Paxalisib + Metformin + Ketogenic Diet for Glioblastoma
Recruiting in Palo Alto (17 mi)
Overseen ByHoward 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
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.
12345Is 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.
12678What 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.
12358Eligibility 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
I have undergone radiation therapy before.
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.
I have a new diagnosis of glioblastoma without MGMT methylation.
My cancer has not worsened after radiation treatment.
My cancer is a type of brain tumor called glioblastoma, not located in the lower back part of my brain.
I am taking less than 4mg of dexamethasone daily.
I am mostly able to care for myself.
I have received radiation therapy for brain cancer following official guidelines.
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.
I have a family history of high triglycerides.
I have had severe pancreatitis or lack of pancreatic enzyme production.
My cancer has grown despite receiving chemoradiation.
I have had weight loss surgery in the past.
I have had severe kidney stones that needed treatment by a specialist.
My tumor has a mutation in the IDH-1 or IDH-2 gene.
I have been treated with bevacizumab or drugs targeting the PI3K pathway.
Participant Groups
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.
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
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
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Weill Cornell MedicineNew York, NY
Loading ...
Who is running the clinical trial?
Weill Medical College of Cornell UniversityLead Sponsor
Kazia Therapeutics LimitedIndustry Sponsor
References
Metformin influences progression in diabetic glioblastoma patients. [2022]Changes in metabolism, including high glucose serum levels, seem to influence the initiation of malignancy as well as recurrence. Therefore, limiting the energy supply in tumor cells with the antidiabetic drug metformin might be a useful approach to inhibit glioma cell progression. However, little is known about the effects of endocrine disorders (e.g., diabetes mellitus, corticosteroid therapy, and metformin therapy) on progression and survival in primary glioblastoma patients.
Effects of Metformin as Add-On Therapy against Glioblastoma: An Old Medicine for Novel Oncology Therapeutics. [2022]Glioblastoma is the most aggressive primary brain malignancy in adults, with a poor prognosis of about 14 months. Recent evidence ascribed to metformin (MET), an antihyperglycemic drug, the potential to reduce cancer incidence and progression, but the molecular mechanisms underlying these effects need to be better investigated.
Treatment of malignant gliomas with ketogenic or caloric restricted diets: A systematic review of preclinical and early clinical studies. [2022]Patients with malignant gliomas have a poor prognosis. Diets that lower blood glucose, such as ketogenic or caloric restricted diets (KCRDs), are hypothesized to reduce tumor growth and improve survival. In this systematic review, we summarize preclinical and clinical data on KCRDs in gliomas.
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]Glioblastoma (GBM) has a poor prognosis after standard treatment. Recently, metformin has been shown to have an antitumor effect on glioma cells. We performed the first randomized prospective phase II clinical trial to investigate the clinical efficacy and safety of metformin in patients with recurrent or refractory GBM treated with low-dose temozolomide.
ERGO: a pilot study of ketogenic diet in recurrent glioblastoma. [2023]Limiting dietary carbohydrates inhibits glioma growth in preclinical models. Therefore, the ERGO trial (NCT00575146) examined feasibility of a ketogenic diet in 20 patients with recurrent glioblastoma. Patients were put on a low-carbohydrate, ketogenic diet containing plant oils. Feasibility was the primary endpoint, secondary endpoints included the percentage of patients reaching urinary ketosis, progression-free survival (PFS) and overall survival. The effects of a ketogenic diet alone or in combination with bevacizumab was also explored in an orthotopic U87MG glioblastoma model in nude mice. Three patients (15%) discontinued the diet for poor tolerability. No serious adverse events attributed to the diet were observed. Urine ketosis was achieved at least once in 12 of 13 (92%) evaluable patients. One patient achieved a minor response and two patients had stable disease after 6 weeks. Median PFS of all patients was 5 (range, 3-13) weeks, median survival from enrollment was 32 weeks. The trial allowed to continue the diet beyond progression. Six of 7 (86%) patients treated with bevacizumab and diet experienced an objective response, and median PFS on bevacizumab was 20.1 (range, 12-124) weeks, for a PFS at 6 months of 43%. In the mouse glioma model, ketogenic diet alone had no effect on median survival, but increased that of bevacizumab-treated mice from 52 to 58 days (p
