Therapeutic Targeting of Sex Differences in Pediatric Brain Tumor Glycolysis

The investigators will develop the concept of a sex-specific therapeutic intervention for gliomas that is based upon dietary carbohydrate restriction. The investigators will integrate metabolomics tools and FDG-PET imaging to validate the ketogenic diet on a sex-specific basis.

Study Overview

• Status: Terminated
• Conditions: Pediatric Brain Tumor
• Intervention / Treatment: Procedure: Ketogenic diet; Drug: BCNU

• Study Type: Interventional
• Enrollment (Actual): 2
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of a recurrent primary brain tumor with no curative therapy available.
• Measurable disease using pediatric Response Assessment in Neuro-Oncology Criteria (RANO) criteria.
• Life expectancy > 12 weeks
• Prior treatment with radiation alone, chemotherapy alone or combined radiation and chemotherapy is allowed.
• Patient is < 21 years of age

• Normal bone marrow and organ function as defined below:

  • Leukocytes ≥ 3,000/mcL
  • Absolute neutrophil count ≥ 1,500/mcl
  • Platelets ≥ 100,000/mcl
  • Total bilirubin ≤ 1.5 x IULN
  • AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN
  • Creatinine ≤ IULN OR creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal
  • Normal room air oxygenation must be documented. If room air oxygen saturation is less than 97%, a diffusion capacity of carbon monoxide (DLCO) of greater than 80%, must be demonstrated.
• Karnofsky or Lansky performance score of ≥ 60
• Patients of childbearing potential must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a female patient become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.
• Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).

Exclusion Criteria:

• Patient does not have any of the following conditions as they are contraindicated for ketogenic diet:

  • Primary and secondary carnitine deficiency
  • Carnitine palmitoyltransferase I or II deficiency
  • Carnitine translocase deficiency
  • Mitochondrial β-oxidation defects
  • Pyruvate carboxylase deficiency
  • Glycogen storage diseases
  • Ketolysis defects
  • Ketogenesis defects
  • Porphyria
  • Prolonged QT syndrome
  • Liver insufficiency
  • Renal insufficiency
  • Pancreatic insufficiency
  • Pulmonary insufficiency
  • Hyper insulinism
• Pregnant and/or breastfeeding. Female patients of childbearing potential must have a negative pregnancy test within 14 days of study entry.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Ketogenic Diet; Caregivers (and participating children) attend intro ketogenic diet class (4 - 30 min lectures); Clinic visit with neurologist, nurse, and dietitian prior to hospital admission and then once every 3 months; Laboratory studies prior to hospital admission and then at each follow-up visit; Hospital admission (3-5 day) to start the ketogenic diet; Standard of care chemotherapy with BCNU for up to 2 years; Ketogenic diet can continue for up to 2 years

Procedure: Ketogenic diet; Children under 2 years will immediately start on a full calorie classical 3:1 ketogenic diet. The 3:1 ratio indicates that the diet contains 3 g of fat for every 1 g of protein + carbohydrate, which results in about 87% of calories coming from fat.; Children 2 years or older will skip breakfast and lunch on the day of admission but start a full calorie 3:1 ketogenic diet at dinner.; Drug: BCNU; -Standard of care; Other Names: BiCNU; Carmustine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility of combining a ketogenic diet with chemotherapy in children with relapsed brain tumors as measured by the number of patients who can recruited with 3 years	The study will be defined as being feasible if all 15 patients can be recruited within 3 years; Please note that feasibility of the study is dependent on both primary outcome measures	Through completion of enrollment of all participants (estimated to be 3 years)
Feasibility of combining a ketogenic diet with chemotherapy in children with relapsed brain tumors as measured by if at least 80% of the patients comply with the intervention	-The study will be defined as being feasible if at least 80% of the patients comply with the intervention as defined as achieving 80% of the targeted level of ketosis as assessed from laboratory measures and 80% of the planned BCNU doses --Please note that feasibility of the study is dependent on both primary outcome measures	Up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tolerability of combining a ketogenic diet with chemotherapy in male children with relapsed brain tumors versus female children with relapsed brain tumors as measured by toxicity	All toxicities will be summarized by noting the count of participants who experience each toxicity; The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for all toxicity reporting.	Up to 2 years
Tumor response of male children with relapsed brain tumors to a ketogenic diet combined with chemotherapy versus female children with relapsed brain tumors as measured by progression-free survival (PFS)	PFS is defined as the duration of time from start of treatment to time of radiographic progression or death due to any cause, whichever occurs first.; Progression will be defined by the Response Assessment in Neuro-Oncology (RANO) working group guideline.	Up to 10 years

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Investigators: Principal Investigator: Andrew Cluster, M.D., Washington University School of Medicine

Publications and helpful links

Helpful Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2019
• Primary Completion (Actual): November 1, 2022
• Study Completion (Actual): November 1, 2022

Study Registration Dates

• First Submitted: June 20, 2018
• First Submitted That Met QC Criteria: July 18, 2018
• First Posted (Actual): July 19, 2018

Study Record Updates

• Last Update Posted (Estimate): December 12, 2022
• Last Update Submitted That Met QC Criteria: December 7, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms; Neoplasms by Site; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Carmustine
• Other Study ID Numbers: 201806141

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes