50 Participants Needed

Trametinib + Everolimus for Recurrent Brain Cancer

Recruiting at 17 trial locations
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Overseen ByAubrie Dreschler
Age: < 65
Sex: Any
Trial Phase: Phase 1
Sponsor: University of California, San Francisco
No Placebo GroupAll trial participants will receive the active study treatment (no placebo)

Trial Summary

What is the purpose of this trial?

This phase I trial studies the side effects and best dose of trametinib and everolimus in treating pediatric and young adult patients with gliomas that have come back (recurrent). Trametinib acts by targeting a protein in cells called MEK and disrupting tumor growth. Everolimus is a drug that may block another pathway in tumor cells that can help tumors grow. Giving trametinib and everolimus may work better to treat low and high grade gliomas compared to trametinib or everolimus alone.

Will I have to stop taking my current medications?

The trial requires participants to stop taking certain medications, including strong inducers or inhibitors of CYP3A4/5, some anti-convulsant drugs, and herbal preparations like St. John's wort, at least 7 days before enrolling. If you're taking any of these, you may need to stop or switch medications before joining the trial.

What data supports the effectiveness of the drug combination Trametinib and Everolimus for recurrent brain cancer?

Research shows that combining everolimus with other drugs targeting similar pathways can be effective in treating certain brain tumors, with some patients experiencing partial responses or stable disease. This suggests potential benefits of using everolimus in combination therapies for brain cancer.12345

What safety data exists for Trametinib and Everolimus in humans?

Everolimus has been studied for safety in children with epilepsy related to tuberous sclerosis, showing some promise but with limited evidence. Trametinib has been used in children with brain tumors, with side effects like skin issues, mouth sores, fever, and fatigue, especially when combined with other treatments.14678

How is the drug combination of Trametinib and Everolimus unique for treating recurrent brain cancer?

The combination of Trametinib and Everolimus is unique because it targets two different pathways involved in cancer growth: Trametinib inhibits the MEK pathway, while Everolimus inhibits the mTOR pathway. This dual approach may help overcome resistance that can develop with treatments targeting only one pathway.123910

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 pediatric and young adult patients with recurrent gliomas, including those with low grade (WHO I-II) or high grade (III-VI) tumors. It's open to participants who've had prior treatments and have stable neurological deficits. They must not be pregnant, agree to use contraception, and meet specific health criteria like adequate blood counts and organ function.

Inclusion Criteria

Serum albumin >= 2 g/dL
Peripheral absolute neutrophil count (ANC) >= 1000/mm^3 (unsupported)
Left ventricular ejection fraction (LVEF) >= 50%
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Exclusion Criteria

Female participants of childbearing potential must have a negative serum or urine pregnancy test within 72 hours of enrollment AND within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
I am not pregnant or breastfeeding.
I haven't taken strong medication, certain fruits, or herbal supplements in the last 7 days.
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Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a combination of trametinib and everolimus in a dose-escalation study, with treatment repeating every 28 days for up to 26 cycles

Up to 24 months
Monthly visits for each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-ups at 30 days, every 3 months for 1 year, then every 6 months for 5 years

5 years

Treatment Details

Interventions

  • Everolimus
  • Trametinib
Trial OverviewThe trial is testing the combination of two drugs: Trametinib targets a protein called MEK to stop tumor growth, while Everolimus blocks a different pathway that helps tumors grow. The goal is to see if using both drugs together is more effective than using them separately in treating gliomas.
Participant Groups
1Treatment groups
Experimental Treatment
Group I: Treatment (trametinib, everolimus)Experimental Treatment2 Interventions
Patients receive dosing per their assigned dose level. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity.

Everolimus is already approved in United States, European Union for the following indications:

🇺🇸
Approved in United States as Afinitor for:
  • Advanced renal cell carcinoma
  • Subependymal giant cell astrocytoma
  • Progressive neuroendocrine tumors of pancreatic origin
  • Advanced hormone receptor-positive, HER2-negative breast cancer
  • Tuberous sclerosis complex-associated partial-onset seizures
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Approved in European Union as Votubia for:
  • Subependymal giant cell astrocytoma
  • Renal angiomyolipoma
  • Tuberous sclerosis complex-associated partial-onset seizures
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Approved in United States as Zortress for:
  • Prevention of organ rejection in kidney transplant patients

Find a Clinic Near You

Who Is Running the Clinical Trial?

