Mycophenolate Mofetil Combined with Radiation Therapy for the Treatment of Recurrent Glioblastoma or Gliosarcoma
This early phase I/I trial evaluates how well mycophenolate mofetil combined with radiation therapy in treating patients with glioblastoma or gliosarcoma that has come back (recurrent). Mycophenolate mofetil may be used in combination with other medications to keep the body from attacking and rejecting a transplanted organ (such as a kidney, liver, heart). It belongs to a class of medications called immune-suppressants. It works by weakening the body's defense system (immune system) to help your body accept the new organ. Mycophenolate mofetil combined with radiation therapy may work better in treating patients with recurrent glioblastoma or gliosarcoma.
Inclusion Criteria
- Age 18 or older
- Karnofsky performance status (KPS) 60 or greater
- Recurrent glioblastoma or recurrent gliosarcoma or recurrent World Health Organization (WHO) grade 4 astrocytoma
- Multidisciplinary brain tumor board consensus of tumor progression based on imaging and-or clinical factors
- Candidate for clinically indicated re-resection or biopsy of glioblastoma or gliosarcoma per treating physician(s) (Phase 0)
- Absolute neutrophil count (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
- Candidate for clinically indicated re-irradiation of glioblastoma or gliosarcoma per treating physician(s) (Phase I)
- No more than one prior course of radiation for GBM (Phase I)
- Newly diagnosed glioblastoma or gliosarcoma or WHO Grade 4 astrocytoma (Phase I)
- No prior chemotherapy or radiation treatment for glioblastoma or gliosarcoma (Phase I)
- 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) (Phase I)
Exclusion Criteria
- Lack of histopathological diagnosis of the tumor
- Gliomatosis cerebri pattern (tumor involving three or more lobes) of disease
- Leptomeningeal disease
- Use of bevacizumab within 8 weeks of study enrollment
- Known history of human immunodeficiency virus (HIV)
- Active hepatitis B or C infection
- Active systemic or central nervous system (CNS) infection
- Grade 4 lymphopenia (if absolute blood lymphocyte count [ALC] < 0.5, patient must be on pneumocystis jirovecii prophylaxis)
- Estimated creatinine clearance (CrCl) < 25 ml/min
- History of organ transplantation
- Patients with known hypoxanthine-guanine phosphoribosyl-transferase deficiency
- Serious intercurrent illness
- History of allergic reaction or hypersensitivity to mycophenolate mofetil or mycophenolic acid or any component of the drug product
- Known immunosuppressive condition from autoimmune disease, immune deficiency syndrome, or chronic immunosuppressive therapy
- Inability to undergo magnetic resonance imaging (MRI) brain with and without contrast
- Medical contraindication for MMF per treating physician(s)
- Pregnant or lactating women
- Patients with known phenylketonuria
- 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)
- Use of bevacizumab within 8 weeks of study enrollment (Phase I)
- Radiation within 6 months prior to study enrollment (phase I)
- Prior surgery within 4 weeks of re-irradiation (phase I)
- Increase in steroid requirement within 7 days of study enrollment (stable or decreasing dose allowed) (phase I)
- Prior chemotherapy or radiation therapy for glioblastoma or gliosarcoma (Phase I)
- History of hypersensitivity reactions to temozolomide or any other ingredients in temozolomide and dacarbazine (Phase I)
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT04477200.
PRIMARY OBJECTIVES:
I. To measure the concentration of mycophenolic acid (MPA) in tumors from patients who undergo re-resection for glioblastoma (GBM). (Phase 0)
II. To determine the dose-limiting toxicity (DLT) and maximally tolerated dose (MTD) of mycophenolate mofetil (MMF) when combined with re-irradiation in patients with recurrent GBM. (Phase I)
III. To determine the DLT and MTD of MMF when combined with standard upfront chemoradiation in patients with newly diagnosed GBM. (Phase I)
SECONDARY OBJECTIVES:
I. To determine guanosine triphosphate (GTP) concentrations in recurrent GBM tissue re-resected after 1 week of MMF administration. (Phase 0)
II. To describe the adverse events associated with MMF when administered with re-irradiation in recurrent GBM patients, and with standard up front chemoradiation in newly diagnosed GBM. (Phase I)
III. To compare the overall survival of patients with recurrent GBM treated with MMF and re-irradiation to historical control of patients who were treated with re-irradiation alone. (Phase I)
IV. To compare the patterns of recurrence after re-irradiation with concurrent MMF to patterns of failure in patients treated with reirradiation alone. (Phase I)
EXPLORATORY OBJECTIVES:
I. To measure GTP level in re-resected GBM tumor tissue in patients who undergo standard of care re-resection without MMF administration.
II. To measure circulating MPA levels in plasma after 1 week of MMF administration and determine if these levels correlate with intratumoral MPA concentrations.
III. To measure circulating MPA levels in plasma after 1 week of MMF administration and determine if these levels correlate with survival after, and toxicity with combined treatment with MMF and radiation.
IV. Describe overall survival of patients with newly diagnosed GBM treated with MMF combined with standard of care.
OUTLINE: This is a dose-escalation study of mycophenolate mofetil.
PHASE 0: Patients with recurrent or progressive GBM receive mycophenolate mofetil orally (PO) twice daily (BID) for 1 week prior to re-resection in the absence of disease progression and unacceptable toxicity.
PHASE I: Patients with recurrent or progressive GBM receive mycophenolate mofetil PO BID for 1 week prior to re-irradiation to the evening of final dose radiation in the absence of disease progression and unacceptable toxicity.
PHASE I: Patients with newly diagnosed GBM receive mycophenolate mofetil PO BID for 1 week prior to and concurrent to radiation to the evening of the final dose of radiation and standard of care temozolomide each cycle. During the adjuvant phase, patients receive mycophenolate mofetil PO BID to one day prior to and concurrent to cyclic temozolomide.
After completions of study treatment, patients are followed up every 6 months.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationUniversity of Michigan Rogel Cancer Center
Principal InvestigatorNathan Clarke
- Primary IDUMCC 2019.192
- Secondary IDsNCI-2020-11569, HUM00175785
- ClinicalTrials.gov IDNCT04477200