Mycophenolate Mofetil Combined With Radiation Therapy in Glioblastoma

• ClinicalTrials.gov Identifier: NCT04477200
• Recruitment Status: Recruiting
• First Posted: July 20, 2020
• Last Update Posted: July 11, 2022
• Sponsor: University of Michigan Rogel Cancer Center
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): University of Michigan Rogel Cancer Center

Tracking Information

• First Submitted Date: July 14, 2020
• First Posted Date: July 20, 2020
• Last Update Posted Date: July 11, 2022
• Actual Study Start Date: August 5, 2020
• Estimated Primary Completion Date: October 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 10, 2022)

• Concentration of mycophenolic acid (MPA) in tumor tissue in Phase 0 participants [ Time Frame: At 1 week ]
  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.
• Number of recurrent phase 1 participants who experience dose-limiting toxicities (DLTs) at each dose level [ Time Frame: Up to 28 days following completion of MMF + RT (up to ~9 weeks) ]
  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.
• Number of newly diagnosed phase 1 participants who experience dose-limiting toxicities (DLTs) at each dose level -- DLT1 period [ Time Frame: Up to 28 days following completion of MMF + RT + TMZ (up to ~11 weeks) ]
  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.
• Number of newly diagnosed phase 1 participants who experience dose-limiting toxicities (DLTs) at each dose level -- DLT2 period [ Time Frame: During the first 2 cycles (8 weeks) of MMF with adjuvant TMZ (up to ~19 weeks) ]
  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.

Original Primary Outcome Measures (submitted: July 14, 2020)

• Phase 0: Concentration of mycophenolic acid (MPA) in tumor tissue [ Time Frame: After one week of MMF administration ]
  The concentration of MPA (the active metabolite of mycophenolate mofetil [MMF]) in tumor tissue, measured by mass spectrometry on a continuous scale.
• Phase 1: Number of participants who experience dose-limiting toxicities (DLTs) at each dose level [ Time Frame: Up to 28 days following completion of radiation and MMF ]
  DLT defined per protocol and assessed per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0

Current Secondary Outcome Measures (submitted: January 10, 2022)

• Concentrations of guanosine triphosphate (GTP) in tumor tissue in Phase 0 participants [ Time Frame: After one week of MMF administration ]
  The concentrations of GTP in tumor tissue, measured by mass spectrometry on a continuous scale. This measure includes all phase 0 participants.
• Adverse events associated with treatment in all Phase 1 Participants [ Time Frame: Up to 28 days following completion of MMF + RT (up to ~9 weeks) ]
  Toxicities at each dose level will be tabulated, categorized by grade and attribution. This measure includes all phase 1 participants.
• Adverse events associated with treatment in newly diagnosed phase 1 participants [ Time Frame: Up to 28 days following completion of MMF with adjuvant temozolomide (up to ~15 months) ]
  Toxicities at each dose level will be tabulated, categorized by grade and attribution. This measure includes only newly diagnosed phase 1 participants.
• Overall Response Rate in phase 1 participants with recurrent GBM/GS [ Time Frame: Until study stops or death; up to approximately 3 years. ]
  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.
• Median Progression Free Survival (PFS) in phase 1 participants with recurrent GBM/GS [ Time Frame: Until study stops or death; up to approximately 3 years. ]
  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.
• Median Freedom from Local Progression (FFLP) in phase 1 participants with recurrent GBM/GS [ Time Frame: Until study stops or death; up to approximately 3 years. ]
  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.
• Median Overall Survival (OS) in phase 1 participants with recurrent GBM/GS [ Time Frame: Until study stops or death; up to approximately 3 years. ]
  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.

