Phase 0/I Dose Escalation Study of Mycophenolate Mofetil Combined With Radiation Therapy in Glioblastoma
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 68
- 试验地点
- 2
- 主要终点
- Number of newly diagnosed phase 1 participants who experience dose-limiting toxicities (DLTs) at each dose level -- DLT1 period
研究概览
简要总结
This is a phase 0/1 dose-escalation trial to determine the maximum tolerated dose of Mycophenolate Mofetil (MMF) when administered with radiation, in patients with glioblastoma or gliosarcoma.
详细描述
The goal of the Phase 0 component is to determine if MMF achieves active concentrations in brain tumors. Eight participants in Phase 0 will receive MMF for one week before undergoing an already planned biopsy or re-resection (surgical removal) of glioblastoma or gliosarcoma (GBM/GS). A small portion of the tumor, removed as part of clinical care, will be used for testing in this study. Sixty additional participants will be enrolled in the Phase 1 component of the trial (30 with recurrent GBM/GS and 30 with newly diagnosed GBM/GS). The goal of the Phase 1 component is to find the dose of MMF that works best without causing severe side effects (the maximum tolerated dose) when combined with radiation in recurrent GBM/GS and with radiation and chemotherapy in newly diagnosed GBM/GS. Participants in Phase 0 who meet the eligibility criteria for the Phase 1 component may participate in both phases.
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
- •Glioblastoma or gliosarcoma (recurrent or newly diagnosed).
- •Karnofsky Performance Status 60 or greater.
- •Phase 0: Candidate for clinically indicated re-resection or biopsy of glioblastoma or gliosarcoma per treating physician(s).
- •Phase 1, Recurrent: Candidate for clinically indicated re-irradiation of glioblastoma or gliosarcoma per treating physician(s) (No more than one prior course of radiation for GBM).
- •Phase 1, Newly Diagnosed: 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).
- •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.
排除标准
- •Lack of histopathological diagnosis of the tumor.
- •Gliomatosis cerebri pattern (tumor involving 3 or more lobes) of disease.
- •Leptomeningeal disease.
- •Use of bevacizumab within 8 weeks of study enrollment.
- •Known history of HIV.
- •Active hepatitis B or C infection.
- •Active systemic or central nervous system (CNS) infection.
- •Grade 4 lymphopenia (if ALC <0.5, patient must be on Pneumocystis jirovecii prophylaxis).
- •Estimated CrCl < 25 ml/min.
- •History of organ transplantation.
- •Patients with known hypoxanthine-guanine phosphoribosyl-transferase deficiency.
- •Serious intercurrent disease.
- •History of allergic reaction or hypersensitivity to mycophenolate mofetil or mycophenolic acid or any component of the drug product; or medical contraindication for MMF per treating physician(s).
- •Known immunosuppressive condition from autoimmune disease, immune deficiency syndrome, or chronic immunosuppressive therapy.
- •Inability to undergo MRI brain with and without contrast.
- •Pregnant or lactating women.
- •Patients with known phenylketonuria.
- •Phase 0: 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).
- •Phase I: Increase in steroid requirement within 7 days of study enrollment (stable or decreasing dose allowed).
- •Phase I, Recurrent: Radiation within 6 months prior to study enrollment.
- •Phase I, Recurrent: Surgery within 4 weeks of re-irradiation.
- •Phase I, Newly Diagnosed: History of hypersensitivity reactions to temozolomide or any other ingredients in temozolomide and dacarbazine.
- •Phase I, Newly Diagnosed: Prior chemotherapy or radiation therapy for glioblastoma or gliosarcoma.
