Mycophenolate Mofetil in Combination with Standard of Care for the Treatment of Glioblastoma
This phase I/Ib trial tests the safety, side effects, and best dose of mycophenolate mofetil in combination with temozolomide and/or radiation therapy (standard of care) in treating patients with glioblastoma. Mycophenolate mofetil is an immunosuppressant drug that is typically used to prevent organ rejection in transplant recipients. However, mycophenolate mofetil may also help chemotherapy with temozolomide work better by making tumor cells more sensitive to the drug. The purpose of this trial is to determine if mycophenolate mofetil combined with temozolomide can stop glioblastoma.
Inclusion Criteria
- GROUPS 1-3: Histologically confirmed glioblastoma (GBM), IDH wild-type (by immunohistochemistry [IHC] R132H negative [neg] or sequencing). Astrocytoma with molecular features of GBM are eligible.
- GROUPS 1-3: Newly diagnosed glioblastoma and: * Group 1: Received surgical resection or biopsy followed by chemoradiation; * Group 2: Received surgical resection or biopsy only; * Group 3: Received surgical resection or biopsy only
- GROUP S (SUB-GROUP S1 and SUB-GROUP S2): Recurrent glioblastoma and scheduled to undergo a standard-of-care surgical resection
- GROUP R: Recurrent glioblastoma
- Stable or decreasing dose of corticosteroids equivalent to =< 8 mg dexamethasone daily, for >= 7 days prior to registration. * Note: There are no restrictions on steroid use on study
- Patients must be age >= 18 years.
- Patients must exhibit a Karnofsky performance status >= 70.
- Leukocytes (white blood cells [WBC]) >= 3,000/mcL (within 14 days prior to study registration)
- Absolute neutrophil count (ANC) >= 1,500/mcL (within 14 days prior to study registration)
- Hemoglobin (Hgb) >= 8 g/dL (within 14 days prior to study registration) (transfusion may be used for eligibility if >= 7 days)
- Platelets (PLT) >= 100,000/mcL (within 14 days prior to study registration) (transfusion or growth factor may be used for eligibility if >= 7 days).
- Total bilirubin =< 2x institutional upper limit of normal (ULN) (within 14 days prior to study registration)
- Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase [SGOT])/Alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN (within 14 days prior to study registration)
- Creatinine =< 1.5 x Institutional ULN (within 14 days prior to study registration)
- International normalized ratio (INR) =< 1.5 x ULN (within 14 days prior to study registration)
- Prothrombin time (PT)/Partial thromboplastin Time (PTT) =< 1.5 x ULN (within 14 days prior to study registration)
- Females of childbearing potential (FOCBP) must agree to use adequate contraception (or abstinence) from time of informed consent, for the duration of study therapy, and for 6 months following completion of therapy. Should a female patient become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men must agree to use adequate contraception (or abstinence) and refrain from donating sperm from time of informed consent, for the duration of study therapy, and 3 months (or 90 days, whichever is greater) after completion of therapy * NOTE: A FOCBP is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: ** Has not undergone a hysterectomy or bilateral oophorectomy ** Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for > 12 months) * NOTE: MMF may reduce blood levels of the hormones from the oral contraceptive pill and could theoretically reduce its effectiveness. Choices for adequate contraception should be discussed with the treating physician
- FOCBP must have a negative pregnancy test within 14 days prior to registration on study.
- Patient or their legally authorized representative must provide written, signed, and dated informed consent prior to study registration. Patient or their legally authorized representative (LAR) must have the ability to understand and the willingness to sign a written informed consent document. The patient or their LAR must be willing and able to comply with the protocol for the duration of the study. * NOTE: no study-specific screening procedures may be performed until written consent has been obtained.
Exclusion Criteria
- Patients who are receiving any other investigational agents. * Exception: COVID-19 vaccine and treatment is allowed
- Patients who have a prior or concurrent malignancy that may interfere with study treatment or safety. * NOTE: Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible, per principal investigator (PI) discretion
- Patients who have a history of allergic reactions attributed to compounds of similar chemical composition to temozolomide or mycophenolate mofetil.
- Patients with spinal cord and diffuse leptomeningeal disease GBM
- Patients requiring live vaccinations within 2 weeks of initiation of MMF and/or TMZ therapy. Consider completion of vaccination with live vaccines prior to starting immunosuppressive therapy, as indicated.
- Patients on viral-vector based therapy due to increased risk for disseminated herpetic infection.
- Patients who have an uncontrolled intercurrent illness including, but not limited to any of the following, are not eligible: * Have uncontrolled epilepsy * Have an uncontrolled intercurrent illness * Concurrent malignancy (outside of glioblastoma) that requires tumor directed treatment * Known deficiency of hypoxanthine-guanin-phosphoribosyltransferase (HGPRT) deficiency, e.g. Lesch-Nyhan- oder Kelley-Seegmiller-Syndrome. * Known concurrent shingles, herpes, CMV (cytomegalovirus) infection * Known concurrent opportunistic fungal infection * Known concurrent or history of unexplained opportunistic infection * Known immunodeficiency that could lead to opportunistic infections * Psychiatric illness/social situations that would limit compliance with study requirements * Any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the patient’s safety or study endpoints.
- Female patients who are pregnant or nursing. Pregnant women are excluded from this study because temozolomide is an alkylating agent with potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with temozolomide, breastfeeding should be discontinued if the mother is treated with temozolomide.
