Ketogenic Diet as Adjunctive Treatment in Refractory/End-stage Glioblastoma Multiforme: a Pilot Study
Condition: Glioblastoma Multiforme
MeSH terms: Glioblastoma
Study type: Interventional
Phase: Phase 1

Summary: 
      The first weekly KD meal package will be given to the patient at the study site. The patient
      will be instructed in how to process the week-long meal plan package content. Participants
      will measure urine ketone bodies with Ketostix 2x day and blood for glucose and ketone levels
      using self-administered Precision Xtra® Meter (Abbot Diabetes Care, Alameda, CA, USA)
      starting with the first day of the diet. Self-administered blood checks for glucose and
      ketone bodies will be done in fasted state in the morning and 2 hours post-prandially in the
      evening. Participants will be seen on day 7 of treatment by the study nutritionist and a
      study investigator-physician (separately) to review possible AEs, and for further education
      about the diet. Study staff will review and evaluate the participant's method of urine ketone
      and blood glucose and ketone levels testing. Subsequently, participants will be seen at one,
      2 weeks, and 4 weeks after KG diet initiation, and then monthly. KD treatment will last until
      exit criteria are met or for 6 months, whichever comes first. Exit criteria are the primary
      outcome measures, the first of either (a) cerebral edema requiring steroid rescue therapy or
      (b) death.

      Treatment will occur in outpatient office setting at the Mid-Atlantic Epilepsy and Sleep
      Center, Bethesda, MD. The location of subsequent treatment administration may change to
      hospital setting at Holy Cross Hospital should a patient need hospitalization during the
      study for any reason, as determined by the patient's clinical care needs.
    

Detailed description: 
      Malignant gliomas are the most common type of brain tumor in adults. They are the second
      leading cause of cancer mortality in people under the age of 35 and the fourth leading cause
      in those under the age of 54. Standard therapy for glioblastoma multiforme (GBM) includes
      surgery followed by radiation and chemotherapy. Despite optimal treatment the prognosis
      remains poor. Patients with GBM have a median survival of approximately 10-15 months.
      Essentially all patients suffer recurrent disease, usually within 8 months of diagnosis. For
      patients with malignant glioma whose tumors recur, the median time to tumor progression is
      9-13 weeks with the current standard of treatment for recurrent glioblastoma, bevacizumab
      (AVASTIN®). There is an urgent need for more effective therapies.

      GBM cancer cells depend on glucose for energy supply and survival. When glucose levels are
      reduced, normal brain cells metabolize ketone bodies for energy. Brain tumor cells cannot do
      so. This makes the tumor cells vulnerable to death using therapies that target glucose
      metabolism. In brain cancer patients, high blood glucose levels are associated with reduced
      survival. In mice, reduction in circulating glucose levels through ketogenic diet (KD)
      reduces tumor growth

      Ketogenic diet (KD) reduces blood glucose levels while elevating levels of ketone bodies, and
      may thus be beneficial in the treatment of GBM as a non-toxic metabolic therapy. KD is a high
      fat, low carbohydrate diet used for treatment of refractory seizures. There have been two
      case reports of KD use in patients with GBM showing slowing of tumor progression.

      Ketogenic diet (KD) is a high fat, low protein, low carbohydrate diet that is an effective
      treatment of refractory epilepsy in children. The diet consists of long chain saturated
      triglycerides with a 3:1 or 4:1 [fat] : [protein + carbohydrate] ratio by weight, with 87-90%
      of calories derived from fat. The investigators have recently evaluated KD with caloric
      restriction of 1600 kcal /day in adults with refractory epilepsy. The diet was well
      tolerated. Side effects included mild nausea (n=2), mild diarrhea (n= 2), and mild
      constipation (n=2). No subjects stopped treatment because of side effects. Mild transient
      hunger was experienced by 3 subjects but there was no clinically significant hunger.

      The goal of the present study is to evaluate efficacy, safety and tolerability of 4:1 KD in a
      small number of patients with GBM progressing or recurring after standard treatment of
      surgery, radiation and chemotherapy with temozolamide and, after further rescue threrapy with
      bevacizumab (AVASTIN®), as the first step in evaluation of therapeutic potential of KD in the
      treatment of GBM. This will be a small, open label pilot study. 6 patients with GBM recurring
      or progressing after surgery, radiation and chemotherapy (temazolamide) and after further
      rescue treatment with bevacizumab will be treated with 4:1 [fat]:[protein+carbohydrate]
      ratio, 1600 kcal/day diet. Survival, time to steroid rescue treatment and progression free
      survival will be compared to historical controls with life expectancy of ≤ 3 months.

      The diet (KD) will consist of pre-made meals, including breakfast, lunch, dinner and two
      snacks, one each between breakfast and lunch and lunch and dinner, with a 2 week-long meal
      plan consisting of different recipes for each day of the month, with repeating 2-week-long
      cycles. The diet will be supplemented with vitamins, calcium and phosphorus supplements to
      meet the requirements of US Dietary Reference Intakes (DRI) standard. Treatment will last 6
      months. Primary aims of the study will be to (1) obtain pilot data on efficacy of ketogenic
      diet as adjunctive treatment of treatment-refractory glioblastoma multiforme, (2) evaluate
      the safety of ketogenic diet as adjunctive treatment of treatment-refractory glioblastoma
      multiforme, and (3) evaluate tolerability of ketogenic diet as adjunctive treatment of
      treatment-refractory glioblastoma multiforme.

      Participants will be evaluated in face-to face visit during weeks 1, 2 and 4 of the study,
      then monthly. Primary outcome measures will include (a) survival time and (b) time to
      dexamethasone rescue therapy for cerebral edema, determined by treating physician, and (c)
      adverse events. Secondary outcome measures will include MRI progression, treatment
      compliance, hunger scale scores, fasting serum glucose and BOH levels.
    

Intervention name(s): ketogenic diet
Intervention type(s): Other
Intervention description(s): Treatment will consist of ketogenic diet. KD will consist of 4:1 [fat] : [protein+carbohydrate] weight ratio with 1600 kcal restriction. The diet will be supplemented with vitamins, calcium, phosphorus, zinc and selenium supplements to meet the requirements of US Dietary Reference Intakes (DRI) standard.
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Glioblastoma multiforme, ketogenic diet, neoplasm