A Phase 1/1b Adaptive Dose Escalation Study of Mycophenolate Mofetil (MMF) in Combination With Standard of Care for Patients With Glioblastoma
A Phase 1/1b Adaptive Dose Escalation Study of Mycophenolate Mofetil (MMF) in Combination With Standard of Care for Patients With 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.
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).
II. Phase 1b (Groups 3 and R): To estimate median and corresponding 95% CI for progression-free survival (PFS) and overall survival (OS).
III. Phase 0 (Group S; Sub-Group S1 and Sub-Group S2): To evaluate drug uptake and target effect in the brain.
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).
III. To estimate overall survival (OS). IV. To estimate the overall response rate (ORR) per RANO 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.
EXPLORATORY OBJECTIVES:
I. To investigate the relationship between the molecular signature of individual glioblastoma multiforme (GBM) with clinical outcome, by measuring levels of serum mycophenolic acid in patient's plasma post MMF administration.
Ia. Perform molecular characterization of all GBM tissues by ribonucleic acid sequencing (RNAseq) 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. Group R only: To assess early efficacy of mycophenolate mofetil (MMF) in combination with temozolomide (TMZ) in recurrent GBM.
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 who have already undergone surgery or biopsy followed by chemoradiation receive TMZ orally (PO) once daily (QD) on days 1-5 of each cycle and MMF PO twice daily (BID). Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
GROUP 2: Patients with unmethylated glioblastoma who have already undergone surgery or biopsy receive TMZ PO QD on days 1-5 of each cycle and MMF PO BID. 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.
GROUP S: Patients planning to undergo surgery receive MMF PO BID and TMZ PO QD for 5 days prior to surgery in the absence of disease progression or unacceptable toxicity.
PART 2: Patients are assigned to Group 3 or enrolled to Group R.
GROUP 3: Patients who have already undergone surgery or biopsy receive TMZ PO QD on days 1-5 of each cycle and MMF PO BID. 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.
After completion of study treatment, patients are followed up at 30 days and then every 3 months for up to 18 months.
Group R (Recurrent): MMF + TMZ at MTD. Enrollment to begin concurrently with Group 3.Group R will be given the MTD for temozolomide + MMF via the same schedule and dosing as the adjuvant group (Group 1) and will open once the RP2D from Group 1 has been determined. Patients receive TMZ PO QD on days 1-5 of each cycle and MMF PO BID. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
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 S: Newly suspected glioblastoma or recurrent glioblastoma, and scheduled to undergo a standard of care surgical resection or biopsy.
Group R: Recurrent glioblastoma.
Stable or decreasing dose of corticosteroids equivalent to =< 8 mg dexamethasone daily, for >= 7 days prior to registration.
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 child-bearing potential (FOCBP) must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) from time of informed consent, for the duration of study participation, and for 3 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 treated or enrolled on this protocol must also agree to use adequate contraception from time of informed consent, for the duration of study participation, and 4 months after completion of administration.
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:
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.
Exclusion Criteria:
Patients who are receiving any other investigational agents.
Patient who have a prior or concurrent malignancy that may interfere with study treatment or safety.
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:
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).
Patients who require treatment with a therapy that is categorized as a "prohibited therapy" as listed in Section 4.10 of the protocol and who are unable to safety discontinue the prohibited therapy prior to the first dose of MMF or TMZ.