What is the mechanism of action of this treatment?

Common treatments for Glioblastoma, such as Paxalisib and Metformin, work by targeting key pathways involved in tumor growth and metabolism. Paxalisib inhibits the PI3K/AKT/mTOR pathway, which is essential for cell proliferation and survival, thereby reducing tumor growth and promoting cancer cell death. Metformin activates AMPK and inhibits mitochondrial function, leading to decreased energy production in cancer cells and increased cell death. These mechanisms are significant for Glioblastoma patients as they address the aggressive nature of the tumor by disrupting its metabolic and growth processes, potentially improving treatment efficacy.

What side effects are associated with this type of intervention?

Common treatments for glioblastoma, particularly those involving PI3K inhibitors like Paxalisib and AMPK activators/mitochondrial inhibitors like Metformin, have specific side effects. PI3K inhibitors often cause hyperglycemia, rash, diarrhea, and fatigue. Metformin is generally well-tolerated but can lead to gastrointestinal issues such as nausea, vomiting, and diarrhea, and rarely, lactic acidosis. Combining these treatments may result in overlapping toxicities, especially gastrointestinal and metabolic disturbances.

What prior FDA approvals exist?

The FDA has approved several treatments for glioblastoma, including temozolomide, an oral alkylating agent, and bevacizumab, an anti-VEGF monoclonal antibody. While these drugs do not directly target the PI3K pathway or AMPK activation, they represent the mainstay of glioblastoma treatment. Investigational treatments like Paxalisib, a PI3K inhibitor, and Metformin, known for its AMPK activation and mitochondrial inhibition, are being studied for their potential to target glioblastoma through different mechanisms, potentially offering new therapeutic options.

What other types of research exist?

Promising novel alternatives for Glioblastoma treatment in 2024 include: 1) Bevacizumab (angiogenesis inhibitor) combined with platinum-based chemotherapy, 2) Cabozantinib (tyrosine kinase inhibitor) for targeting multiple pathways, 3) PARP inhibitors like Olaparib for patients with specific genetic mutations, and 4) mTOR inhibitors such as Everolimus, especially in combination with other agents like Octreotide. These alternatives have shown potential in clinical trials and may offer new avenues for treatment.

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Anti-diabetic drug

Paxalisib + Metformin + Ketogenic Diet for Glioblastoma

Phase 2

Recruiting

Led By Howard Fine, MD

Research Sponsored by Weill Medical College of Cornell University

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Patient must have had previous radiation.

Histologically-confirmed glioblastoma (WHO Grade IV glioma); tumors situated primarily in the infratentorial compartment will be excluded.

Must not have

Any ongoing malignancy requiring treatment currently or expected to require treatment in the next 12 months.

Known hypersensitivity or intolerance to paxalisib or metformin.

Timeline

Screening 3 weeks

Treatment Varies

Follow Up at 6 months after the start of study treatment

Awards & highlights

No Placebo-Only Group

Summary

This trial is for patients with new or recurring aggressive brain cancer called glioblastoma. They will take two drugs regularly and follow a high-fat, low-carb diet. The treatment aims to block cancer growth signals and reduce the energy supply to cancer cells.

Who is the study for?

This trial is for adults with newly diagnosed or recurring glioblastoma, specifically those who have had radiation and show no tumor progression post-radiation. Participants must not be allergic to metformin, should have a life expectancy over 12 weeks, and agree to use contraception. Exclusions include other anti-glioma treatments, certain surgeries or conditions like severe diabetes (A1C > 7.5%), specific genetic mutations (IDH-1, IDH-2), or being on a ketogenic diet for more than two weeks prior.

What is being tested?

The study tests the safety and effects of Paxalisib taken daily alongside Metformin while maintaining a high fat, low carbohydrate ketogenic diet in patients with glioblastoma. It aims to understand how this combination affects the cancer's behavior.

What are the potential side effects?

Potential side effects may include typical reactions to medication such as digestive issues due to metformin; however, specifics about Paxalisib's side effects are not provided but could align with common drug reactions like fatigue or nausea.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I have undergone radiation therapy before.

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I have been diagnosed with a specific type of brain tumor called glioblastoma, and it is not located in the lower back part of my brain.

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I have a new diagnosis of glioblastoma without MGMT methylation.

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My cancer has not worsened after radiation treatment.

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My cancer is a type of brain tumor called glioblastoma, not located in the lower back part of my brain.

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I am taking less than 4mg of dexamethasone daily.

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I am mostly able to care for myself.

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I have received radiation therapy for brain cancer following official guidelines.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I am not currently receiving, nor expected to need, cancer treatment in the next year for another cancer.

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I am allergic or react badly to paxalisib or metformin.

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I am not currently on any standard or experimental brain tumor treatments.

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I have a family history of high triglycerides.

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I have had severe pancreatitis or lack of pancreatic enzyme production.

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My cancer has grown despite receiving chemoradiation.

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I have had weight loss surgery in the past.

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I have had severe kidney stones that needed treatment by a specialist.

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My tumor has a mutation in the IDH-1 or IDH-2 gene.

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I have been treated with bevacizumab or drugs targeting the PI3K pathway.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ at 6 months after the start of study treatment

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~at 6 months after the start of study treatment

This trial's timeline: 3 weeks for screening, Varies for treatment, and at 6 months after the start of study treatment for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Progression-free survival, defined as the survival rate at 6 months

Secondary study objectives

Change in insulin levels

Change in tumor glucose uptake values

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

2Treatment groups

Experimental Treatment

Group I: Arm 2: Recurrent glioblastoma, regardless of methylation statusExperimental Treatment3 Interventions

Group II: Arm 1: Newly diagnosed MGMT unmethylated glioblastomaExperimental Treatment3 Interventions

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Metformin

2006

Completed Phase 4

~2430

0 / 18Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Common treatments for Glioblastoma, such as Paxalisib and Metformin, work by targeting key pathways involved in tumor growth and metabolism. Paxalisib inhibits the PI3K/AKT/mTOR pathway, which is essential for cell proliferation and survival, thereby reducing tumor growth and promoting cancer cell death. Metformin activates AMPK and inhibits mitochondrial function, leading to decreased energy production in cancer cells and increased cell death. These mechanisms are significant for Glioblastoma patients as they address the aggressive nature of the tumor by disrupting its metabolic and growth processes, potentially improving treatment efficacy.