Trametinib + Everolimus for Recurrent Brain Cancer

Recruiting at 17 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

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. ^{1 2 3 4 5}

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. ^{1 4 6 7 8}

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. ^{1 2 3 9 10}

Research Team

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%

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

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 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.

Participant Groups

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+

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.

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 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 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 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]

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 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]

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 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]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Everolimus and PTK/ZK show synergistic growth inhibition in the orthotopic BL16/BL6 murine melanoma model. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Everolimus and erlotinib as second- or third-line therapy in patients with advanced non-small-cell lung cancer. [2015]

3. United States pubmed.ncbi.nlm.nih.gov

Dual inhibition of BRAF and mTOR in BRAFV600E -mutant pediatric, adolescent, and young adult brain tumors. [2021]

4. United States 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. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Safety and activity of vandetanib in combination with everolimus in patients with advanced solid tumors: a phase I study. [2022]

6. England 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. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Trametinib-based Treatment of Pediatric CNS Tumors: A Single Institutional Experience. [2021]

8. England 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. [2022]

9. Ireland pubmed.ncbi.nlm.nih.gov

Phase I study of trametinib in combination with whole brain radiation therapy for brain metastases. [2023]

10. United States pubmed.ncbi.nlm.nih.gov

Pilot study of the combination of EGFR and mTOR inhibitors in recurrent malignant gliomas. [2022]