Sitagliptin in Recurrent/Progressive Grade 4 Glioma

Targeting Myeloid-Derived Suppressor Cells in Patients With Recurrent/Progressive Grade 4 Glioma: Phase 1 Trial of Sitagliptin

Sitagliptin, when combined with standard-of-care drug bevacizumab, is being tested to 1) find out if it is effective at treating gliomas that have returned or progressed after treatment, and 2) find out what the highest dose of sitagliptin is appropriate to give when combined with bevacizumab.

Study Overview

• Status: Not yet recruiting
• Conditions: Glioma; Glioblastoma; Recurrent Glioblastoma; Recurrent Glioma; Grade 4 Malignant Glioma of Brain (Disorder)
• Intervention / Treatment: Drug: Sitagliptin; Biological: Bevacizumab

Detailed Description

In this Phase I trial, it is proposed that sitagliptin will be used to inhibit Myeloid Derived Suppressor Cells (MDSCs) in recurrent Glioblastoma (GBM). As this trial designed is for patients with recurrent GBM, patients will receive standard of care, bevacizumab, in addition to sitagliptin. The goal of this trial is to provide the proof of concept that suppressing MDSCs via sitagliptin is safe and feasible in patients with recurrent GBMs.

In the Phase Ib component, a standard 3+3 design and dose de-escalation will be used to determine the maximal tolerated dose (MTD) of sitagliptin in combination with bevacizumab in non-surgical patients with recurrent GBM.

After completion of the Phase Ib part, the study will proceed to the pilot phase. In the pilot phase component, 12 patients with recurrent GBM, who will receive pre-operative treatment with sitagliptin for at least 5 days at the MTD determined in phase 1b, will be enrolled. These patients will then undergo surgical resection of the tumor. All patients will receive postoperative sitagliptin in addition to standard-of-care bevacizumab. Tumor tissue will undergo dissociation and single-cell sequencing, immune profiling, and whole genome sequencing. The goal of the pilot phase is to obtain preliminary evidence demonstrating a reduction in the concentration of circulating MDSCs after the treatment of sitagliptin and to provide preliminary evidence of sitagliptin in reducing infiltrating MDSCs in the GBM tumor microenvironment. Patients will have their steroid dosing reduced to the equivalence of 4 mg dexamethasone per day or lower for at least 5 days prior to preoperative sitagliptin.

• Study Type: Interventional
• Enrollment (Estimated): 45
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Kailin Yang, MD, PhD; Phone Number: +1 319 356 3630; Email: kailin-yang@uiowa.edu

Study Locations

• United States
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Health Care
      • Contact: Kailin Yang, MD, PhD; Phone Number: +1 319 356 3630; Email: kailin-yang@uiowa.edu
      • Principal Investigator: Kailin Yang, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Phase 1b

• Subjects must have histologically or cytologically confirmed WHO grade 4 glioma for which disease recurrence/progression is diagnosed by the treating physician.
• Subjects must not have received sitagliptin or bevacizumab for this disease.
• Age >18 years
• Performance status: ECOG performance status 0-2

• Subjects must have adequate organ function and laboratory parameters within 21 days of study entry as defined below:

  1. Hemoglobin ≥ 9 g/dl
  2. Absolute neutrophil count ≥ 1,500/mcL
  3. Platelet count ≥ 100,000/mcL
  4. Total bilirubin < 1.5 x institutional upper limit of normal (ULN)
  5. AST (SGOT) ≤ 3 X institutional ULN
  6. ALT (SGPT) ≤ 3 X institutional ULN
  7. Calculated creatinine clearance > 50 mL/min
  8. Urine protein screened by urine analysis for urine protein creatinine (UPC) ratio. For UPC ratio > 0.5, 24-hour urine protein must be obtained and must be < 1000 mg.

