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Targeting Pediatric Brain Tumors With Sodium Glucose Cotransporter 2 Inhibitors (SGLT2i)

Primary Purpose

Pediatric Brain Tumor

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Dapagliflozin
Carmustine
Sponsored by
Washington University School of Medicine
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pediatric Brain Tumor

Eligibility Criteria

6 Years - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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 between 6 and 21 years old (inclusive)
  • 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 legal guardian/legally authorized representative, if applicable).

Exclusion Criteria:

  • Current or previous treatment with SGLT2i or thiazolidinedione.
  • Current use of high dose dexamethasone (exceeding 4 mg/day). Seven days prior to start of dapagliflozin and carmustine, patients receiving dexamethasone must be on a stable or decreasing dose (≤ 0.1 mg/kg/day or maximum 4 mg/day). Note that it is preferred that patients not be on dexamethasone during the study.
  • A history of other malignancy with the exceptions of malignancies for which all treatment was completed at least 2 years before registration with no evidence of disease and locally treated skin squamous or basal cell carcinoma.
  • Type 1 diabetes or current insulin treatment.
  • History of stroke or transient ischemic attack (in the last 5 years).
  • HbA1c > 8.5%. The rationale is that this is the level that would require addition of insulin. However, insulin use is excluded in this study due to the increased risk of ketoacidosis.
  • Currently receiving any other investigational agents.
  • A history of allergic reactions attributed to compounds of similar chemical or biologic composition to dapagliflozin, carmustine or other agents used in the study.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, peripheral arterial disease, ketoacidosis, severe kidney disease (estimated glomerular filtration rate eGFR < 30 mL/min/1.73m2), symptomatic hypotension, and chronic/frequent urinary tract infections or yeast infections.
  • Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of study entry.
  • Patients with HIV are eligible unless their CD4+ T-cell counts are < 350 cells/mcL or they have a history of AIDS-defining opportunistic infection within the 12 months prior to registration. Concurrent treatment with effective ART according to DHHS treatment guidelines is recommended.

Sites / Locations

  • Washington University School of MedicineRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Dapagliflozin + Standard of Care carmustine chemotherapy (Ages 6-10)

Dapagliflozin + Standard of Care carmustine chemotherapy (Ages 11-21)

Arm Description

Dapagliflozin will be initiated by mouth once daily at the same time as standard of care carmustine chemotherapy. Dapagliflozin 5 mg by mouth once daily on days 1-84 (duration of study) All patients will stop taking dapagliflozin after 12 weeks of treatment, corresponding to 2 cycles of carmustine. Carmustine chemotherapy dose adjustments will be made per oncologist's judgement.

Dapagliflozin will be initiated by mouth once daily at the same time as standard of care carmustine chemotherapy. Dapagliflozin will be initiated at 5 mg by mouth once caily, days 1-4 (2 weeks) Dapagliflozin will be escalated to 10 mg by mouth once daily for the remaining 10 weeks Dose adjustment will need to be approved by endocrinologist Dr. Sprague/or another attending MD diabetologist at SLCH/WUSM on the HRPO-approved study team. This dose is reflective of current clinical practice for diabetes and heart failure. All patients will stop taking dapagliflozin after 12 weeks of treatment, corresponding to 2 cycles of carmustine. Carmustine chemotherapy dose adjustments will be made per oncologist's judgment.

Outcomes

Primary Outcome Measures

Number and type of adverse events experienced by participants
-Adverse events will be graded by CTCAE (version 5.0).

Secondary Outcome Measures

Change in blood glucose
Change in ketones
Change in HbA1c
Tumor response rate
Tumor response will be evaluated using the updated response assessment criteria for high-grade gliomas: Response Assessment in Neuro-Oncology (RANO) working group guideline. Tumor response rate = number of participants with complete or partial response.
Feasibility of regimen
-Feasibility is defined as the successful enrollment of a total of 20 evaluable patients to the study within 3 years and the optimal dose of dapagliflozin is at least 5 mg.
Changes in fructosamine
Changes in c-peptide
Changes in glucagon

Full Information

First Posted
August 26, 2022
Last Updated
April 4, 2023
Sponsor
Washington University School of Medicine
Collaborators
Children's Discovery Institute
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1. Study Identification

Unique Protocol Identification Number
NCT05521984
Brief Title
Targeting Pediatric Brain Tumors With Sodium Glucose Cotransporter 2 Inhibitors (SGLT2i)
Official Title
Targeting Pediatric Brain Tumors With Sodium Glucose Cotransporter 2 Inhibitors (SGLT2i)
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Recruiting
Study Start Date
April 3, 2023 (Actual)
Primary Completion Date
August 31, 2026 (Anticipated)
Study Completion Date
November 30, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Washington University School of Medicine
Collaborators
Children's Discovery Institute

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a longitudinal, dose-finding, open label safety and tolerability phase Ib treatment study. The study hypothesis is that dapagliflozin will be well-tolerated by brain tumor patients on chemotherapy as assessed by tolerability and side effect profiles.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pediatric Brain Tumor

