Mycophenolate Mofetil in Combination With Standard of Care for the Treatment of Glioblastoma

  • STATUS
    Recruiting
  • End date
    Jan 3, 2027
  • participants needed
    60
  • sponsor
    Northwestern University
Updated on 7 October 2022
corticosteroids
growth factor
karnofsky performance status
dexamethasone
neutrophil count
immunohistochemistry
tumor cells
aptt
temozolomide
astrocytoma
recurrent glioblastoma

Summary

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.

Description

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).

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.

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.

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.

Details
Condition Astrocytoma, Glioblastoma, Glioblastoma, IDH-Wildtype, MGMT-Unmethylated Glioblastoma, Recurrent Glioblastoma
Treatment radiation therapy, mycophenolate mofetil, quality-of-life assessment, Temozolomide
Clinical Study IdentifierNCT05236036
SponsorNorthwestern University
Last Modified on7 October 2022

Eligibility

Yes No Not Sure

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 and have documented unmethylated glioblastoma (may have been done at an outside facility)
Group 3: Received surgical resection or biopsy only
GROUP S: Newly suspected glioblastoma or recurrent glioblastoma, and scheduled to
undergo a standard of care surgical resection or biopsy
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 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
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)
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
Patient 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
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