Trametinib + Everolimus for Recurrent Brain Cancer
Recruiting in Palo Alto (17 mi)
+17 other locations
Age: < 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
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
Breakthrough Therapy
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.
12345What 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.
14678How 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.
123910Eligibility 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%
+32 more
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.
+4 more
Trial 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
Participant Groups
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.
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, United States 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Scott CovenIndianapolis, IN
University of California, San Diego Rady Children's HospitalSan Diego, CA
Riley Hospital for ChildrenIndianapolis, IN
John Hopkins UniversityBaltimore, MD
More Trial Locations
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Who Is Running the Clinical Trial?
University of California, San FranciscoLead Sponsor
Novartis PharmaceuticalsIndustry Sponsor
Pediatric Brain Tumor FoundationCollaborator
The Lilabean Foundation for Pediatric Brain Cancer ResearchCollaborator
References
Everolimus and PTK/ZK show synergistic growth inhibition in the orthotopic BL16/BL6 murine melanoma model. [2021]Everolimus (RAD001, Afinitor) is an mTORC1 pathway inhibitor, and vatalanib (PTK/ZK) is a pan VEGF-R tyrosine kinase inhibitor (TKI). These two drugs have been shown to have overlapping but also distinct anti-angiogenic effects. Consequently, we investigated the pharmacokinetics (PK) and pharmacodynamics (PD) of their combination in vivo.
Everolimus and erlotinib as second- or third-line therapy in patients with advanced non-small-cell lung cancer. [2015]The epidermal growth factor receptor inhibitor erlotinib is an approved treatment for chemotherapy-refractory advanced non-small-cell lung cancer (NSCLC). Because activated epidermal growth factor receptor signals through the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway, adding the oral mTOR inhibitor everolimus to erlotinib may improve efficacy by blocking multiple components of the same pathway. We conducted a phase I study to determine feasible dosages of combination therapy with erlotinib and everolimus for previously treated metastatic or unresectable NSCLC.
Dual inhibition of BRAF and mTOR in BRAFV600E -mutant pediatric, adolescent, and young adult brain tumors. [2021]Although BRAF inhibition has demonstrated activity in BRAFV600 -mutated brain tumors, ultimately these cancers grow resistant to BRAF inhibitor monotherapy. Parallel activation of the phosphatidylinositol 3-kinase-mammalian target of rapamycin pathway has been implicated as a mechanism of primary and secondary resistance to BRAF inhibition. Moreover, it has been shown specifically that mTOR signaling activation occurs in BRAF-mutant brain tumors. We therefore conducted phase 1 trials combining vemurafenib with everolimus, enrolling five pediatric and young adults with BRAFV600 -mutated brain tumors. None of the patients required treatment discontinuation as a result of adverse events. Overall, two patients (40%) had a partial response and one (20%) had 12 mo of stable disease as best response. Co-targeting BRAF and mTOR in molecularly selected brain cancers should be further investigated.
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]Approval of the mTOR inhibitors for the treatment of mRCC was based on efficacy in poor-risk patients in the first-line setting for temsirolimus and in vascular endothelial growth factor inhibitor-refractory patients for everolimus. We strove to characterize temsirolimus and everolimus use and effectiveness in the first-line setting.
Safety and activity of vandetanib in combination with everolimus in patients with advanced solid tumors: a phase I study. [2022]Preclinical studies suggest that combining vandetanib (VAN), a multi-tyrosine kinase inhibitor of rearranged during transfection (RET) proto-oncogene, vascular endothelial growth factor receptor (VEGFR), and epidermal growth factor receptor (EGFR), with everolimus (EV), a mammalian target of rapamycin (mTOR) inhibitor, may improve antitumor activity. We determined the safety, maximum tolerated dose (MTD), recommended phase II dose (RP2D), and dose-limiting toxicities (DLTs) of VAN + EV in patients with advanced solid cancers and the effect of combination therapy on cancer cell proliferation and intracellular pathways.
Efficacy and safety of Everolimus in children with TSC - associated epilepsy - Pilot data from an open single-center prospective study. [2022]Epilepsy occurs in up to 90 % of all individuals with tuberous sclerosis complex (TSC). In 67 % disease onset is during childhood. In ≥ 50 % seizures are refractory to currently available treatment options. The mTOR-Inhibitor Everolimus (Votubia®) was approved for the treatment of subependymal giant cell astrocytoma (SEGA) and renal angiomyolipoma (AML) in Europe in 2011. It's anticonvulsive/antiepileptic properties are promising, but evidence is still limited. Study aim was to evaluate the efficacy and safety of Everolimus in children and adolescents with TSC-associated epilepsies.
Trametinib-based Treatment of Pediatric CNS Tumors: A Single Institutional Experience. [2021]MEK inhibitors are an emerging therapy with increasing use in mitogen-activated protein kinase-driven central nervous system (CNS) tumors. There is limited data regarding efficacy and toxicity in pediatric patients. We report our clinical experience with trametinib-based therapy for the treatment of 14 consecutive pediatric patients with recurrent low-grade glioma (N=11) or high-grade CNS tumors (N=3) with MAP kinase pathway mutations. Patients received trametinib as monotherapy (N=9) or in combination (N=5) with another antineoplastic agent. Nine patients (64%) were progression free during treatment. Five patients showed a partial response, while 4 had stable disease. Two patients (14%) progressed on therapy. All partial responses were in patients with low-grade tumors. The remaining 3 patients were not evaluable due to toxicity limiting duration of therapy. Two of 3 patients with low-grade glioma with leptomeningeal dissemination showed radiographic treatment response. Five patients reported improved clinical symptoms while on trametinib. Adverse events on trametinib-based therapy included dermatologic, mouth sores, fever, gastrointestinal, infection, neutropenia, headache, and fatigue, and were more common in patients using combination therapy. Trametinib-based therapy demonstrated signals of efficacy in our single institutional cohort of pediatric patients with mitogen-activated protein kinase-driven CNS tumors. Our observations need to be confirmed in a clinical trial setting.
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]Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been used for various benign tumours associated with tuberous sclerosis complex. We assessed the efficacy and safety of two trough exposure concentrations of everolimus, 3-7 ng/mL (low exposure) and 9-15 ng/mL (high exposure), compared with placebo as adjunctive therapy for treatment-resistant focal-onset seizures in tuberous sclerosis complex.
Phase I study of trametinib in combination with whole brain radiation therapy for brain metastases. [2023]Trametinib is a MEK inhibitor with intracranial activity indicated for BRAF-mutant metastatic malignancies. Yet, the safety of trametinib concurrent with whole brain radiation therapy (WBRT) is unknown. We performed a single-institution, prospective, 3 + 3, phase I clinical trial to determine the maximum tolerated dose (MTD) of trametinib with WBRT.
Pilot study of the combination of EGFR and mTOR inhibitors in recurrent malignant gliomas. [2022]Malignant gliomas are frequently characterized by amplification of the epidermal growth factor receptor (EGFR) and loss of PTEN tumor suppressor gene. Twenty-eight heavily pretreated patients with recurrent malignant gliomas were administered EGFR inhibitors (gefitinib or erlotinib) in combination with the mTOR (mammalian target of rapamycin) inhibitor sirolimus. The regimens were reasonably well tolerated. Nineteen percent of patients experienced a partial response and 50% had stable disease. Six-month progression-free survival for glioblastoma patients was 25%.