Trametinib + Everolimus for Recurrent Brain Cancer

Recruiting at 19 trial locations

Overseen By Aubrie Dreschler

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: University of California, San Francisco

Must not be taking: CYP3A4/5 inducers, Herbal meds

Disqualifiers: Pregnancy, HIV, Hepatitis B/C, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 24 months

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines how the drugs trametinib and everolimus work together to treat brain tumors called gliomas in young people, particularly when the tumors have returned after treatment. Trametinib targets a protein that promotes tumor growth, while everolimus (also known as Afinitor, Votubia, or Zortress) blocks another pathway used by tumors. The trial aims to determine the optimal doses and assess whether the combination is more effective than each drug alone. It is designed for individuals who have undergone treatments like chemotherapy or radiation for low or high-grade gliomas but still have the disease. Those who have had surgery alone for low-grade glioma without additional treatments are not eligible. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking research.

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.

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

Research has shown that both trametinib and everolimus have been somewhat safe in earlier studies. Everolimus was tested in children with certain brain tumors and was generally well-tolerated. Some children experienced side effects, but these were usually manageable. A common side effect was high fat levels in the blood, yet the drug helped control the disease for many patients.

When combined with everolimus, trametinib appeared to control tumor growth for about 9.3 months on average. This suggests the combination was somewhat effective and did not cause severe side effects for most patients.

As this trial is in an early phase, it primarily focuses on assessing the safety of the drug combination and determining the right dose. While some evidence exists from past studies, researchers are still exploring the full safety of this treatment for recurring brain cancer. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about trametinib combined with everolimus for recurrent brain cancer because it offers a fresh approach compared to traditional treatments like surgery, radiation, and chemotherapy. Trametinib is unique as it specifically targets and inhibits the MEK enzyme, which plays a role in cancer cell growth, while everolimus blocks the mTOR pathway that cancer cells use to survive and multiply. This dual mechanism could potentially stop cancer cells more effectively than current options, providing hope for improved outcomes in patients with recurrent brain cancer.

What evidence suggests that trametinib and everolimus might be an effective treatment for recurrent brain cancer?

Research shows that combining trametinib and everolimus may help treat certain brain tumors. In this trial, participants will receive both trametinib, which targets a protein called MEK to inhibit tumor growth, and everolimus, which blocks another pathway tumors use to grow. Previous studies in children with similar conditions found that these drugs might work better together than alone. Other studies have shown that everolimus successfully treats certain brain tumors, with many patients experiencing stable disease for several months. These findings suggest that the combination could be a promising option for treating recurring gliomas. ^{1 3 5 6 7}

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 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%

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Everolimus
• Trametinib

Trial Overview The 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.

How Is the Trial Designed?

Group I: Treatment (trametinib, everolimus) Experimental Treatment 2 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

Approved in European Union as Votubia for:

• Subependymal giant cell astrocytoma
• Renal angiomyolipoma
• Tuberous sclerosis complex-associated partial-onset seizures

Approved in United States as Zortress for:

• Prevention of organ rejection in kidney transplant patients

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

Novartis Pharmaceuticals

Chief Executive Officer since 2018

MD from Harvard Medical School

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+

Published Research Related to This Trial

The combination of vandetanib (VAN) and everolimus (EV) was found to be safe and showed promising antitumor activity in a phase I trial involving 80 patients with advanced solid tumors, with a maximum tolerated dose of 300 mg for VAN and 10 mg for EV.

Out of the evaluable patients, 10% achieved a partial response and 51% had stable disease, with a median overall survival of 10.5 months, indicating that this combination therapy could be effective for patients with refractory solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and activity of vandetanib in combination with everolimus in patients with advanced solid tumors: a phase I study. Cascone, T., Sacks, RL., Subbiah, IM., et al.[2022]

In a study of 15 children and adolescents with drug-resistant TSC-associated epilepsy, Everolimus demonstrated significant efficacy, with 80% of patients responding to treatment and 58% achieving seizure freedom after a median follow-up of 22 months.

Despite transient side effects in 93% of patients, Everolimus was well-tolerated, indicating it could be a promising treatment option for TSC-related epilepsies when monitored by experienced healthcare providers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of Everolimus in children with TSC - associated epilepsy - Pilot data from an open single-center prospective study. Samueli, S., Abraham, K., Dressler, A., et al.[2022]

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.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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]

In a study of 28 heavily pretreated patients with recurrent malignant gliomas, the combination of EGFR inhibitors (gefitinib or erlotinib) and the mTOR inhibitor sirolimus was reasonably well tolerated, indicating a favorable safety profile for this treatment approach.

