Mycophenolate Mofetil Combined With Radiation Therapy in Glioblastoma

Phase 0/I Dose Escalation Study of Mycophenolate Mofetil Combined With Radiation Therapy in Glioblastoma

This is a phase 0/1 dose-escalation trial to determine the maximum tolerated dose of Mycophenolate Mofetil (MMF) when administered with radiation, in patients with glioblastoma or gliosarcoma.

Study Overview

• Status: Active, not recruiting
• Conditions: Recurrent Glioblastoma; Newly Diagnosed Glioblastoma; Recurrent Gliosarcoma; Recurrent Astrocytoma, Grade IV; Newly Diagnosed Gliosarcoma; Newly Diagnosed Astrocytoma, Grade IV
• Intervention / Treatment: Drug: Mycophenolate Mofetil; Procedure: Re-resection (as part of standard of care); Drug: Mycophenolate Mofetil; Drug: Mycophenolate Mofetil; Radiation: Radiation Therapy; Radiation: Radiation Therapy; Drug: Temozolomide

Detailed Description

The goal of the Phase 0 component is to determine if MMF achieves active concentrations in brain tumors. Eight participants in Phase 0 will receive MMF for one week before undergoing an already planned biopsy or re-resection (surgical removal) of glioblastoma or gliosarcoma (GBM/GS). A small portion of the tumor, removed as part of clinical care, will be used for testing in this study. Sixty additional participants will be enrolled in the Phase 1 component of the trial (30 with recurrent GBM/GS and 30 with newly diagnosed GBM/GS). The goal of the Phase 1 component is to find the dose of MMF that works best without causing severe side effects (the maximum tolerated dose) when combined with radiation in recurrent GBM/GS and with radiation and chemotherapy in newly diagnosed GBM/GS. Participants in Phase 0 who meet the eligibility criteria for the Phase 1 component may participate in both phases.

• Study Type: Interventional
• Enrollment (Actual): 68
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Rogel Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Glioblastoma or gliosarcoma (recurrent or newly diagnosed).
• Karnofsky Performance Status 60 or greater.
• Phase 0: Candidate for clinically indicated re-resection or biopsy of glioblastoma or gliosarcoma per treating physician(s).
• Phase 1, Recurrent: Candidate for clinically indicated re-irradiation of glioblastoma or gliosarcoma per treating physician(s) (No more than one prior course of radiation for GBM).
• Phase 1, Newly Diagnosed: Candidate for upfront standard of care chemoradiation for glioblastoma or gliosarcoma per treating physician(s), to start no earlier than 14 days post- operatively from last definitive surgery for glioblastoma or gliosarcoma (if more than one surgery done. Ex. biopsy prior to resection).
• ANC >=1,500 cells/mm^3 within 14 days prior to enrollment.
• Patient (men and childbearing age women) agrees to the use of highly effective contraception during study participation and for at least 6 weeks for female patients and 90 days for male patients after final MMF administration.
• Ability to understand and the willingness to sign a written informed consent.

Exclusion Criteria:

