Multiple Targeted Therapies for Meningioma

Recruiting in Palo Alto (17 mi)

+726 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Alliance for Clinical Trials in Oncology

Must not be taking: CYP3A4 inhibitors, CYP3A inducers

Disqualifiers: Uncontrolled hypertension, Diabetes, Hepatitis, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial studies four drugs to treat patients with worsening meningioma. These drugs work by blocking enzymes that the tumor cells need to grow. The trial focuses on patients whose tumors have specific genetic mutations.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, specifically strong inhibitors of CYP3A4, 14 days before joining the study if you have certain genetic mutations. If you are taking medications that affect CYP3A4 or CYP2D6, you may need to stop them, so it's important to discuss your current medications with the study team.

What data supports the effectiveness of the drugs Abemaciclib, Capivasertib, GSK2256098, and Vismodegib for treating meningioma?

While there is no direct evidence for these specific drugs in treating meningioma, research shows that targeted therapies focusing on pathways like Pi3K-Akt-mTOR and cell cycle regulation are being explored for aggressive meningiomas. Additionally, inhibitors of pathways like mTOR and FAK have shown some promise in clinical trials, suggesting potential for similar targeted drugs. ^{1 2 3 4 5}

How is the drug combination of Abemaciclib, Capivasertib, GSK2256098, and Vismodegib unique for treating meningioma?

This drug combination targets multiple pathways involved in tumor growth, such as the Pi3K-Akt-mTOR and MAP kinase pathways, and focuses on cell cycle regulation, which is different from traditional treatments that have shown limited effectiveness. It offers a novel approach by addressing various genetic mutations and signaling pathways specific to meningiomas, potentially providing a more personalized and effective treatment option. ^{1 2 3 5 6}

Eligibility Criteria

This trial is for adults with progressive meningiomas, including those with neurofibromatosis and stable CNS tumors. Participants can have had prior treatments and must have measurable disease growth documented by MRI or CT scans. Specific genetic alterations are required, and there's no limit on the number of previous therapies. Exclusions include uncontrolled gastric ulcers, allergies to similar drugs, certain medication restrictions based on genetics, recent major surgery, uncontrolled hypertension, and recent abdominal complications.

Inclusion Criteria

I have diabetes and specific genetic changes.

My brain tumor has been confirmed as meningioma by a pathology review.

My cancer is visible on scans and has grown or remained after surgery.

Exclusion Criteria

My high blood pressure is not under control.

I have not had major surgery in the last 28 days.

I am not on medications that affect certain genetic changes.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive treatment based on their mutation status: SMO inhibitor, FAK inhibitor, AKT inhibitor, or CDK inhibitor. Treatment cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up every 6 months for a maximum of 5 years from registration.

5 years

Treatment Details

Interventions

• Abemaciclib (Protein Kinase Inhibitor)
• Capivasertib (Protein Kinase Inhibitor)
• GSK2256098 (Protein Kinase Inhibitor)
• Vismodegib (Hedgehog Pathway Inhibitor)

Trial Overview The study tests how well four drugs—Vismodegib, FAK Inhibitor GSK2256098, Capivasertib, and Abemaciclib—work in treating growing or worsening meningiomas. These drugs aim to halt tumor cell growth by blocking enzymes needed for cell proliferation.

Participant Groups

Group I: Arm D (abemaciclib) Experimental Treatment 1 Intervention

Patients receive abemaciclib PO Q12H. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group II: Arm C (capivasertib) Experimental Treatment 1 Intervention

Patients receive capivasertib PO BID on days 1-4. Treatment repeats every 7 days for up to 1 cycle (28 days) in the absence of disease progression or unacceptable toxicity.