  9. Patients on full-dose anticoagulants (e.g., warfarin or LMW heparin) must meet both of the following criteria:

     • No active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices)
     • In-range INR (between 2 and 3) on a stable dose of oral anticoagulant or on a stable dose of low molecular weight heparin
• Subjects must have the ability to understand and the willingness to sign a written informed consent document.
• Women of childbearing potential must have a negative pregnancy test within 7 days prior to treatment start. Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and through 30 days after the last dose of study drug. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and through 30 days after the last dose of study drug.
• Subjects must be able to swallow whole tablets.
• Participants must have controlled blood pressure, defined as systolic blood pressure ≤ 160 mg Hg or diastolic pressure ≤ 100 mg Hg, with or without antihypertensive therapy
• Electrocardiogram without evidence of acute cardiac ischemia within 14 days prior study registration

• Subjects must have the following minimum intervals from prior treatments:

  • surgery - 4 weeks
  • nitrosoureas - 6 weeks
  • cytotoxic chemotherapy - standard intervals depending on the most recent regimen. i.e., for temozolomide 5 of 28, 23 days after most recent temozolomide; for temozolomide 21 of 28 days, 7 days after most recent dose; etoposide 14 of 21 days, 7 days after last dose.
  • For drugs not listed, the research nurse, treating investigator, and principal investigator will determine the appropriate interval.
  • Investigational therapy or non-cytotoxic therapy - 2 weeks
  • For bevacizumab - 4 weeks from the expected date of protocol surgery
• Subject is not deemed as a surgical candidate.

Pilot Phase

• Subjects must have histologically or cytologically confirmed WHO grade 4 glioma for which disease recurrence/progression is diagnosed by the treating physician.
• Subjects must not have received sitagliptin or bevacizumab for this disease.
• Age >18 years
• Performance status: ECOG performance status 0-2

• Subjects must have adequate organ function and laboratory parameters within 21 days of study entry as defined below:

  1. Hemoglobin ≥ 9 g/dl
  2. Absolute neutrophil count ≥ 1,500/mcL
  3. Platelet count ≥ 100,000/mcL
  4. Total bilirubin < 1.5 x institutional upper limit of normal (ULN)
  5. AST (SGOT) ≤ 3 X institutional ULN
  6. ALT (SGPT) ≤ 3 X institutional ULN
  7. Calculated creatinine clearance > 50 mL/min
  8. Urine protein screened by urine analysis for urine protein creatinine (UPC) ratio. For UPC ratio > 0.5, 24-hour urine protein must be obtained and must be < 1000 mg.

  9. Patients on full-dose anticoagulants (e.g., warfarin or LMW heparin) must meet both of the following criteria:

     • No active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices)
     • In-range INR (between 2 and 3) on a stable dose of oral anticoagulant or on a stable dose of low molecular weight heparin
• Subjects must have the ability to understand and the willingness to sign a written informed consent document.
• Women of childbearing potential must have a negative pregnancy test within 7 days of treatment start. Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and through 30 days after the last dose of study drug. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and through 30 days after the last dose of study drug.
• Subjects must be able to swallow whole tablets.
• Subjects must have controlled blood pressure, defined as systolic blood pressure ≤ 160 mg Hg or diastolic pressure ≤ 100 mg Hg, with or without antihypertensive therapy
• Electrocardiogram without evidence of acute cardiac ischemia within 14 days prior to treatment start

• Subjects must have the following minimum intervals from prior treatments:

  • surgery - 4 weeks
  • nitrosoureas - 6 weeks
  • cytotoxic chemotherapy - standard intervals depending on the most recent regimen. i.e., for temozolomide 5 of 28, 23 days after most recent temozolomide; for temozolomide 21 of 28 days, 7 days after most recent dose; etoposide 14 of 21 days, 7 days after last dose.
  • For drugs not listed, the research nurse, treating investigator, and principal investigator will determine the appropriate interval.
  • Investigational therapy or non-cytotoxic therapy - 2 weeks
  • For bevacizumab - 4 weeks from the expected date of protocol surgery
• Subject is deemed as a surgical candidate.

