Paxalisib + Metformin + Ketogenic Diet for Glioblastoma

Overseen by Howard Fine, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Weill Medical College of Cornell University

Must be taking: Paxalisib, Metformin

Must not be taking: Bevacizumab, PI3K inhibitors

Disqualifiers: Type 1 diabetes, QT interval ≥ 450 msec, ongoing malignancy, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot take medications that affect the metabolism of paxalisib, such as certain enzyme inducers or inhibitors. It's best to discuss your current medications with the trial team to ensure they don't interfere with the study.

What data supports the effectiveness of the treatment Paxalisib + Metformin + Ketogenic Diet for Glioblastoma?

Research suggests that metformin, a drug commonly used for diabetes, may help slow down the growth of glioblastoma, a type of brain cancer. Additionally, ketogenic diets, which are low in carbohydrates, might reduce tumor growth and improve survival in patients with malignant gliomas. ^{1 2 3 4 5}

Is the combination of Paxalisib, Metformin, and a Ketogenic Diet safe for humans?

The ketogenic diet appears safe and well-tolerated during glioblastoma treatment, with no severe side effects reported. Metformin, commonly used for diabetes, has been studied in cancer patients and is generally considered safe, though its effects on glioblastoma survival are unclear. There is no specific safety data available for Paxalisib in this context. ^{1 2 6 7 8}

What makes the treatment with Paxalisib, Metformin, and a Ketogenic Diet unique for glioblastoma?

This treatment is unique because it combines Paxalisib, a drug targeting cancer cell growth, with Metformin, which limits energy supply to tumor cells, and a ketogenic diet that reduces glucose availability, potentially starving the tumor of its primary fuel sources. ^{1 2 3 5 8}

Research Team

Howard Fine, MD

Principal Investigator

Weill Medical College of Cornell University

Eligibility Criteria

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.

Inclusion Criteria

Your doctor believes that you will live for at least 12 more weeks.

Able and willing, in the judgment of the investigator, to meet all protocol-required treatments, investigations and visits.

My cancer has an unmethylated MGMT status, or I can't take temozolomide due to its methylated status.

Exclusion Criteria

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

I am allergic or react badly to paxalisib or metformin.

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

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive daily paxalisib and metformin while maintaining a ketogenic diet

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

8 weeks

Treatment Details

Interventions

• Ketogenic Diet (Behavioural Intervention)
• Metformin (Anti-diabetic drug)
• Paxalisib (PI3K Inhibitor)

Trial Overview 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.

Participant Groups

Group I: Arm 2: Recurrent glioblastoma, regardless of methylation status Experimental Treatment 3 Interventions

Group II: Arm 1: Newly diagnosed MGMT unmethylated glioblastoma Experimental Treatment 3 Interventions

Metformin is already approved in Canada, Japan, China, Switzerland for the following indications:

Approved in Canada as Glucophage for:

• Type 2 diabetes

Approved in Japan as Glucophage for:

• Type 2 diabetes

Approved in China as Glucophage for:

• Type 2 diabetes

Approved in Switzerland as Glucophage for:

• Type 2 diabetes

Who Is Running the Clinical Trial?

Weill Medical College of Cornell University

Lead Sponsor

Trials

1,103

Recruited

1,157,000+

Dr. Robert Min

Weill Medical College of Cornell University

Chief Executive Officer since 2024

MD, MBA

Dr. Adam R. Stracher

Weill Medical College of Cornell University

Chief Medical Officer since 2024

MD

Kazia Therapeutics Limited

Industry Sponsor

Trials

12

Recruited

1,600+

Findings from Research

In a study of 276 glioblastoma patients, persistent high blood sugar levels and corticosteroid therapy were linked to lower survival rates, highlighting their negative impact on patient outcomes.

Diabetic patients treated with metformin showed longer progression-free survival, suggesting that metformin may have a beneficial effect in managing glioblastoma, warranting further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin influences progression in diabetic glioblastoma patients. Adeberg, S., Bernhardt, D., Ben Harrabi, S., et al.[2022]

Metformin (MET) significantly reduces the viability and proliferation of glioblastoma endothelial cells, promoting apoptosis through increased activity of caspases 3/7, indicating its potential as a therapeutic agent against this aggressive brain cancer.

MET also decreases angiogenesis and invasiveness in glioblastoma cells by altering sphingolipid metabolism, suggesting it could be safely repurposed as an add-on therapy in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Metformin as Add-On Therapy against Glioblastoma: An Old Medicine for Novel Oncology Therapeutics. Guarnaccia, L., Navone, SE., Masseroli, MM., et al.[2022]

Preclinical studies indicate that ketogenic or caloric restricted diets (KCRDs) can reduce tumor growth in malignant gliomas, particularly when blood glucose levels are decreased, although improved survival was only observed in a minority of cases.

