Mycophenolate Mofetil Combined With Radiation Therapy in Glioblastoma

Study Overview
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Brief Summary
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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
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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.

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

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

Intervention / Treatment
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* Drug: Mycophenolate Mofetil
* Radiation: Radiation Therapy
* Procedure: Re-resection (as part of standard of care)
* Drug: Temozolomide
* Drug: Mycophenolate Mofetil
* Drug: Mycophenolate Mofetil
* Radiation: Radiation Therapy


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Phase 0 will include 8 participants; eligible participants from phase 0 may continue on to phase 1.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 0 - Recurrent glioblastoma (GBM) / gliosarcoma (GS)<br>Mycophenolate mofetil | Drug: Mycophenolate Mofetil<br>* 500-2000mg orally twice daily, one week prior to re-resection (2 participants at each of 4 dose levels: 500mg, 1000mg, 1500mg and 2000mg)<br>* Other names: MMF;Procedure: Re-resection (as part of standard of care)<br>* Re-resection or biopsy of tumor as part of standard of care<br>|
| Experimental: Phase 1 - Recurrent GBM / GS<br>Mycophenolate mofetil; radiation therapy | Radiation: Radiation Therapy<br>* 40.5 Gy in 15 fractions<br>* Other names: RT;Drug: Mycophenolate Mofetil<br>* 250-2000mg orally twice daily, one week prior to and concurrent with RT.<br>* Other names: MMF;|
| Experimental: Phase 1 - Newly Diagnosed GBM / GS<br>Mycophenolate mofetil; radiation therapy; temozolomide | Drug: Temozolomide<br>* 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.<br>* Other names: TMZ;Drug: Mycophenolate Mofetil<br>* 250-2000mg orally twice daily, one week prior to and concurrent with RT and cyclic chemotherapy with temozolomide.<br>* Other names: MMF;Radiation: Radiation Therapy<br>* 60 Gy in 30 fractions<br>* Other names: RT;|

What is the study measuring?
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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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent Glioblastoma, recurrent Gliosarcoma, newly diagnosed Glioblastoma, newly diagnosed Gliosarcooma, Recurrent Astrocytoma, Grade IV, Newly Diagnosed Astrocytoma, Grade IV