Clinical trial NCT04730869: 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
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Glioblastoma
Keywords: cancer
glioblastoma
metabolic therapy
fasting
ketogenic diet
Lead sponsor: Waikato Hospital
Sponsor class: OTHER
Collaborators: name: Wellington Hospital
First posted: 2021-01-29
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Mean daily blood glucose-to-ketone ratio during chemoradiation
timeFrame: 9 weeks
Secondary outcomes:
measure: Mean daily blood glucose-to-ketone ratio during adjuvant chemotherapy
timeFrame: 24 weeks
measure: Mean daily blood glucose-to-ketone ratio during the MTP, calculated separately on fasting and ketogenic diet days
timeFrame: 33 weeks
measure: Change in weight
timeFrame: 33 weeks
measure: Safety as measured by National Cancer Institute Common Terminology Criteria for Adverse Events (version 4)
timeFrame: 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
measure: Change in performance status as measured by Eastern Cooperative Oncology Group Performance Status scale
timeFrame: 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
measure: Change in leisure/exercise activity as measured by Godin Leisure-Time Exercise questionnaire
timeFrame: 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
measure: Change in quality of life as measured by Functional Assessment of Cancer Therapy - Brain questionnaire
timeFrame: 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
measure: Progression-free survival
timeFrame: From date of biopsy-confirmed diagnosis to date of first documented progression, whichever came first, up to 33 weeks
measure: Overall survival
timeFrame: From date of biopsy-confirmed diagnosis to date of death from any cause, whichever came first, up to 33 weeks
Other outcomes:
Locations:
city: Hamilton
country: New Zealand
facility: Waikato Hospital
state: Waikato
Study officials:
affiliation: Waikato Hospital
name: Matthew CL Phillips, FRACP
role: PRINCIPAL_INVESTIGATOR
References: