Clinical trial NCT04477200: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Recurrent Glioblastoma
Recurrent Gliosarcoma
Recurrent Astrocytoma, Grade IV
Newly Diagnosed Glioblastoma
Newly Diagnosed Gliosarcoma
Newly Diagnosed Astrocytoma, Grade IV
Keywords: recurrent Glioblastoma
recurrent Gliosarcoma
newly diagnosed Glioblastoma
newly diagnosed Gliosarcooma
Recurrent Astrocytoma, Grade IV
Newly Diagnosed Astrocytoma, Grade IV
Lead sponsor: University of Michigan Rogel Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2020-07-20
Enrollment: 68
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Phase 0 will include 8 participants; eligible participants from phase 0 may continue on to phase 1.
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Concentration of mycophenolic acid (MPA) in tumor tissue in Phase 0 participants
timeFrame: At 1 week
measure: Number of recurrent phase 1 participants who experience dose-limiting toxicities (DLTs) at each dose level
timeFrame: Up to 28 days following completion of MMF + RT (up to ~9 weeks)
measure: Number of newly diagnosed phase 1 participants who experience dose-limiting toxicities (DLTs) at each dose level -- DLT1 period
timeFrame: Up to 28 days following completion of MMF + RT + TMZ (up to ~11 weeks)
measure: Number of newly diagnosed phase 1 participants who experience dose-limiting toxicities (DLTs) at each dose level -- DLT2 period
timeFrame: During the first 2 cycles (8 weeks) of MMF with adjuvant TMZ (up to ~19 weeks)
Secondary outcomes:
measure: Concentrations of guanosine triphosphate (GTP) in tumor tissue in Phase 0 participants
timeFrame: After one week of MMF administration
measure: Adverse events associated with treatment in all Phase 1 Participants
timeFrame: Up to 28 days following completion of MMF + RT (up to ~9 weeks)
measure: Adverse events associated with treatment in newly diagnosed phase 1 participants
timeFrame: Up to 28 days following completion of MMF with adjuvant temozolomide (up to ~15 months)
measure: Overall Response Rate in phase 1 participants with recurrent GBM/GS
timeFrame: Until study stops or death; up to approximately 3 years.
measure: Median Progression Free Survival (PFS) in phase 1 participants with recurrent GBM/GS
timeFrame: Until study stops or death; up to approximately 3 years.
measure: Median Freedom from Local Progression (FFLP) in phase 1 participants with recurrent GBM/GS
timeFrame: Until study stops or death; up to approximately 3 years.
measure: Median Overall Survival (OS) in phase 1 participants with recurrent GBM/GS
timeFrame: Until study stops or death; up to approximately 3 years.
Other outcomes:
Locations:
city: Ann Arbor
country: United States
facility: University of Michigan Rogel Cancer Center
state: Michigan
Study officials:
affiliation: University of Michigan Rogel Cancer Center
name: Nathan Clarke, MD
role: PRINCIPAL_INVESTIGATOR
References: