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Metabolic Therapy Program In Conjunction With Standard Treatment For Glioblastoma

Primary Purpose

Glioblastoma

Status
Recruiting
Phase
Not Applicable
Locations
New Zealand
Study Type
Interventional
Intervention
Standard Treatment Plus Metabolic Therapy Program
Sponsored by
Waikato Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Glioblastoma focused on measuring cancer, glioblastoma, metabolic therapy, fasting, ketogenic diet

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Age 18 years or greater.
  2. Newly-diagnosed histologically-confirmed GBM.
  3. ECOG Performance Status 0-2.
  4. Planned for 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.

Sites / Locations

  • Waikato HospitalRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Standard treatment in conjunction with MTP

Arm Description

Standard: Concurrent chemoradiation - Radiation (60-Gy in 30 fractions over 6 weeks) with daily oral temozolomide. Adjuvant chemotherapy - Daily oral temozolomide (5 days per 4-week cycle, starting 4 weeks after completion of chemoradiation, with at least 6 cycles intended). MTP: - Two 5-day fasts (allowing water, salt, tea, coffee, and a magnesium supplement) during chemoradiation followed by a 5-day fast during each adjuvant chemotherapy cycle, with a time-restricted modified ketogenic diet (one or two 1-hour eating windows per day, allowing oils, meats, vegetables, nuts, seeds, limited berries, and a multivitamin) between fasts.

Outcomes

Primary Outcome Measures

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)

Secondary Outcome Measures

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)
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
Change in weight
Weight (kg)
Safety as measured by National Cancer Institute Common Terminology Criteria for Adverse Events (version 4)
Number of adverse events (of any grade)
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)
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)
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)
Progression-free survival
Progression-free survival
Overall survival
Overall survival

Full Information

First Posted
December 22, 2020
Last Updated
July 31, 2023
Sponsor
Waikato Hospital
Collaborators
Wellington Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT04730869
Brief Title
Metabolic Therapy Program In Conjunction With Standard Treatment For Glioblastoma
Official Title
Feasibility, Safety, and Efficacy of a Metabolic Therapy Program in Conjunction With Standard Treatment for Glioblastoma
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Recruiting
Study Start Date
May 26, 2021 (Actual)
Primary Completion Date
December 1, 2024 (Anticipated)
Study Completion Date
December 1, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Waikato Hospital
Collaborators
Wellington Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

Brief 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.
Detailed 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Glioblastoma
Keywords
cancer, glioblastoma, metabolic therapy, fasting, ketogenic diet

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
22 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Standard treatment in conjunction with MTP
Arm Type
Experimental
Arm Description
Standard: Concurrent chemoradiation - Radiation (60-Gy in 30 fractions over 6 weeks) with daily oral temozolomide. Adjuvant chemotherapy - Daily oral temozolomide (5 days per 4-week cycle, starting 4 weeks after completion of chemoradiation, with at least 6 cycles intended). MTP: - Two 5-day fasts (allowing water, salt, tea, coffee, and a magnesium supplement) during chemoradiation followed by a 5-day fast during each adjuvant chemotherapy cycle, with a time-restricted modified ketogenic diet (one or two 1-hour eating windows per day, allowing oils, meats, vegetables, nuts, seeds, limited berries, and a multivitamin) between fasts.
Intervention Type
Other
Intervention Name(s)
Standard Treatment Plus Metabolic Therapy Program
Intervention Description
See description under "Arms."
Primary Outcome Measure Information:
Title
Mean daily blood glucose-to-ketone ratio during chemoradiation
Description
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)
Time Frame
9 weeks
Secondary Outcome Measure Information:
Title
Mean daily blood glucose-to-ketone ratio during adjuvant chemotherapy
Description
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)
Time Frame
24 weeks
Title
Mean daily blood glucose-to-ketone ratio during the MTP, calculated separately on fasting and ketogenic diet days
Description
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
Time Frame
33 weeks
Title
Change in weight
Description
Weight (kg)
Time Frame
33 weeks
Title
Safety as measured by National Cancer Institute Common Terminology Criteria for Adverse Events (version 4)
Description
Number of adverse events (of any grade)
Time Frame
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
Title
Change in performance status as measured by Eastern Cooperative Oncology Group Performance Status scale
Description
Eastern Cooperative Oncology Group Performance Status scale (scores range from 0 to 5, with higher scores indicating lower performance status)
Time Frame
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
Title
Change in leisure/exercise activity as measured by Godin Leisure-Time Exercise questionnaire
Description
Godin Leisure-Time Exercise questionnaire (scores range from 0 to no maximum, with higher scores indicating higher leisure/exercise activity)
Time Frame
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
Title
Change in quality of life as measured by Functional Assessment of Cancer Therapy - Brain questionnaire
Description
Functional Assessment of Cancer Therapy - Brain questionnaire (scores range from 0 to 200, with higher scores indicating higher quality of life)
Time Frame
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
Title
Progression-free survival
Description
Progression-free survival
Time Frame
From date of biopsy-confirmed diagnosis to date of first documented progression, whichever came first, up to 33 weeks
Title
Overall survival
Description
Overall survival
Time Frame
From date of biopsy-confirmed diagnosis to date of death from any cause, whichever came first, up to 33 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age 18 years or greater. Newly-diagnosed histologically-confirmed GBM. ECOG Performance Status 0-2. Planned for 6 weeks of standard chemoradiation for GBM. If receiving dexamethasone, the dose must be ≤ 4 mg daily (and not increasing) upon commencement of the MTP. Exclusion Criteria: Ineligible for standard treatment for GBM due to poor performance status, co-morbidities, or inability to give informed consent. Type 1 diabetes. A medical or psychiatric disorder that, in the opinion of the investigators, would make it unlikely that the patient could adhere to the MTP.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Matthew CL Phillips, FRACP
Phone
+64274057415
Email
Matthew.Phillips@waikatodhb.health.nz
First Name & Middle Initial & Last Name or Official Title & Degree
Michael Jameson, PhD, FRCP
Phone
+64274057415
Email
Michael.Jameson@waikatodhb.health.nz
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Matthew CL Phillips, FRACP
Organizational Affiliation
Waikato Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Waikato Hospital
City
Hamilton
State/Province
Waikato
ZIP/Postal Code
3204
Country
New Zealand
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Matthew CL Phillips, FRACP
Phone
0274057415
Email
Matthew.Phillips@waikatodhb.health.nz

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Upon reasonable request for research purposes only, de-identified patient data may be shared with other investigators.
IPD Sharing Time Frame
Starting immediately upon publication.
IPD Sharing Access Criteria
Upon reasonable request for research purposes.
Citations:
PubMed Identifier
32290213
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.
Results Reference
background
PubMed Identifier
28582760
Citation
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.
Results Reference
background
PubMed Identifier
20009300
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.
Results Reference
background
PubMed Identifier
26217661
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.
Results Reference
background
PubMed Identifier
24343361
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.
Results Reference
background
PubMed Identifier
31627405
Citation
Phillips MCL. Fasting as a Therapy in Neurological Disease. Nutrients. 2019 Oct 17;11(10):2501. doi: 10.3390/nu11102501.
Results Reference
background
PubMed Identifier
32457832
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.
Results Reference
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Metabolic Therapy Program In Conjunction With Standard Treatment For Glioblastoma

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