University of California, San Francisco

Lead Sponsor

Trials
2,636
Recruited
19,080,000+

Novartis Pharmaceuticals

Industry Sponsor

Trials
2,963
Recruited
4,275,000+
Founded
1996
Headquarters
Basel, Switzerland
Known For
Precision medicine
Top Products
Gleevec, Cosentyx, Entresto, Kisqali
Dr. Vas Narasimhan profile image

Dr. Vas Narasimhan

Novartis Pharmaceuticals

Chief Executive Officer since 2018

MD from Harvard Medical School

Dr. Shreeram Aradhye profile image

Dr. Shreeram Aradhye

Novartis Pharmaceuticals

Chief Medical Officer since 2021

MD

Pediatric Brain Tumor Foundation

Collaborator

Trials
2
Recruited
80+

The Lilabean Foundation for Pediatric Brain Cancer Research

Collaborator

Trials
1
Recruited
50+

Findings from Research

The combination of everolimus and vatalanib (PTK/ZK) showed at least additive and potentially synergistic anti-tumor effects in a mouse model of melanoma, enhancing efficacy without increasing toxicity compared to either drug alone.
Pharmacokinetic studies revealed that vatalanib increased the plasma concentration of everolimus, but this interaction did not fully explain the enhanced anti-tumor activity, suggesting that the two drugs may work together through distinct mechanisms.
Everolimus and PTK/ZK show synergistic growth inhibition in the orthotopic BL16/BL6 murine melanoma model.O'Reilly, T., Lane, HA., Wood, JM., et al.[2021]
In a phase I study involving 94 patients with advanced non-small-cell lung cancer (NSCLC), the combination of the mTOR inhibitor everolimus and the EGFR inhibitor erlotinib showed acceptable tolerability, with maximum tolerated doses established at 5 mg of everolimus daily or 50 mg weekly alongside 150 mg of erlotinib daily.
The combination therapy resulted in disease control for a median duration of 9.3 months in patients receiving daily everolimus, with some achieving complete or partial responses, indicating potential efficacy in treating chemotherapy-refractory NSCLC.
Everolimus and erlotinib as second- or third-line therapy in patients with advanced non-small-cell lung cancer.Papadimitrakopoulou, VA., Soria, JC., Jappe, A., et al.[2015]
In a phase 1 trial involving five pediatric and young adult patients with BRAFV600-mutated brain tumors, the combination of vemurafenib (a BRAF inhibitor) and everolimus (an mTOR inhibitor) showed promising results, with 40% of patients achieving a partial response and 20% maintaining stable disease for 12 months.
No patients experienced treatment discontinuation due to adverse events, suggesting that this combination therapy is safe and warrants further investigation for treating BRAF-mutant brain cancers.
Dual inhibition of BRAF and mTOR in BRAFV600E -mutant pediatric, adolescent, and young adult brain tumors.Sen, S., Tanaka, R., Khatua, S., et al.[2021]

References

Everolimus and PTK/ZK show synergistic growth inhibition in the orthotopic BL16/BL6 murine melanoma model. [2021]
Everolimus and erlotinib as second- or third-line therapy in patients with advanced non-small-cell lung cancer. [2015]
Dual inhibition of BRAF and mTOR in BRAFV600E -mutant pediatric, adolescent, and young adult brain tumors. [2021]
First-line Mammalian target of rapamycin inhibition in metastatic renal cell carcinoma: an analysis of practice patterns from the International Metastatic Renal Cell Carcinoma Database Consortium. [2021]
Safety and activity of vandetanib in combination with everolimus in patients with advanced solid tumors: a phase I study. [2022]
Efficacy and safety of Everolimus in children with TSC - associated epilepsy - Pilot data from an open single-center prospective study. [2022]
Trametinib-based Treatment of Pediatric CNS Tumors: A Single Institutional Experience. [2021]
Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. [2022]
Phase I study of trametinib in combination with whole brain radiation therapy for brain metastases. [2023]
10.United Statespubmed.ncbi.nlm.nih.gov
Pilot study of the combination of EGFR and mTOR inhibitors in recurrent malignant gliomas. [2022]