A Phase 1/1b Adaptive Dose Escalation Study of Mycophenolate Mofetil (MMF) in Combination With Standard of Care for Patients With Glioblastoma
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 86
- 试验地点
- 3
- 主要终点
- Maximum tolerated dose/recommended phase 2 dose (MTD/RP2D) for mycophenolate mofetil (MMF) (Group 1)
研究概览
简要总结
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.
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
- •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 >=
- •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.
排除标准
- •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.
- •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.
研究组 & 干预措施
Group 1 (TMZ, MMF)
Patients who have already undergone surgery or biopsy followed by chemoradiation 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.
干预措施: Mycophenolate Mofetil (Drug)
Group 1 (TMZ, MMF)
Patients who have already undergone surgery or biopsy followed by chemoradiation 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.
干预措施: Quality-of-Life Assessment (Other)
Group 1 (TMZ, MMF)
Patients who have already undergone surgery or biopsy followed by chemoradiation 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.
干预措施: Temozolomide (Drug)
Group 2 (TMZ, MMF, radiation therapy)
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.
干预措施: Mycophenolate Mofetil (Drug)
Group 2 (TMZ, MMF, radiation therapy)
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.
干预措施: Quality-of-Life Assessment (Other)
Group 2 (TMZ, MMF, radiation therapy)
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.
干预措施: Radiation Therapy (Radiation)
Group 2 (TMZ, MMF, radiation therapy)
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.
干预措施: Temozolomide (Drug)
Group 3 (TMZ, MMF, radiation therapy)
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.
干预措施: Mycophenolate Mofetil (Drug)
Group 3 (TMZ, MMF, radiation therapy)
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.
干预措施: Quality-of-Life Assessment (Other)
Group 3 (TMZ, MMF, radiation therapy)
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.
干预措施: Radiation Therapy (Radiation)
Group 3 (TMZ, MMF, radiation therapy)
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.
干预措施: Temozolomide (Drug)
Group S (pre-surgical MMF, TMZ)
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.
干预措施: Mycophenolate Mofetil (Drug)
Group S (pre-surgical MMF, TMZ)
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.
干预措施: Quality-of-Life Assessment (Other)
Group S (pre-surgical MMF, TMZ)
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.
干预措施: Temozolomide (Drug)
结局指标
主要结局
Maximum tolerated dose/recommended phase 2 dose (MTD/RP2D) for mycophenolate mofetil (MMF) (Group 1)
时间窗: Up to completion of first cycle of treatment + 7 days (1 cycle = 28 days)
Will be based on treatment-emergent and drug related toxicity of grade \>= 3 during the first cycle of treatment. MTD indicates maximum tolerated dose for dose limiting toxicity (DLT). DLT is defined as side effects of a drug or other treatment that are serious enough to prevent an increase in dose or level of that treatment. Recommended phase 2 dose (RP2D) is the highest dose of a drug or treatment that does not cause unacceptable side effects. For the purposes of this study, RP2D is interchangeable with MTD. DLTs and Adverse Events (AEs) will be assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v). 5.0.
MTD/RP2D for MMF (Group 2)
时间窗: Up to 6 weeks + 7 days
Will be based on treatment-emergent and drug related toxicity of grade \>= 3 during focal radiation treatment. MTD indicates maximum tolerated dose for DLT. DLT is defined as side effects of a drug or other treatment that are serious enough to prevent an increase in dose or level of that treatment. RP2D is the highest dose of a drug or treatment that does not cause unacceptable side effects. For the purposes of this study, RP2D is interchangeable with MTD. DLTs and AEs will be assessed by CTCAE v.5.0.
次要结局
- Frequency of adverse events(Up to 30 days after completion of study treatment)
- Overall survival (OS)(From time of diagnosis until the patient initiates subsequent anti-cancer therapy, completes study participation, or experiences death from any cause (whichever is sooner), assessed up to 18 months)
- Progression Free Survival (PFS)(From baseline until the patient experiences disease progression, initiates subsequent anti-cancer therapy, completes study participation, or experiences death from any cause (whichever is sooner), assessed up to 18 months)
- Overall response rate (ORR)(From baseline, the patient experiences disease progression, the patient initiates subsequent anti-cancer therapy, or the patient completes study participation (whichever occurs first), assessed up to 18 months)
- Quality of life (QOL)(Up to 6 cycles (1 cycle = 28 days))