- Patients who are unable to swallow oral medication or have problems/ diseases that affect absorption of oral medication.
- Patients with a known history of human immunodeficiency virus (HIV), hepatitis B virus (HBV), and/or hepatitis C virus (HCV). * Note: Temozolomide and mycophenolate mofetil are immunosuppressive agents. Patients with a known history of HIV, HBV, and HCV, and unexplained opportunistic infections are not eligible due to safety reasons
- Patients who require treatment with a therapy that is categorized as a “prohibited therapy” and who are unable to safety discontinue the prohibited therapy prior to the first dose of MMF or TMZ
Additional locations may be listed on ClinicalTrials.gov for NCT05236036.
Locations matching your search criteria
United States
Illinois
Chicago
Lake Forest
Warrenville
PRIMARY OBJECTIVE:
I. To evaluate the recommended phase 2 dose (RP2D) for mycophenolate mofetil (MMF) in combination with radiation therapy as well as in combination with temozolomide (TMZ). (Phase 1 [Groups 1 and 2])
II. To estimate median and corresponding 95% confidence interval (CI) for progression-free survival (PFS) and overall survival (OS). (Phase 1b [Groups 3 and R])
III. To evaluate drug uptake and target effect in the brain. (Phase 0 [Group S; Sub-Group S1 and Sub-Group S2])
SECONDARY OBJECTIVES:
I. To evaluate the safety profile of mycophenolate mofetil (MMF) in combination with temozolomide (TMZ).
II. To estimate progression free survival (PFS) per Response Assessment in Neuro-Oncology Criteria (RANO) 2.0 criteria.
III. To estimate overall survival (OS).
IV. To estimate the overall response rate (ORR) per RANO 2.0 criteria.
V. To evaluate quality of life per Functional Assessment of Cancer Therapy Scale-Brain (FACT-Br) for patients treated with mycophenolate mofetil and/or temozolomide.
VI. To evaluate the safety profile of mycophenolate mofetil (MMF) in combination with temozolomide (TMZ).
EXPLORATORY OBJECTIVES:
I. To investigate the relationship between the molecular signature of individual glioblastoma multiforme (GBM) with clinical outcome, using a variety of approaches, as described below:
Ia. Perform molecular characterization of all GBM tissues by ribonucleic acid sequencing (RNA-seq) analysis.
Ib. Perform bulk metabolomics for GBM tissue;
Ic. Measure plasma and serum concentration of mycophenolic acid, the MMF's primary active metabolite, during and after combination therapy;
Id. Measure IMPDH activity assay in patients’ peripheral blood mononuclear cells (PBMCs) as well as in GBM tissue;
Ie. Analyze relevant gene mutations from standard of care next generation sequencing (NGS) tumor gene mutation data, if available.
II. To assess early efficacy of mycophenolate mofetil (MMF) in combination with temozolomide (TMZ) in recurrent GBM. (Group R only)
OUTLINE: This is a dose-escalation study of MMF (Part 1), followed by a dose-expansion study (Part 2).
PART 1: Patients are assigned to 1 of 3 groups.
GROUP 1: Patients receive TMZ orally (PO) once daily (QD) on days 1-5 of each cycle and MMF PO twice daily (BID) on days 1-28 of each cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo magnetic resonance imaging (MRI) and blood sample collection throughout the study.
GROUP 2: Patients receive TMZ PO QD on days 1-5 of each cycle and MMF PO BID on days 1-28 of each cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Starting at the same time as TMZ and MMF administration, patients also receive radiation therapy daily, 5 days per week, for 6 weeks. Patients also undergo MRI and blood sample collection throughout the study.
GROUP S: Patients are randomized to 1 of 2 sub-groups.
SUB-GROUP S1: Patients receive TMZ PO QD for 5 days prior to surgery in the absence of disease progression or unacceptable toxicity. After surgery, patients receive TMZ PO QD on days 1-5 of each cycle and MMF PO BID on days 1-28 of each cycle. Cycles repeat every 28 days for 5 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI and blood sample collection throughout the study.
SUB-GROUP S2: Patients receive MMF PO BID on days 1-28 of each cycle and TMZ PO QD for 5 days prior to surgery in the absence of disease progression or unacceptable toxicity. After surgery, patients receive MMF PO BID on days 1-28 of each cycle and TMZ PO QD on days 1-5 of each cycle. Cycles repeat every 28 days for 5 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI and blood sample collection throughout the study.
PART 2: Patients are assigned to 1 of 2 Groups.
GROUP 3: Patients receive TMZ PO QD on days 1-5 of each cycle and MMF PO BID on days 1-28 of each cycle. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Starting at the same time as TMZ and MMF administration, patients also receive radiation therapy daily, 5 days per week, for 6 weeks. Patients also undergo MRI and blood sample collection throughout the study.
GROUP R: Patients receive TMZ PO QD on days 1-5 of each cycle and MMF PO BID on days 1-28 of each cycle. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI and blood sample collection throughout the study.
After completion of study treatment, patients are followed up at 30 days and then every 3 months for up to 18 months.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationNorthwestern University
Principal InvestigatorPriya Kumthekar Bhasin
- Primary IDNU 21C01
- Secondary IDsNCI-2021-12424, STU00215766
- ClinicalTrials.gov IDNCT05236036