Group III: Arm B (FAK inhibitor GSK2256098) Experimental Treatment 1 Intervention

Patients receive FAK inhibitor GSK2256098 PO BID. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. (CLOSED TO ACCRUAL JULY 2017)

Group IV: Arm A (vismodegib) Experimental Treatment 1 Intervention

Patients receive vismodegib PO QD. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. (CLOSED TO ACCRUAL FEBRUARY 2018)

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

🇺🇸 Approved in United States as Verzenio for:

• Hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer
• HR+, HER2- node-positive early breast cancer

🇪🇺 Approved in European Union as Verzenio for:

• HR+, HER2- advanced or metastatic breast cancer
• HR+, HER2- node-positive early breast cancer

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Pacific Central Coast Health Center-San Luis Obispo San Luis Obispo, CA

University of Miami Miller School of Medicine-Sylvester Cancer Center Miami, FL

Liberty Radiation Oncology Center Liberty, MO

Benefis Healthcare- Sletten Cancer Institute Great Falls, MT

More Trial Locations

Who Is Running the Clinical Trial?

Alliance for Clinical Trials in Oncology Lead Sponsor

Brain Science Foundation Collaborator

GlaxoSmithKline Industry Sponsor

Genentech, Inc. Industry Sponsor

National Cancer Institute (NCI) Collaborator

References

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

Apatinib in recurrent anaplastic meningioma: a retrospective case series and systematic literature review. [2021] Up to now, no proven effective medical therapy for surgery and radiation-refractory anaplastic meningioma (AM) exists. Patients with vascular endothelial growth factor receptor 2 (VEGFR-2) positive meningiomas showed significantly shorter progression-free survival. Apatinib is a small-molecule antiangiogenic agent that selectively inhibits VEGFR-2. We report three cases of recurrent AM (VEGFR-2 positive) treated with apatinib. After apatinib treatment, the best outcome for all three patients was the partial response. The Progression-free survival was 17.3 months, 10.3 months, and 14+ months, respectively. The third patient lost follow-up after the last review. The overall survival was 28.5 months and 18 months, respectively. The main adverse events were hypertension, hand-foot syndrome, and myelosuppression. Apatinib is active in recurrent AM patients and this is the first report in the world. It is promising to launch a Phase II clinical trial of apatinib to further evaluate its efficacy on AM.

2. Switzerland pubmed.ncbi.nlm.nih.gov

Emerging Medical Treatments for Meningioma in the Molecular Era. [2020] Meningiomas are the most common type of primary central nervous system tumors. Approximately, 80% of meningiomas are classified by the World Health Organization (WHO) as grade I, and 20% of these tumors are grade II and III, considered high-grade meningiomas (HGMs). Clinical control of HGMs, as well as meningiomas that relapse after surgery, and radiation therapy is difficult, and novel therapeutic approaches are necessary. However, traditional chemotherapies, interferons, hormonal therapies, and other targeted therapies have so far failed to provide clinical benefit. During the last several years, next generation sequencing has dissected the genetic heterogeneity of meningioma and enriched our knowledge about distinct oncogenic pathways driving different subtypes of meningiomas, opening up a door to new personalized targeted therapies. Molecular classification of meningioma allows a new design of clinical trials that assign patients to corresponding targeted agents based on the tumor genetic subtypes. In this review, we will shed light on emerging medical treatments of meningiomas with a particular focus on the new targets identified with genomic sequencing that have led to clinical trials testing novel compounds. Moreover, we present recent development of patient-derived preclinical models that provide platforms for assessing targeted therapies as well as strategies with novel mechanism of action such as oncolytic viruses.

