Metabolic Therapy Program In Conjunction With Standard Treatment For Glioblastoma

Glioblastoma Clinical Trial

Official title:

Feasibility, Safety, and Efficacy of a Metabolic Therapy Program in Conjunction With Standard Treatment for Glioblastoma

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04730869
• Other study ID #: RD020132
• Secondary ID: U1111-1262-0203G
• Status: Recruiting
• Phase: N/A
• Start date: May 26, 2021
• Est. completion date: December 1, 2024

Study information

• Verified date: July 2023
• Source: Waikato Hospital
• Contact: Matthew CL Phillips, FRACP
• Phone: +64274057415
• Email: Matthew.Phillips[@]waikatodhb.health.nz
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Glioblastoma (GBM), a very aggressive brain tumour, is one of the most malignant of all cancers and is associated with a poor prognosis. The majority of GBM cells display damaged mitochondria (the "batteries" of cells), so they rely on an alternate method for producing energy called the Warburg Effect, which relies nearly exclusively on glucose (in contrast, normal cells can use other molecules, such as fatty acids and fat-derived ketones, for energy). Metabolic interventions, such as fasting and ketogenic diets, target cancer cell metabolism by enhancing mitochondria function, decreasing blood glucose levels, and increasing blood ketone levels, creating an advantage for normal cells but a disadvantage for cancer cells. Preliminary experience at Waikato Hospital has shown that a metabolic therapy program (MTP) utilizing fasting and ketogenic diets is feasible and safe in people with advanced cancer, and may provide a therapeutic benefit. We aim to determine whether using an MTP concurrently with standard oncological treatment (chemoradiation followed by adjuvant chemotherapy) is feasible and safe in patients with GBM, and has treatment outcomes consistent with greater overall treatment efficacy than in published trials.

Description:

Gliomas are tumours that originate from glial cells in the central nervous system. The most common histological subtype is GBM, which accounts for nearly 50% of all malignant brain tumours. Despite aggressive multimodal treatment, the median survival for GBM is poor (8-15 months).

Although cancer is regarded as a genetic disease, it may be perceived as a metabolic disorder. The majority of human cancers, including GBM, display low numbers of mitochondria, most of which are structurally damaged, resulting in defective cell respiration. To compensate, cancer cells greatly increase their uptake of glucose, which is fermented (regardless of oxygen concentration, a process known as the Warburg Effect) to generate energy. Cancer cells also rely on increased growth signaling pathways involving insulin, insulin-like growth factor-1, and mammalian target of rapamycin to support their unbridled growth and proliferation. Cancer cells may therefore be vulnerable to interventions that selectively target their abnormal metabolism.

Metabolic interventions, such as fasting and ketogenic diets, target cancer cell metabolism and may be effective alongside standard treatments in advanced cancers. Fasting is a voluntary abstinence from food and drink for a controlled period of time (typically, 12 hours to 3 weeks in humans), whereas ketogenic diets are high-fat, adequate-protein, low-carbohydrate diets that stimulate the body to create a fasting-like metabolic state. Fasting and ketogenic diets stimulate mitochondria biogenesis, decrease blood glucose, increase liver production of fat-derived ketones (which serve as a major alternative energy source for most normal cells within the body, but cannot be utilized by cancer cells), and decrease growth factor availability. Thus, fasting and ketogenic diets provide an advantage for normal cells but a disadvantage to cancer cells by enhancing mitochondria biogenesis and function, depriving cancer cells of their major fuel, and creating a cell environment unfavourable for unbridled growth and proliferation.

Preliminary experience at Waikato Hospital has shown that a metabolic therapy program (MTP) consisting of fasting and/or a ketogenic diet is feasible, safe, and may be effective in patients with advanced cancer, including GBM. In a recent case report, a metabolic strategy (7-day fast every 1-2 months, with a ketogenic diet between fasts) resulted in the near-complete regression of a stage IVA metastatic thymoma after 2 years. Moreover, we are currently observing 8 glioblastoma patients who voluntarily consented to undergo fasting and ketogenic diet therapy in a manner similar to what we propose to use in this study; at an average of 4-5 months, all patients have completed the fasts and adhered to their ketogenic diet, experiencing only mild adverse effects.

On this background, we aim to determine whether using an MTP concurrently with standard oncological treatment (chemoradiation followed by adjuvant chemotherapy) is feasible and safe, and has treatment outcomes consistent with greater overall treatment efficacy than in published trials, in patients with GBM.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 22
• Est. completion date: December 1, 2024
• Est. primary completion date: December 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Age 18 years or greater.

2. Newly-diagnosed histologically-confirmed GBM.

3. ECOG Performance Status 0-2.

4. Planned for 6 weeks of standard chemoradiation for GBM.

5. If receiving dexamethasone, the dose must be = 4 mg daily (and not increasing) upon commencement of the MTP.

Exclusion Criteria:

1. Ineligible for standard treatment for GBM due to poor performance status, co-morbidities, or inability to give informed consent.

2. Type 1 diabetes.

3. A medical or psychiatric disorder that, in the opinion of the investigators, would make it unlikely that the patient could adhere to the MTP.

Related Conditions & MeSH terms

• Glioblastoma

Intervention

Other:
• Standard Treatment Plus Metabolic Therapy Program
See description under "Arms."