The treatment resulted in a 19% partial response rate and 50% of patients achieving stable disease, with a 25% six-month progression-free survival rate specifically for glioblastoma patients, suggesting potential efficacy in this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pilot study of the combination of EGFR and mTOR inhibitors in recurrent malignant gliomas. Doherty, L., Gigas, DC., Kesari, S., et al.[2022]

In a phase 3 study involving 366 patients with tuberous sclerosis complex and treatment-resistant seizures, everolimus significantly reduced seizure frequency compared to placebo, with response rates of 28.2% for low-exposure and 40.0% for high-exposure everolimus.

The safety profile of everolimus was acceptable, with serious adverse events occurring in 14% of patients in both the low and high exposure groups, indicating that while there are risks, the benefits in seizure reduction were notable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. French, JA., Lawson, JA., Yapici, Z., et al.[2022]

In a phase I clinical trial involving 10 patients with brain metastases, trametinib combined with whole brain radiation therapy (WBRT) was found to be highly toxic, with a maximum tolerated dose (MTD) of less than 1.5 mg due to significant side effects like thrombocytopenia and diarrhea.

The study indicated that 89% of patients completed the therapy as planned, but the trial was closed early due to a shift in treatment practices towards stereotactic radiosurgery (SRS), highlighting the need for further research on the safety of trametinib in combination with SRS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of trametinib in combination with whole brain radiation therapy for brain metastases. Palmer, JD., Prasad, RN., Fabian, D., et al.[2023]

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.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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 study of 14 pediatric patients with recurrent low-grade glioma or high-grade CNS tumors, 64% were progression-free while receiving trametinib, indicating promising efficacy for this MEK inhibitor in treating MAP kinase pathway mutations.

While trametinib showed potential benefits, including partial responses and improved clinical symptoms in some patients, adverse events were common, particularly in those receiving combination therapy, highlighting the need for careful monitoring and further clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trametinib-based Treatment of Pediatric CNS Tumors: A Single Institutional Experience. Paul, MR., Pehlivan, KC., Milburn, M., et al.[2021]

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.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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 study of 127 patients with metastatic renal cell carcinoma (mRCC) receiving mTOR inhibitors as first-line therapy, everolimus showed a longer median overall survival (15.9 months) compared to temsirolimus (12.5 months).

The choice of mTOR inhibitor was influenced by patient characteristics, with temsirolimus often used for poor-risk disease and non-clear cell histology, while everolimus was primarily selected for clinical trial participation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Harshman, LC., Kroeger, N., Rha, SY., et al.[2021]

Citations

1. withpower.com withpower.com/trial/phase-1-glioma-11-2020-e9e29

Trametinib + 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 ...

2. pnoc.us pnoc.us/clinical-trial/pnoc021/

PNOC021 - Clinical Trial A Phase I Trial Evaluating the Combination of Trametinib and Everolimus in Pediatric and Young Adult Patients with Recurrent Low Grade Gliomas and High-Grade ...

3. braintumorcenter.ucsf.edu braintumorcenter.ucsf.edu/clinical-trial/trametinib-and-everolimus-treatment-pediatric-and-young-adult-patients-recurrent-low

Trametinib and Everolimus for the Treatment of Pediatric ... Administering both trametinib and everolimus simultaneously to treat LGG may work more efficiently compared to giving trametinib or everolimus separately. This ...

4. ascopubs.org ascopubs.org/doi/abs/10.1200/JCO.23.01838

Everolimus for Children With Recurrent or Progressive Low ... The 6-month PFS was 67.4% (95% CI, 60.0 to 80.0) and median PFS was 11.1 months (95% CI, 7.6 to 19.8). Hypertriglyceridemia was the most common ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10311254/

Unlocking the power of precision medicine for pediatric low ... Everolimus has been successful in treating subependymal giant cell astrocytoma, a subtype of pLGG, and has demonstrated seizure control and ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04485559

Study Details | NCT04485559 | Trametinib and Everolimus ... 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 ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7566451/

A phase II study of continuous oral mTOR inhibitor everolimus ... Everolimus results in disease stability/shrinkage in recurrent NF1 low-grade gliomas. 3. Oral everolimus is well tolerated in children with NF1 and recurrent ...