3. France pubmed.ncbi.nlm.nih.gov

Innovative treatments for meningiomas. [2023] Multi-recurrent high-grade meningiomas remain an unmet medical need in neuro-oncology when iterative surgeries and radiation therapy sessions fail to control tumor growth. Nevertheless, the last 10years have been marked by multiple advances in the comprehension of meningioma tumorigenesis via the discovery of new driver mutations, the identification of activated intracellular signaling pathways, and DNA methylation analyses, providing multiple potential therapeutic targets. Today, Anti-VEGF and mTOR inhibitors are the most used and probably the most active drugs in aggressive meningiomas. Peptide radioactive radiation therapy aims to target SSTR2A receptors, which are strongly expressed in meningiomas, but have an insufficient effect in most aggressive meningiomas, requiring the development of new techniques to increase the dose applied to the tumor. Based on the multiple potential intracellular targets, multiple targeted therapy clinical trials targeting Pi3K-Akt-mTOR and MAP kinase pathways as well as cell cycle and particularly, cyclin D4-6 are ongoing. Recently discovered driver mutations, SMO, Akt, and PI3KCA, offer new targets but are mostly observed in benign meningiomas, limiting their clinical relevance mainly to rare aggressive skull base meningiomas. Therefore, NF2 mutation remains the most frequent mutation and main challenging target in high-grade meningioma. Recently, inhibitors of focal adhesion kinase (FAK), which is involved in tumor cell adhesion, were tested in a phase 2 clinical trial with interesting but insufficient activity. The Hippo pathway was demonstrated to interact with NF2/Merlin and could be a promising target in NF2-mutated meningiomas with ongoing multiple preclinical studies and a phase 1 clinical trial. Recent advances in immune landscape comprehension led to the proposal of the use of immunotherapy in meningiomas. Except in rare cases of MSH2/6 mutation or high tumor mass burden, the activity of PD-1 inhibitors remains limited; however, its combination with various radiation therapy modalities is particularly promising. On the whole, therapeutic management of high-grade meningiomas is still challenging even with multiple promising therapeutic targets and innovations.

4. England pubmed.ncbi.nlm.nih.gov

Prospective phase II trial of the dual mTORC1/2 inhibitor vistusertib for progressive or symptomatic meningiomas in persons with neurofibromatosis 2. [2023] Label="Background" NlmCategory="UNASSIGNED">Meningiomas occur in 80% of persons with neurofibromatosis 2 (NF2) and cause significant mortality and morbidity, yet there are no effective medical treatments. NF2-deficient tumors have constitutive activation of mammalian/mechanistic target of rapamycin (mTOR), and treatment with mTORC1 inhibitors results in growth arrest in a minority of tumors, with paradoxical activation of the mTORC2/AKT pathway. We studied the effect of vistusertib, a dual mTORC1/mTORC2 inhibitor, in NF2 patients with progressive or symptomatic meningiomas.

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

Everolimus and Octreotide for Patients with Recurrent Meningioma: Results from the Phase II CEVOREM Trial. [2021] Label="PURPOSE">Aggressive meningiomas that progress after surgery/radiotherapy represent an unmet medical need. Strong and constant expression of SSTR2A receptors and activation of the Pi3K/Akt/mTOR pathway have been demonstrated in meningiomas. The combination of everolimus, an mTOR inhibitor, and octreotide, a somatostatin agonist, has shown additive antitumor effect in vitro. The phase II CEVOREM trial investigated the efficacy of this combination on recurrent meningiomas.

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

Antiangiogenic treatment of meningiomas. [2020] Meningiomas are the most common intracranial tumors and the majority of cases is curable by surgical resection. Incompletely resected tumors and tumors with signs of increased malignancy (WHO grade II and III tumors) are prone to recur. In meningiomas relapsing after surgical resection and after exhaustion of radiotherapeutic options, drug therapy is to be considered. A variety of drugs has been studied in meningiomas, including hydroxyurea, temozolomide, irinotecan, interferon-alpha, mifepristone, octreotide analogues, megestrol acetate, bevacizumab, sunitinib, vatalinib, imatinib, erlotinib, and gefitinib. Unfortunately, most of these agents have shown no or very limited activity against meningiomas and cannot be recommended for clinical use. Compounds with antiangiogenic properties, i.e., bevacizumab, sunitinib, and vatalinib have shown potential efficacy in uncontrolled studies and should be investigated further, ideally in randomized clinical trials. Emerging clinical studies will evaluate novel medical treatment approaches including the tetra-hydroisoquinoline alkaloid trabectedin (European Organisation for Research and Treatment of Cancer (EORTC) phase II trial 1320) and SMO or AKT inhibitors in molecularly selected cases.