Locations

Country	Name	City	State
New Zealand	Waikato Hospital	Hamilton	Waikato

Sponsors (2)

Lead Sponsor	Collaborator
Waikato Hospital	Wellington Hospital

Country where clinical trial is conducted

New Zealand, 

References & Publications (7)

Anjum K, Shagufta BI, Abbas SQ, Patel S, Khan I, Shah SAA, Akhter N, Hassan SSU. Current status and future therapeutic perspectives of glioblastoma multiforme (GBM) therapy: A review. Biomed Pharmacother. 2017 Aug;92:681-689. doi: 10.1016/j.biopha.2017.05.125. Epub 2017 Jun 3. Erratum In: Biomed Pharmacother. 2018 Mar 8;101:820. — View Citation

Phillips MCL, Murtagh DKJ, Sinha SK, Moon BG. Managing Metastatic Thymoma With Metabolic and Medical Therapy: A Case Report. Front Oncol. 2020 May 5;10:578. doi: 10.3389/fonc.2020.00578. eCollection 2020. — View Citation

Phillips MCL. Fasting as a Therapy in Neurological Disease. Nutrients. 2019 Oct 17;11(10):2501. doi: 10.3390/nu11102501. — View Citation

Rajaratnam V, Islam MM, Yang M, Slaby R, Ramirez HM, Mirza SP. Glioblastoma: Pathogenesis and Current Status of Chemotherapy and Other Novel Treatments. Cancers (Basel). 2020 Apr 10;12(4):937. doi: 10.3390/cancers12040937. — View Citation

Seyfried BT, Kiebish M, Marsh J, Mukherjee P. Targeting energy metabolism in brain cancer through calorie restriction and the ketogenic diet. J Cancer Res Ther. 2009 Sep;5 Suppl 1:S7-15. doi: 10.4103/0973-1482.55134. — View Citation

Seyfried TN, Flores RE, Poff AM, D'Agostino DP. Cancer as a metabolic disease: implications for novel therapeutics. Carcinogenesis. 2014 Mar;35(3):515-27. doi: 10.1093/carcin/bgt480. Epub 2013 Dec 16. — View Citation

Seyfried TN. Cancer as a mitochondrial metabolic disease. Front Cell Dev Biol. 2015 Jul 7;3:43. doi: 10.3389/fcell.2015.00043. eCollection 2015. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mean daily blood glucose-to-ketone ratio during chemoradiation	Proportion of patients able to sustain functional ketosis (defined as a mean daily blood glucose-to-ketone ratio of =6) during chemoradiation (defined as the beginning of the first fast through to 3 weeks following completion of chemoradiation)	9 weeks
Secondary	Mean daily blood glucose-to-ketone ratio during adjuvant chemotherapy	Proportion of patients able to sustain functional ketosis during adjuvant chemotherapy (defined as the beginning of the first adjuvant chemotherapy fast through to completion of adjuvant chemotherapy)	24 weeks
Secondary	Mean daily blood glucose-to-ketone ratio during the MTP, calculated separately on fasting and ketogenic diet days	Proportion of patients able to sustain functional ketosis during the MTP (defined as the beginning of chemoradiation through to the end of adjuvant chemotherapy), calculated separately each fasting and ketogenic diet phase	33 weeks
Secondary	Change in weight	Weight (kg)	33 weeks
Secondary	Safety as measured by National Cancer Institute Common Terminology Criteria for Adverse Events (version 4)	Number of adverse events (of any grade)	After each week (7 days) during chemoradiation, then after cycle 1 (28 days) of adjuvant chemotherapy, then after every 2 cycles (56 days) of adjuvant chemotherapy
Secondary	Change in performance status as measured by Eastern Cooperative Oncology Group Performance Status scale	Eastern Cooperative Oncology Group Performance Status scale (scores range from 0 to 5, with higher scores indicating lower performance status)	After each week (7 days) during chemoradiation, then after cycle 1 (28 days) of adjuvant chemotherapy, then after every 2 cycles (56 days) of adjuvant chemotherapy
Secondary	Change in leisure/exercise activity as measured by Godin Leisure-Time Exercise questionnaire	Godin Leisure-Time Exercise questionnaire (scores range from 0 to no maximum, with higher scores indicating higher leisure/exercise activity)	After each week (7 days) during chemoradiation, then after cycle 1 (28 days) of adjuvant chemotherapy, then after every 2 cycles (56 days) of adjuvant chemotherapy
Secondary	Change in quality of life as measured by Functional Assessment of Cancer Therapy - Brain questionnaire	Functional Assessment of Cancer Therapy - Brain questionnaire (scores range from 0 to 200, with higher scores indicating higher quality of life)	After each week (7 days) during chemoradiation, then after cycle 1 (28 days) of adjuvant chemotherapy, then after every 2 cycles (56 days) of adjuvant chemotherapy
Secondary	Progression-free survival	Progression-free survival	From date of biopsy-confirmed diagnosis to date of first documented progression, whichever came first, up to 33 weeks
Secondary	Overall survival	Overall survival	From date of biopsy-confirmed diagnosis to date of death from any cause, whichever came first, up to 33 weeks