• Lack of histopathological diagnosis of the tumor.
• Gliomatosis cerebri pattern (tumor involving 3 or more lobes) of disease.
• Leptomeningeal disease.
• Use of bevacizumab within 8 weeks of study enrollment.
• Known history of HIV.
• Active hepatitis B or C infection.
• Active systemic or central nervous system (CNS) infection.
• Grade 4 lymphopenia (if ALC <0.5, patient must be on Pneumocystis jirovecii prophylaxis).
• Estimated CrCl < 25 ml/min.
• History of organ transplantation.
• Patients with known hypoxanthine-guanine phosphoribosyl-transferase deficiency.
• Serious intercurrent disease.
• History of allergic reaction or hypersensitivity to mycophenolate mofetil or mycophenolic acid or any component of the drug product; or medical contraindication for MMF per treating physician(s).
• Known immunosuppressive condition from autoimmune disease, immune deficiency syndrome, or chronic immunosuppressive therapy.
• Inability to undergo MRI brain with and without contrast.
• Pregnant or lactating women.
• Patients with known phenylketonuria.
• Phase 0: Patients undergoing biopsy who are deemed unlikely to have sufficient tissue to spare for research purposes (e.g., those whose tumors are in an eloquent brain location where all tissue taken must be used for diagnostic purposes).
• Phase I: Increase in steroid requirement within 7 days of study enrollment (stable or decreasing dose allowed).
• Phase I, Recurrent: Radiation within 6 months prior to study enrollment.
• Phase I, Recurrent: Surgery within 4 weeks of re-irradiation.
• Phase I, Newly Diagnosed: History of hypersensitivity reactions to temozolomide or any other ingredients in temozolomide and dacarbazine.
• Phase I, Newly Diagnosed: Prior chemotherapy or radiation therapy for glioblastoma or gliosarcoma.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 0 - Recurrent glioblastoma (GBM) / gliosarcoma (GS); Mycophenolate mofetil	Drug: Mycophenolate Mofetil; 500-2000mg orally twice daily, one week prior to re-resection (2 participants at each of 4 dose levels: 500mg, 1000mg, 1500mg and 2000mg); Other Names: MMF; Procedure: Re-resection (as part of standard of care); Re-resection or biopsy of tumor as part of standard of care; Drug: Mycophenolate Mofetil; 250-2000mg orally twice daily, one week prior to and concurrent with RT.; Other Names: MMF; Drug: Mycophenolate Mofetil; 250-2000mg orally twice daily, one week prior to and concurrent with RT and cyclic chemotherapy with temozolomide.; Other Names: MMF
Experimental: Phase 1 - Recurrent GBM / GS; Mycophenolate mofetil; radiation therapy	Drug: Mycophenolate Mofetil; 500-2000mg orally twice daily, one week prior to re-resection (2 participants at each of 4 dose levels: 500mg, 1000mg, 1500mg and 2000mg); Other Names: MMF; Drug: Mycophenolate Mofetil; 250-2000mg orally twice daily, one week prior to and concurrent with RT.; Other Names: MMF; Drug: Mycophenolate Mofetil; 250-2000mg orally twice daily, one week prior to and concurrent with RT and cyclic chemotherapy with temozolomide.; Other Names: MMF; Radiation: Radiation Therapy; 40.5 Gy in 15 fractions; Other Names: RT; Radiation: Radiation Therapy; 60 Gy in 30 fractions; Other Names: RT
Experimental: Phase 1 - Newly Diagnosed GBM / GS; Mycophenolate mofetil; radiation therapy; temozolomide	Drug: Mycophenolate Mofetil; 500-2000mg orally twice daily, one week prior to re-resection (2 participants at each of 4 dose levels: 500mg, 1000mg, 1500mg and 2000mg); Other Names: MMF; Drug: Mycophenolate Mofetil; 250-2000mg orally twice daily, one week prior to and concurrent with RT.; Other Names: MMF; Drug: Mycophenolate Mofetil; 250-2000mg orally twice daily, one week prior to and concurrent with RT and cyclic chemotherapy with temozolomide.; Other Names: MMF; Radiation: Radiation Therapy; 40.5 Gy in 15 fractions; Other Names: RT; Radiation: Radiation Therapy; 60 Gy in 30 fractions; Other Names: RT; Drug: Temozolomide; Temozolomide capsules are an approved oral chemotherapeutic drug for the treatment of adult patients with newly diagnosed GBM/GS concomitantly with radiotherapy and then as adjuvant treatment. The dosing and timing of temozolomide therapy will be determined as per standard-of-care for the individual patient by the treating oncologist.; Other Names: TMZ