Exclusion Criteria (for phase 1b and pilot phase)

The presence of any of the following will exclude a subject from study enrollment:

• Prior treatment toxicities not resolved to ≤ Grade 1 according to NCI CTCAE Version 5.0 except for alopecia and neuropathy.
• Subjects receiving any other investigational agents.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to sitagliptin, bevacizumab, or other chemotherapy agents.
• Subjects with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Known HIV-positive subjects on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with sitagliptin and/or bevacizumab. In addition, these subjects are at increased risk of lethal infections when treated with marrow suppressive therapy.
• Other malignancy within the past 2 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the cervix or vulva; c) prostate cancer of Gleason Score 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas.
• Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn's disease, malabsorption, or Grade ≥2 (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events Version 5.0 [CTCAE v.5.0] diarrhea of any etiology at screening).
• Known active infection with hepatitis B or hepatitis C virus.
• Pregnant or breastfeeding.
• Subjects who receive insulin or sulfonylurea for diabetes mellitus.
• Subjects with history of type 1 diabetes, uncontrolled type 2 diabetes, hypoglycemia requiring medical intervention, or those who are deemed not suitable to receive sitagliptin at the discretion of the investigators.
• Unable or unwilling to swallow tablets.
• Evidence of significant medical illness, abnormal laboratory finding, or psychiatric illness/social situations that would, in the Investigator's judgment, make the patient inappropriate for this study.
• Arterial ischemic event (e.g., unstable angina, myocardial infarction, stroke) within 6 months of study entry.
• Subjects with history of hematologic bleeding disorder.

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: Standard of care Bevacizumab in addition to Sitagliptin; Phase I: Bevacizumab in combination with Sitagliptin Phase Ib: a standard 3+3 design and dose de-escalation will be used to determine the maximal tolerated dose (MTD) of sitagliptin in combination with bevacizumab on non-surgical patients with recurrent GBM Pilot: 12 patients with recurrent GBM, will receive pre-operative treatment with sitagliptin for at least 5 days at the MTD determined in phase 1b. These patients will then undergo surgical resection of the tumor. All patients will receive postoperative sitagliptin in addition to standard-of-care bevacizumab

Drug: Sitagliptin; Sitagliptin, PO dose to be determined by Phase I dose de-escalation, cycle length 28 days. Treatment until progression.; Biological: Bevacizumab; Bevacizumab, IV, 10 mg/kg days 1 and 15 every 28 days, until progression.; Other Names: Avastin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase Ib: Dose-limiting toxicities as measured by CTCAE v5.0	A dose limiting toxicity (DLT) is defined as any of the following sitagliptin-related adverse event (AE) that occurs during the DLT period (first day of treatment through completion of cycle 2 of therapy; each cycle is 28 days), graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 5.0	First day of treatment through completion of cycle 2 of therapy (each cycle is 28 days)
Pilot: Change in participants' concentration of circulating MDSCs with treatment	A two-sided p-value for a test of the null hypothesis, that the ΔPost-Pre in MDSCs is equal to 0 versus the alternative, that it is not equal to 0, will be computed using a one-sample test. In addition, the mean and two-sided 95% confidence interval will be reported.	From pre- to post-treatment (end of post-op cycle 1; each cycle is 28 days).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-free survival (EFS)	Time from study treatment initiation to progression which precludes surgery, recurrence or death due to any cause	From study treatment initiation through three years
Overall survival (OS)	Time from study treatment initiation to death due to any cause	From study treatment initiation through three years

Collaborators and Investigators

• Sponsor: Kailin Yang, MD, PhD
• Investigators: Principal Investigator: Kailin Yang, MD, PhD, University of Iowa

Study record dates

Study Major Dates

• Study Start (Estimated): May 31, 2026
• Primary Completion (Estimated): May 1, 2029
• Study Completion (Estimated): May 1, 2030

Study Registration Dates

• First Submitted: April 10, 2026
• First Submitted That Met QC Criteria: April 16, 2026
• First Posted (Actual): April 21, 2026

Study Record Updates

• Last Update Posted (Actual): April 21, 2026
• Last Update Submitted That Met QC Criteria: April 16, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Astrocytoma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Glioma; Amino Acids, Peptides, and Proteins; Proteins; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azoles; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Pyrazines; Triazoles; Bevacizumab; Sitagliptin Phosphate
• Other Study ID Numbers: 202512310

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