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

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Recurrent Glioblastoma; Recurrent Gliosarcoma; Recurrent Astrocytoma, Grade IV; Newly Diagnosed Glioblastoma; Newly Diagnosed Gliosarcoma; Newly Diagnosed Astrocytoma, Grade IV	Drug: Mycophenolate Mofetil; Radiation: Radiation Therapy; Procedure: Re-resection (as part of standard of care); Drug: Temozolomide	Phase 1

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 68 participants
• 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
• Official Title: Phase 0/I Dose Escalation Study of Mycophenolate Mofetil Combined With Radiation Therapy in Glioblastoma
• Actual Study Start Date: August 5, 2020
• Estimated Primary Completion Date: October 2024
• Estimated Study Completion Date: October 2027

Arms and Interventions

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 Name: MMF; Procedure: Re-resection (as part of standard of care); Re-resection or biopsy of tumor as part of standard of care
Experimental: Phase 1 - Recurrent GBM / GS; Mycophenolate mofetil; radiation therapy	Radiation: Radiation Therapy; 40.5 Gy in 15 fractions; Other Name: RT; Drug: Mycophenolate Mofetil; 250-2000mg orally twice daily, one week prior to and concurrent with RT.; Other Name: MMF
Experimental: Phase 1 - Newly Diagnosed GBM / GS; Mycophenolate mofetil; radiation therapy; temozolomide	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 and cyclic chemotherapy with temozolomide.; Other Name: MMF; Radiation: Radiation Therapy; 60 Gy in 30 fractions; Other Name: RT

Outcome Measures

Primary Outcome Measures :

1. 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.

2. 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.

3. 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.

4. 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.

Secondary Outcome Measures :

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, Michigan

University of Michigan Rogel Cancer Center; Recruiting

Ann Arbor, Michigan, United States, 48109

Contact: Cancer AnswerLine 800-865-1125 CancerAnswerLine@med.umich.edu

Principal Investigator: Yoshie Umemura, M.D.

Sponsors and Collaborators

University of Michigan Rogel Cancer Center

National Cancer Institute (NCI)

Investigators

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

More Information

• Responsible Party: University of Michigan Rogel Cancer Center
• ClinicalTrials.gov Identifier: NCT04477200
• Other Study ID Numbers: UMCC 2019.192; HUM00175785 ( Other Identifier: University of Michigan ); R37CA258346 ( U.S. NIH Grant/Contract )
• First Posted: July 20, 2020
• Last Update Posted: July 11, 2022
• Last Verified: July 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Keywords provided by University of Michigan Rogel Cancer Center:

recurrent Glioblastoma; recurrent Gliosarcoma; newly diagnosed Glioblastoma; newly diagnosed Gliosarcooma; Recurrent Astrocytoma, Grade IV; Newly Diagnosed Astrocytoma, Grade IV

Additional relevant MeSH terms:

Glioblastoma; Astrocytoma; Gliosarcoma; Recurrence; Disease Attributes; Pathologic Processes; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Mycophenolic Acid; Temozolomide; Antibiotics, Antineoplastic; Antineoplastic Agents; Antibiotics, Antitubercular; Antitubercular Agents; Anti-Bacterial Agents; Anti-Infective Agents; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Alkylating; Alkylating Agents