Paxalisib With a High Fat, Low Carb Diet and Metformin for Glioblastoma

NCT05183204 | Suspended Phase 2 DMC FDA Drug

• 1 other identifier: 21-05023537
• Study Type: interventional
• Target: 33
• Locations: 1 country
• Sites: 1

Brief Summary

This study is for patients with newly diagnosed glioblastoma, as well as patients who have recurring glioblastoma. Subjects will be given daily paxalisib and metformin while also maintaining a ketogenic 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 approved by the Food and Drug Administration to treat type 2 diabetes), and to see what effects it has on glioblastoma.

Conditions

Glioblastoma

Outcome Measures

Primary Outcomes (1)

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

  Measured by the occurrence of a progression event as per RANO criteria or death due to any cause prior to 6 months

  At 6 months after the start of study treatment

Secondary Outcomes (3)

• Overall survival, defined as the time of first study treatment to death from any cause

  From the start of study enrollment until death, up to approximately 18 months

• Change in insulin levels

  From baseline assessments through 8 weeks post-treatment

• Change in tumor glucose uptake values

  From baseline assessments through 8 weeks post-treatment

Study Arms (2)

Arm 1: Newly diagnosed MGMT unmethylated glioblastoma

EXPERIMENTAL

Drug: Paxalisib; Drug: Metformin; Other: Ketogenic Diet

Arm 2: Recurrent glioblastoma, regardless of methylation status

EXPERIMENTAL

Drug: Paxalisib; Drug: Metformin; Other: Ketogenic Diet

Interventions

Paxalisib DRUG

Patients will receive paxalisib starting at a dose of 45 mg/day. If well tolerated after 28 days, the dose of paxalisib will be increased to 60 mg/day.

Arm 1: Newly diagnosed MGMT unmethylated glioblastoma; Arm 2: Recurrent glioblastoma, regardless of methylation status

Metformin DRUG

Patients will receive metformin on Cycle 1, Day 1 at a starting dose of 850 mg QD, and if tolerated, will be increased to 850 mg BID on Cycle 2, Day 1 (1700 mg/day). If that dose is tolerated, metformin will be increased to 850 mg TID (2550 mg/day) beginning on Cycle 3, Day 1.

Arm 1: Newly diagnosed MGMT unmethylated glioblastoma; Arm 2: Recurrent glioblastoma, regardless of methylation status

Ketogenic Diet OTHER

The ketogenic diet is high-fat, low carbohydrate diet. Ketogenic diet will be maintained on a continuous basis starting on Cycle 1, Day 1 and continuing throughout the trial.

Arm 1: Newly diagnosed MGMT unmethylated glioblastoma; Arm 2: Recurrent glioblastoma, regardless of methylation status

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically-confirmed glioblastoma (WHO Grade IV glioma); tumors situated primarily in the infratentorial compartment will be excluded.
• Optimal surgical resection performed, with satisfactory clinical recovery in the judgment of the investigator (patients for who whom "optimal" surgical resection is considered only a subtotal resection or a biopsy, will be considered eligible).
• No clear evidence of tumor progression through radiation.
• Patient must have had previous radiation. NOTE: For patients with post-radiation scans suggestive of radiation-induced "pseudoprogression", patients can be consented and enrolled on this trial but investigational treatment will not start until a repeat MRI scan is obtained 4 weeks later (8-9 weeks following completion of radiation). If that scan shows no further tumor progression, despite no interval treatment in those preceding 4-weeks, then it will be assumed that the post-radiation MRI scans represent radiation-induced pseudoprogression rather than true tumor progression. In such a case, patients will start on treatment with paxalisib, the ketogenic diet and metformin. Assessment of PFS will start for such patients from this 8-9 week time point. By contrast, for patients whose 8-9 week "pseudoprogression assessment" MRI scan shows continued tumor progression, then these patients will be assumed to have true tumor progression and will not be eligible to remain treated on this study. Such patients will be deemed for the sake of the study as consented and screened. They will be evaluable for toxicity but not evaluable for response. Such patients may be replaced by an evaluable patient.
• Chemoradiotherapy administered according to the Stupp regimen, with at least 90% of the radiation prescribed dosing administered, and with initiation occurring less than six weeks after surgery and completion occurring 5 weeks prior to accrual into this study.
• Demonstrated unmethylated MGMT promotor status confirmed by validated PCR or alternate genomic analysis; subjects with methylated or indeterminate MGMT status that are unwilling, or otherwise unable, to undergo treatment with temozolomide may be enrolled.
• Patients of any gender, with age ≥ 18 years at the time of randomization.
• Written, signed, and dated informed consent to participate in this study, in a format approved by each site's Institutional Review Board (IRB).
• Life expectancy \> 12 weeks in the judgment of the investigator.
• Karnofsky Performance Status (KPS) ≥ 70.
• If receiving dexamethasone, dose is \< 4mg daily
• No history of allergy or other intolerance to metformin.
• Adequate organ and bone marrow function at the time of screening, including
• White blood cell count (WBC) \> 3,000/µL;
• Absolute neutrophil count \> 1,500/mm3

You may not qualify if:

• Patients with tumors exhibiting mutated isocitrate dehydrogenase-1 or 2 (IDH-1, 2).
• Patients receiving treatment with any other standard or investigational anti-glioma agents (e.g. Optune, bevacizumab).
• Patients with type 1 diabetes or poorly controlled type 2 diabetes with A1C \> 7.5%.
• QT interval of ≥ 450 msec.
• Any ongoing malignancy requiring treatment currently or expected to require treatment in the next 12 months.
• Any pre-existing or inter-current illness or pathology which, in the judgment of the investigator, has the potential to increase the safety risk associated with paxalisib administration, or to confound the results of the study.
• Patients receiving any medications or substances that are moderate and/or potent enzyme inducers or inhibitors which may have an effect on the metabolism of paxalisib.
• Known hypersensitivity or intolerance to paxalisib or metformin.
• Patients unable to undergo an MRI scan.
• Tumor Progression through chemoradiation (see section 4.2.1.4 above regarding question of radiation-induced "pseudoprogression").
• History of bariatric surgery.
• History of severe nephrolithiasis requiring urologic intervention.
• History of severe pancreatitis or pancreatic exocrine insufficiency.
• History of primary hypertriglyceridemia (Familial chylomicronemia, familial hypertriglyceridemia, or familial dysbetalipoproteinemia).
• Cohort 2: Recurrent Glioblastoma

Sponsors & Collaborators

• Weill Medical College of Cornell University: lead
• Kazia Therapeutics Limited: collaborator

Study Sites (1)

Weill Cornell Medicine

New York, New York, 10065, United States

Location

MeSH Terms

Conditions

Glioblastoma

Interventions

Metformin; Diet, Ketogenic

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals; Diet, Carbohydrate-Restricted; Diet Therapy; Nutrition Therapy; Therapeutics; Diet; Nutritional Physiological Phenomena; Diet, Food, and Nutrition; Physiological Phenomena

Study Officials

• Howard Fine, MD

  Weill Medical College of Cornell University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 20, 2021
• First Posted: January 10, 2022
• Study Start: February 14, 2022
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): June 1, 2026
• Last Updated: December 18, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)