Original Secondary Outcome Measures (submitted: July 14, 2020)

• Phase 0: Concentrations of guanosine triphosphate (GTP) in tumor tissue [ Time Frame: After one week of MMF administration ]
  The concentrations of GTP in tumor tissue, measured by mass spectrometry on a continuous scale.
• Phase 0: Concentrations of guanosine triphosphate (GTP) in plasma [ Time Frame: After one week of MMF administration ]
  The concentrations of GTP in plasma, measured by mass spectrometry on a continuous scale.
• Phase 1: Adverse events associated with MMF + re-irradiation [ Time Frame: Up to 28 days following completion of radiation and MMF ]
  Toxicities at each dose level will be tabulated, categorized by grade and attribution.
• Phase 1: Overall Response Rate [ Time Frame: Until study stops or death; up to approximately 3 years. ]
  Determined by standard Response Assessment for Neuro-Oncology (RANO) criteria. The number and proportion of patients wtih progressive disease, stable disease, partial and complete response will be calculated for each dose level and overall.
• Phase 1: Median Progression Free Survival (PFS) [ Time Frame: Until study stops or death; up to approximately 3 years. ]
  PFS defined as time from date of registration to the date of documented progressive disease, other disease related therapy or death. Determined by standard RANO criteria
• Phase 1: Median Freedom from Local Progression (FFLP) [ Time Frame: Until study stops or death; up to approximately 3 years. ]
  FFLP defined as time from date of registration to the date of documented local progressive disease. Determined by standard RANO criteria
• Phase 1: Median Overall Survival (OS) [ Time Frame: Until study stops or death; up to approximately 3 years. ]
  OS defined as time from date of registration to date of death or last follow up.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Mycophenolate Mofetil Combined With Radiation Therapy in Glioblastoma
• Official Title: Phase 0/I Dose Escalation Study of Mycophenolate Mofetil Combined With Radiation Therapy in Glioblastoma
• Brief Summary: 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.
• 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
• Study Phase: Phase 1

Study Design

Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

Phase 0 will include 8 participants; eligible participants from phase 0 may continue on to phase 1.

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

• Recurrent Glioblastoma
• Recurrent Gliosarcoma
• Recurrent Astrocytoma, Grade IV
• Newly Diagnosed Glioblastoma
• Newly Diagnosed Gliosarcoma
• Newly Diagnosed Astrocytoma, Grade IV

Intervention

• 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 Name: MMF
• Radiation: Radiation Therapy
  40.5 Gy in 15 fractions
  Other Name: RT
• Procedure: Re-resection (as part of standard of care)
  Re-resection or biopsy of tumor as part of standard of care
• 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 Name: TMZ
• Drug: Mycophenolate Mofetil
  250-2000mg orally twice daily, one week prior to and concurrent with RT.
  Other Name: MMF
• Drug: Mycophenolate Mofetil
  250-2000mg orally twice daily, one week prior to and concurrent with RT and cyclic chemotherapy with temozolomide.
  Other Name: MMF
• Radiation: Radiation Therapy
  60 Gy in 30 fractions
  Other Name: RT

Study Arms

• Experimental: Phase 0 - Recurrent glioblastoma (GBM) / gliosarcoma (GS)
  Mycophenolate mofetil
  Interventions:

  • Drug: Mycophenolate Mofetil
  • Procedure: Re-resection (as part of standard of care)
• Experimental: Phase 1 - Recurrent GBM / GS
  Mycophenolate mofetil; radiation therapy
  Interventions:

  • Radiation: Radiation Therapy
  • Drug: Mycophenolate Mofetil
• Experimental: Phase 1 - Newly Diagnosed GBM / GS
  Mycophenolate mofetil; radiation therapy; temozolomide
  Interventions:

  • Drug: Temozolomide
  • Drug: Mycophenolate Mofetil
  • Radiation: Radiation Therapy

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: January 10, 2022): 68
• Original Estimated Enrollment (submitted: July 14, 2020): 38
• Estimated Study Completion Date: October 2027
• Estimated Primary Completion Date: October 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04477200
• Other Study ID Numbers: UMCC 2019.192; HUM00175785 ( Other Identifier: University of Michigan ); R37CA258346 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: University of Michigan Rogel Cancer Center
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Michigan Rogel Cancer Center
• Original Study Sponsor: Same as current
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: Yoshie Umemura, MD; University of Michigan Rogel Cancer Center

• PRS Account: University of Michigan Rogel Cancer Center
• Verification Date: July 2022