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concentration of Mycophenolic Acid (MPA) in Tumor Tissue in Phase 0 Participants	The concentration of MPA (the active metabolite of mycophenolate mofetil [MMF]) in tumor tissue, measured by mass spectrometry on a continuous scale after one week of MMF administration. This measure includes all phase 0 participants.	At 1 week
Number of Recurrent Phase 1 Participants Who Experience Dose-limiting Toxicities (DLTs) at Each Dose Level	DLT will be defined based on the rate of drug related grade 3-5 adverse events experienced from the start of treatment with MMF and for up to 4 weeks after completion of MMF + radiation therapy (RT). Assessed using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. This measure includes only phase 1 participants with recurrent GBM/GS.	Up to 28 days following completion of MMF + RT (up to ~9 weeks)
Number of Newly Diagnosed Phase 1 Participants Who Experience Dose-limiting Toxicities (DLTs) at Each Dose Level -- DLT1 Period	DLT will be defined based on the rate of drug related grade 3-5 adverse events experienced from the start of treatment with MMF and for up to 4 weeks after completion of MMF + RT + TMZ. Assessed using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. This measure includes only newly diagnosed phase 1 participants.	Up to 28 days following completion of MMF + RT + TMZ (up to ~11 weeks)
Number of Newly Diagnosed Phase 1 Participants Who Experience Dose-limiting Toxicities (DLTs) at Each Dose Level -- DLT2 Period	DLT will be defined based on the rate of drug related grade 3-5 adverse events experienced during the first 2 cycles (8 weeks) of MMF with adjuvant TMZ. (The first cycle of MMF with adjuvant TMZ begins 28 days post-RT.) These will be assessed using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. This measure includes only newly diagnosed phase 1 participants.	During the first 2 cycles (8 weeks) of MMF with adjuvant TMZ (up to ~19 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concentrations of Guanosine Triphosphate (GTP) in Tumor Tissue in Phase 0 Participants	The concentrations of GTP in tumor tissue, measured by mass spectrometry on a continuous scale. This measure includes all phase 0 participants.	After one week of MMF administration
Adverse Events Associated With Treatment in All Phase 1 Participants	Toxicities at each dose level will be tabulated, categorized by grade and attribution. This measure includes all phase 1 participants.	Up to 28 days following completion of MMF + RT (up to ~9 weeks)
Adverse Events Associated With Treatment in Newly Diagnosed Phase 1 Participants	Toxicities at each dose level will be tabulated, categorized by grade and attribution. This measure includes only newly diagnosed phase 1 participants.	Up to 28 days following completion of MMF with adjuvant temozolomide (up to ~15 months)
Overall Response Rate in Phase 1 Participants With Recurrent GBM/GS	Determined by modified Response Assessment for Neuro-Oncology (mRANO) criteria. The number and proportion of patients with progressive disease, stable disease, partial and complete response will be calculated for each dose level and overall. This measure includes only phase 1 participants with recurrent GBM/GS.	Until study stops or death; up to approximately 3 years.
Median Progression Free Survival (PFS) in Phase 1 Participants With Recurrent GBM/GS	PFS defined as time from date of registration to the date of documented progressive disease, other disease related therapy or death. Determined by mRANO criteria. This measure includes only phase 1 participants with recurrent GBM/GS.	Until study stops or death; up to approximately 3 years.
Median Freedom From Local Progression (FFLP) in Phase 1 Participants With Recurrent GBM/GS	FFLP defined as time from date of registration to the date of documented local progressive disease. Determined by mRANO criteria. This measure includes only phase 1 participants with recurrent GBM/GS.	Until study stops or death; up to approximately 3 years.
Median Overall Survival (OS) in Phase 1 Participants With Recurrent GBM/GS	OS defined as time from date of registration to date of death or last follow up. Determined by Kaplan Meier method. This measure includes only phase 1 participants with recurrent GBM/GS.	Until study stops or death; up to approximately 3 years.

Collaborators and Investigators

• Sponsor: University of Michigan Rogel Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Nathan Clarke, MD, University of Michigan Rogel Cancer Center

Publications and helpful links

General Publications

• Zhao G, Newbury P, Ishi Y, Chekalin E, Zeng B, Glicksberg BS, Wen A, Paithankar S, Sasaki T, Suri A, Nazarian J, Pacold ME, Brat DJ, Nicolaides T, Chen B, Hashizume R. Reversal of cancer gene expression identifies repurposed drugs for diffuse intrinsic pontine glioma. Acta Neuropathol Commun. 2022 Oct 23;10(1):150. doi: 10.1186/s40478-022-01463-z.

Study record dates

Study Major Dates

• Study Start (Actual): August 5, 2020
• Primary Completion (Actual): January 6, 2025
• Study Completion (Estimated): November 5, 2027

Study Registration Dates

• First Submitted: July 14, 2020
• First Submitted That Met QC Criteria: July 14, 2020
• First Posted (Actual): July 20, 2020

Study Record Updates

• Last Update Posted (Actual): May 14, 2026
• Last Update Submitted That Met QC Criteria: April 22, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: recurrent Glioblastoma; recurrent Gliosarcoma; newly diagnosed Glioblastoma; newly diagnosed Gliosarcooma; Recurrent Astrocytoma, Grade IV; Newly Diagnosed Astrocytoma, Grade IV
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Gliosarcoma; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Therapeutics; Fatty Acids; Lipids; Azoles; Acids, Acyclic; Carboxylic Acids; Dacarbazine; Triazenes; Imidazoles; Caproates; Temozolomide; Mycophenolic Acid; Radiotherapy
• Other Study ID Numbers: UMCC 2019.192; HUM00175785 (Other Identifier: University of Michigan); R37CA258346 (U.S. NIH Grant/Contract)

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.: Yes