Preliminary clinical data suggest that KCRDs are safe and feasible for glioma patients, but there is not enough evidence yet to confirm their effectiveness in improving survival or quality of life, highlighting the need for further prospective studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of malignant gliomas with ketogenic or caloric restricted diets: A systematic review of preclinical and early clinical studies. Noorlag, L., De Vos, FY., Kok, A., et al.[2022]

In a phase II clinical trial involving 81 patients with recurrent or refractory glioblastoma, the combination of metformin and low-dose temozolomide was well tolerated but did not show a significant clinical benefit in terms of progression-free survival or overall survival compared to the control group receiving placebo and temozolomide.

The median overall survival was 17.22 months for the metformin group versus 7.69 months for the control group, but this difference was not statistically significant, indicating that metformin may not improve outcomes in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of metformin plus low-dose temozolomide in patients with recurrent or refractory glioblastoma: a randomized, prospective, multicenter, double-blind, controlled, phase 2 trial (KNOG-1501 study). Yoon, WS., Chang, JH., Kim, JH., et al.[2023]

The ERGO trial demonstrated that a ketogenic diet is feasible and safe for patients with recurrent glioblastoma, with 92% of evaluable patients achieving urinary ketosis and no serious adverse events reported.

While the ketogenic diet alone showed limited clinical activity, it appeared to enhance the effectiveness of bevacizumab, with a median progression-free survival of 20.1 weeks in patients combining the diet with this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ERGO: a pilot study of ketogenic diet in recurrent glioblastoma. Rieger, J., Bähr, O., Maurer, GD., et al.[2023]

A retrospective study of 53 glioblastoma multiforme patients indicated that a ketogenic diet (KD) is safe and well tolerated during standard treatment, with no severe toxicities reported and only mild fatigue experienced.

Patients on a KD had significantly lower serum glucose levels (mean 84 mg/dl) compared to those on a standard diet (mean 122 mg/dl), suggesting that dietary carbohydrate restriction may positively influence treatment response and prognosis in GBM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting metabolism with a ketogenic diet during the treatment of glioblastoma multiforme. Champ, CE., Palmer, JD., Volek, JS., et al.[2022]

In a pooled analysis of 1,731 glioblastoma patients from three clinical trials, metformin use was not significantly associated with improved overall survival (OS) or progression-free survival (PFS) during or after treatment with radiochemotherapy.

While there was a nonsignificant trend suggesting potential benefits of metformin monotherapy at baseline, this effect was not observed during concurrent treatment with temozolomide and radiotherapy, indicating that metformin does not prolong survival in newly diagnosed glioblastoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of metformin and outcome of patients with newly diagnosed glioblastoma: Pooled analysis. Seliger, C., Genbrugge, E., Gorlia, T., et al.[2020]

The combination of the glutamine antagonist DON and a calorically restricted ketogenic diet (KD-R) effectively targets glioblastoma (GBM) growth in mouse models, leading to tumor cell death and improved survival rates.

This therapeutic strategy not only reduces harmful symptoms like edema and inflammation but also enhances the delivery of DON to the brain, allowing for lower dosages to achieve the desired effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic benefit of combining calorie-restricted ketogenic diet and glutamine targeting in late-stage experimental glioblastoma. Mukherjee, P., Augur, ZM., Li, M., et al.[2023]

References

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

Metformin influences progression in diabetic glioblastoma patients. [2022]

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

Effects of Metformin as Add-On Therapy against Glioblastoma: An Old Medicine for Novel Oncology Therapeutics. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Treatment of malignant gliomas with ketogenic or caloric restricted diets: A systematic review of preclinical and early clinical studies. [2022]

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

Efficacy and safety of metformin plus low-dose temozolomide in patients with recurrent or refractory glioblastoma: a randomized, prospective, multicenter, double-blind, controlled, phase 2 trial (KNOG-1501 study). [2023]

5. Greece pubmed.ncbi.nlm.nih.gov

ERGO: a pilot study of ketogenic diet in recurrent glioblastoma. [2023]

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

Targeting metabolism with a ketogenic diet during the treatment of glioblastoma multiforme. [2022]

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

Use of metformin and outcome of patients with newly diagnosed glioblastoma: Pooled analysis. [2020]

8. England pubmed.ncbi.nlm.nih.gov

Therapeutic benefit of combining calorie-restricted ketogenic diet and glutamine targeting in late-stage experimental glioblastoma. [2023]