Paxalisib + Metformin + Ketogenic Diet for Glioblastoma

Overseen By Howard F Fine, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

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 All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

33 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial evaluates the safety of combining Paxalisib (a new potential drug), Metformin, and a ketogenic diet (low-carb, high-fat) for treating glioblastoma, a type of brain cancer. The study includes individuals newly diagnosed with glioblastoma and those with recurrent cancer. Participants will take Paxalisib and Metformin daily while following a ketogenic diet to assess the combination's impact on their cancer. Suitable candidates include those with glioblastoma who have undergone surgery and radiation but are not experiencing tumor growth from the treatment. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that paxalisib, metformin, and ketogenic diets each have safety information relevant to potential trial participants.

For paxalisib, studies have shown it to be promising in terms of safety and effectiveness for patients with glioblastoma, a type of brain cancer. The FDA has noted its potential for approval based on survival data, indicating a reasonable safety profile.

Metformin, already approved by the FDA for treating type 2 diabetes, has been researched for glioma treatment. Studies have found it safe when combined with other treatments like temozolomide, a common medication for glioblastoma.

A ketogenic diet, high in fat and low in carbohydrates, has been shown to be safe and manageable for glioblastoma patients. Some studies even suggest it might help improve patient outcomes.

In summary, each of these treatments has been well-tolerated in past studies. However, individual experiences can vary, so discussing any concerns with a healthcare provider is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Paxalisib, Metformin, and a ketogenic diet for glioblastoma because these treatments offer a novel approach compared to standard therapies like surgery, radiation, and temozolomide chemotherapy. Paxalisib is particularly intriguing because it targets the PI3K/AKT/mTOR pathway, which is often overactive in glioblastoma, potentially stopping cancer growth more effectively. Metformin, typically used for diabetes, may enhance the cancer-fighting effects and reduce tumor resistance. Additionally, the ketogenic diet could help by starving cancer cells of glucose, their primary energy source, potentially slowing their growth. This multi-faceted strategy aims to tackle glioblastoma’s complexity more comprehensively than traditional methods.

What evidence suggests that this trial's treatments could be effective for glioblastoma?

Research has shown that the drug paxalisib, studied in this trial, may extend the lives of patients with glioblastoma. Specifically, patients taking paxalisib lived an average of 15.54 months, compared to 11.89 months with standard treatment. Metformin, another treatment option in this trial, also shows promise. It can slow tumor growth and extend life when combined with other glioblastoma treatments. Additionally, a ketogenic diet, high in fat and low in carbs, has been linked to better outcomes for brain tumor patients. This combination of treatments might offer a better chance for those with glioblastoma. ^{1 2 6 7 8}

Who Is on the Research Team?

Howard Fine, MD

Principal Investigator

Weill Medical College of Cornell University

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Ketogenic Diet
• Metformin
• Paxalisib

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.

How Is the Trial Designed?

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 European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as Glucophage for:

• Type 2 diabetes

Approved in United States as Glucophage for:

• Type 2 diabetes

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+

Kazia Therapeutics Limited

Industry Sponsor

Trials

12

Recruited

1,600+

Published Research Related to This Trial

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]

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]

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]

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 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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11433106/

The Role of the Ketogenic Diet in Managing Glioblastoma in ... According to the findings of our study, patients with brain tumors who stick to a ketogenic diet are more likely to experience improved survival rates.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9504425/

Ketogenic Diet in the Treatment of Gliomas and Glioblastomas Another study also showed that KD both alone and in combination with RT and temozolomide is able to prolong survival and slow tumor growth in ...

3. cancerresearchuk.org cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-study-comparing-types-of-ketogenic-diet-in-people-with-glioblastoma-keating

A study comparing types of ketogenic diet in people with ... The study compared 2 types of ketogenic diets in people with a glioblastoma (GBM). Glioblastomas are a type of brain tumour. A ketogenic diet is high in fat ...

4. nature.com nature.com/articles/s41598-025-06675-6

A phase 1 safety and feasibility trial of a ketogenic diet plus ... This phase 1 trial demonstrates that KD is safe and feasible for GBM patients receiving SOC, may improve outcomes, and provides a foundation for an NCI-funded ...

5. frontiersin.org frontiersin.org/journals/nutrition/articles/10.3389/fnut.2025.1535921/full

Impact of ketogenic diets on cancer patient outcomes Conclusion: The ketogenic diet was found to improve cancer patients' outcomes more effectively than non-ketogenic diets. Notably, C-reactive ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05183204

NCT05183204 | Paxalisib With a High Fat, Low Carb Diet ... The purpose of this study is to assess the safety of Paxalisib while maintaining a ketogenic diet (a high fat, low carbohydrate diet) and Metformin (a drug ...

7. frontiersin.org frontiersin.org/journals/nutrition/articles/10.3389/fnut.2023.1110291/full

Ketogenic therapies for glioblastoma: Understanding the ... Scientists perform in-depth examinations of the high-fat, low-carbohydrate diet to understand better its effect on brain tumors (gliomas) and survival in mice.

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4063533/

ERGO: A pilot study of ketogenic diet in recurrent ... A ketogenic diet is feasible and safe but probably has no significant clinical activity when used as single agent in recurrent glioma.