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
20 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Dapagliflozin + Standard of Care carmustine chemotherapy (Ages 6-10)
Arm Type
Experimental
Arm Description
Dapagliflozin will be initiated by mouth once daily at the same time as standard of care carmustine chemotherapy. Dapagliflozin 5 mg by mouth once daily on days 1-84 (duration of study) All patients will stop taking dapagliflozin after 12 weeks of treatment, corresponding to 2 cycles of carmustine. Carmustine chemotherapy dose adjustments will be made per oncologist's judgement.
Arm Title
Dapagliflozin + Standard of Care carmustine chemotherapy (Ages 11-21)
Arm Type
Experimental
Arm Description
Dapagliflozin will be initiated by mouth once daily at the same time as standard of care carmustine chemotherapy. Dapagliflozin will be initiated at 5 mg by mouth once caily, days 1-4 (2 weeks) Dapagliflozin will be escalated to 10 mg by mouth once daily for the remaining 10 weeks Dose adjustment will need to be approved by endocrinologist Dr. Sprague/or another attending MD diabetologist at SLCH/WUSM on the HRPO-approved study team. This dose is reflective of current clinical practice for diabetes and heart failure. All patients will stop taking dapagliflozin after 12 weeks of treatment, corresponding to 2 cycles of carmustine. Carmustine chemotherapy dose adjustments will be made per oncologist's judgment.
Intervention Type
Drug
Intervention Name(s)
Dapagliflozin
Intervention Description
Commercially available
Intervention Type
Drug
Intervention Name(s)
Carmustine
Intervention Description
Standard of care
Primary Outcome Measure Information:
Title
Number and type of adverse events experienced by participants
Description
-Adverse events will be graded by CTCAE (version 5.0).
Time Frame
From start of treatment through 30 days after last day of dapagliflozin treatment (estimated to be 4 months)
Secondary Outcome Measure Information:
Title
Change in blood glucose
Time Frame
From baseline through end of treatment (estimated to be 3 months)
Title
Change in ketones
Time Frame
From baseline through end of treatment (estimated to be 3 months)
Title
Change in HbA1c
Time Frame
From baseline through end of treatment (estimated to be 3 months)
Title
Tumor response rate
Description
Tumor response will be evaluated using the updated response assessment criteria for high-grade gliomas: Response Assessment in Neuro-Oncology (RANO) working group guideline. Tumor response rate = number of participants with complete or partial response.
Time Frame
From pre-therapy to post-12 weeks of therapy
Title
Feasibility of regimen
Description
-Feasibility is defined as the successful enrollment of a total of 20 evaluable patients to the study within 3 years and the optimal dose of dapagliflozin is at least 5 mg.
Time Frame
Through completion of treatment for all enrolled patients (estimated to be 39 months)
Title
Changes in fructosamine
Time Frame
From baseline through end of treatment (estimated to be 3 months)
Title
Changes in c-peptide
Time Frame
From baseline through end of treatment (estimated to be 3 months)
Title
Changes in glucagon
Time Frame
From baseline through end of treatment (estimated to be 3 months)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
6 Years
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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 between 6 and 21 years old (inclusive) 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 legal guardian/legally authorized representative, if applicable). Exclusion Criteria: Current or previous treatment with SGLT2i or thiazolidinedione. Current use of high dose dexamethasone (exceeding 4 mg/day). Seven days prior to start of dapagliflozin and carmustine, patients receiving dexamethasone must be on a stable or decreasing dose (≤ 0.1 mg/kg/day or maximum 4 mg/day). Note that it is preferred that patients not be on dexamethasone during the study. A history of other malignancy with the exceptions of malignancies for which all treatment was completed at least 2 years before registration with no evidence of disease and locally treated skin squamous or basal cell carcinoma. Type 1 diabetes or current insulin treatment. History of stroke or transient ischemic attack (in the last 5 years). HbA1c > 8.5%. The rationale is that this is the level that would require addition of insulin. However, insulin use is excluded in this study due to the increased risk of ketoacidosis. Currently receiving any other investigational agents. A history of allergic reactions attributed to compounds of similar chemical or biologic composition to dapagliflozin, carmustine or other agents used in the study. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, peripheral arterial disease, ketoacidosis, severe kidney disease (estimated glomerular filtration rate eGFR < 30 mL/min/1.73m2), symptomatic hypotension, and chronic/frequent urinary tract infections or yeast infections. Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of study entry. Patients with HIV are eligible unless their CD4+ T-cell counts are < 350 cells/mcL or they have a history of AIDS-defining opportunistic infection within the 12 months prior to registration. Concurrent treatment with effective ART according to DHHS treatment guidelines is recommended.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Andrew Cluster, M.D.
Phone
314-273-1451
Email
acluster@wustl.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Andrew Cluster, M.D.
Organizational Affiliation
Washington University School of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Andrew Cluster, M.D.
Phone
314-273-1451
Email
acluster@wustl.edu
First Name & Middle Initial & Last Name & Degree
Andrew Cluster, M.D.
First Name & Middle Initial & Last Name & Degree
Joseph Ippolito, M.D., Ph.D.
First Name & Middle Initial & Last Name & Degree
Jennifer Sprague, M.D., Ph.D.
First Name & Middle Initial & Last Name & Degree
Linda Peterson, M.D.
First Name & Middle Initial & Last Name & Degree
Jingqin (Rosy) Luo, Ph.D.

12. IPD Sharing Statement

Plan to Share IPD
No
Links:
URL
http://www.siteman.wustl.edu
Description
Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Learn more about this trial

Targeting Pediatric Brain Tumors With Sodium Glucose Cotransporter 2 Inhibitors (SGLT2i)

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