HCP_v9_09-18-24.pdf

A Phase I study of Savolitinib in Recurrent, Progressive, or ... During the expansion phases (PK and efficacy), patients with BSA ≥ 2.10 m2 will receive 600 mg flat dose once a day. 1.1. 1 To estimate the ...

6. jto.org jto.org/article/S1556-0864(25)00275-8/fulltext

80P: Final overall survival and long-term safety outcomes ... Treatment-related Grade ≥3 treatment-emergent adverse events occurred in 103 out of 166 pts (62.0%), and the common events were hepatic function abnormal (17.5 ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9776447/

Landscape of Savolitinib Development for the Treatment of ... Savolitinib is also currently the only MET inhibitor that has recorded beneficial OS data in brain metastases, with PFS of 7.0 months and OS of ...