Targeting metabolism with a ketogenic diet during the treatment of glioblastoma multiforme. [2022]Retrospective data suggests that low serum glucose levels during the treatment of glioblastoma multiforme (GBM) may improve clinical outcomes. As such, many patients are implementing a ketogenic diet (KD) in order to decrease serum glucose flux while simultaneously elevating circulating ketones during radiation therapy and chemotherapy for the treatment of GBM. With IRB approval, a retrospective review of patients with high-grade glioma treated with concurrent chemoradiotherapy and adjuvant chemotherapy was carried out from August 2010 to April 2013. Serum glucose and ketone levels, dexamethasone dose, and toxicity of patients undergoing a KD during treatment were also assessed. Blood glucose levels were compared between patients on an unspecified/standard diet and a KD. Toxicity was assessed by Common Terminology Criteria for Adverse Events version 4. In total, 53 patients were analyzed. Six underwent a KD during treatment. The diet was well tolerated with no grade III toxicity and one episode of grade II fatigue. No episodes of symptomatic hypoglycemia were experienced. Four patients are alive at a median follow-up of 14 months. The mean blood glucose of patients on a standard diet was 122 versus 84 mg/dl for those on a KD. Based on this retrospective study, a KD appears safe and well tolerated during the standard treatment of GBM. Dietary restriction of carbohydrates through a KD reduces serum glucose levels significantly, even in conjunction with high dose steroids, which may affect the response to standard treatment and prognosis. Larger prospective trials to confirm this relationship are warranted.
Use of metformin and outcome of patients with newly diagnosed glioblastoma: Pooled analysis. [2020]Metformin has been linked to improve survival of patients with various cancers. There is little information on survival of glioblastoma patients after use of metformin. We assessed the association between metformin use and survival in a pooled analysis of patient data from 1,731 individuals from the randomized AVAglio, CENTRIC and CORE trials. We performed multivariate Cox analyses for overall survival (OS) and progression-free survival (PFS) comparing patients' use of metformin at baseline and/or during concomitant radiochemotherapy (TMZ/RT). Further exploratory analyses investigated the effect of metformin with a history of diabetes and nonfasting glucose levels in relation to OS or PFS of glioblastoma patients. Metformin alone or in any combination was not significantly associated with OS or PFS (at baseline, hazard ratio [HR] for OS = 0.87; 95% confidence interval [CI] = 0.65-1.16; HR for PFS = 0.84; 95% CI = 0.64-1.10; during TMZ/RT HR for OS = 0.97; 95% CI = 0.68-1.38; HR for PFS = 1.02; 95% CI = 0.74-1.41). We found a statistically nonsignificant association of metformin monotherapy with glioblastoma survival at baseline (HR for OS = 0.68; 95% CI = 0.42-1.10; HR for PFS = 0.57; 95% CI = 0.36-0.91), but not during the TMZ/RT period (HR for OS = 0.90; 95% CI = 0.51-1.56; HR for PFS = 1.05; 95% CI = 0.64-1.73). Diabetes mellitus or increased nonfasting glucose levels were not associated with a difference in OS or PFS in our selected study population. Metformin did not prolong survival of patients with newly diagnosed glioblastoma in our analysis. Additional studies may identify patients with specific tumor characteristics that are associated with potential benefit from treatment with metformin, possibly due to metabolic vulnerabilities.
Therapeutic benefit of combining calorie-restricted ketogenic diet and glutamine targeting in late-stage experimental glioblastoma. [2023]Glioblastoma (GBM) is an aggressive primary human brain tumour that has resisted effective therapy for decades. Although glucose and glutamine are the major fuels that drive GBM growth and invasion, few studies have targeted these fuels for therapeutic management. The glutamine antagonist, 6-diazo-5-oxo-L-norleucine (DON), was administered together with a calorically restricted ketogenic diet (KD-R) to treat late-stage orthotopic growth in two syngeneic GBM mouse models: VM-M3 and CT-2A. DON targets glutaminolysis, while the KD-R reduces glucose and, simultaneously, elevates neuroprotective and non-fermentable ketone bodies. The diet/drug therapeutic strategy killed tumour cells while reversing disease symptoms, and improving overall mouse survival. The therapeutic strategy also reduces edema, hemorrhage, and inflammation. Moreover, the KD-R diet facilitated DON delivery to the brain and allowed a lower dosage to achieve therapeutic effect. The findings support the importance of glucose and glutamine in driving GBM growth and provide a therapeutic strategy for non-toxic metabolic management.