研究组 & 干预措施
Phase 0 - Recurrent glioblastoma (GBM) / gliosarcoma (GS)
Mycophenolate mofetil
干预措施: Re-resection (as part of standard of care) (Procedure)
Phase 1 - Newly Diagnosed GBM / GS
Mycophenolate mofetil; radiation therapy; temozolomide
干预措施: Radiation Therapy (Radiation)
Phase 1 - Recurrent GBM / GS
Mycophenolate mofetil; radiation therapy
干预措施: Radiation Therapy (Radiation)
Phase 1 - Recurrent GBM / GS
Mycophenolate mofetil; radiation therapy
干预措施: Mycophenolate Mofetil (Drug)
Phase 0 - Recurrent glioblastoma (GBM) / gliosarcoma (GS)
Mycophenolate mofetil
干预措施: Mycophenolate Mofetil (Drug)
Phase 1 - Newly Diagnosed GBM / GS
Mycophenolate mofetil; radiation therapy; temozolomide
干预措施: Temozolomide (Drug)
Phase 1 - Newly Diagnosed GBM / GS
Mycophenolate mofetil; radiation therapy; temozolomide
干预措施: Mycophenolate Mofetil (Drug)
结局指标
主要结局
Number of newly diagnosed phase 1 participants who experience dose-limiting toxicities (DLTs) at each dose level -- DLT1 period
时间窗: Up to 28 days following completion of MMF + RT + TMZ (up to ~11 weeks)
DLT will be defined based on the rate of drug related grade 3-5 adverse events experienced from the start of treatment with MMF and for up to 4 weeks after completion of MMF + RT + TMZ. Assessed using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. This measure includes only newly diagnosed phase 1 participants.
Number of newly diagnosed phase 1 participants who experience dose-limiting toxicities (DLTs) at each dose level -- DLT2 period
时间窗: During the first 2 cycles (8 weeks) of MMF with adjuvant TMZ (up to ~19 weeks)
DLT will be defined based on the rate of drug related grade 3-5 adverse events experienced during the first 2 cycles (8 weeks) of MMF with adjuvant TMZ. (The first cycle of MMF with adjuvant TMZ begins 28 days post-RT.) These will be assessed using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. This measure includes only newly diagnosed phase 1 participants.
Number of recurrent phase 1 participants who experience dose-limiting toxicities (DLTs) at each dose level
时间窗: Up to 28 days following completion of MMF + RT (up to ~9 weeks)
DLT will be defined based on the rate of drug related grade 3-5 adverse events experienced from the start of treatment with MMF and for up to 4 weeks after completion of MMF + radiation therapy (RT). Assessed using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. This measure includes only phase 1 participants with recurrent GBM/GS.
Concentration of mycophenolic acid (MPA) in tumor tissue in Phase 0 participants
时间窗: At 1 week
The concentration of MPA (the active metabolite of mycophenolate mofetil \[MMF\]) in tumor tissue, measured by mass spectrometry on a continuous scale after one week of MMF administration. This measure includes all phase 0 participants.
Concentration of Mycophenolic Acid (MPA) in Tumor Tissue in Phase 0 Participants
时间窗: At 1 week
The concentration of MPA (the active metabolite of mycophenolate mofetil \[MMF\]) in tumor tissue, measured by mass spectrometry on a continuous scale after one week of MMF administration. This measure includes all phase 0 participants.
Number of Recurrent Phase 1 Participants Who Experience Dose-limiting Toxicities (DLTs) at Each Dose Level
时间窗: Up to 28 days following completion of MMF + RT (up to ~9 weeks)
DLT will be defined based on the rate of drug related grade 3-5 adverse events experienced from the start of treatment with MMF and for up to 4 weeks after completion of MMF + radiation therapy (RT). Assessed using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. This measure includes only phase 1 participants with recurrent GBM/GS.
Number of Newly Diagnosed Phase 1 Participants Who Experience Dose-limiting Toxicities (DLTs) at Each Dose Level -- DLT1 Period
时间窗: Up to 28 days following completion of MMF + RT + TMZ (up to ~11 weeks)
DLT will be defined based on the rate of drug related grade 3-5 adverse events experienced from the start of treatment with MMF and for up to 4 weeks after completion of MMF + RT + TMZ. Assessed using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. This measure includes only newly diagnosed phase 1 participants.
Number of Newly Diagnosed Phase 1 Participants Who Experience Dose-limiting Toxicities (DLTs) at Each Dose Level -- DLT2 Period
时间窗: During the first 2 cycles (8 weeks) of MMF with adjuvant TMZ (up to ~19 weeks)
DLT will be defined based on the rate of drug related grade 3-5 adverse events experienced during the first 2 cycles (8 weeks) of MMF with adjuvant TMZ. (The first cycle of MMF with adjuvant TMZ begins 28 days post-RT.) These will be assessed using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. This measure includes only newly diagnosed phase 1 participants.
次要结局
- Concentrations of guanosine triphosphate (GTP) in tumor tissue in Phase 0 participants(After one week of MMF administration)
- Median Progression Free Survival (PFS) in phase 1 participants with recurrent GBM/GS(Until study stops or death; up to approximately 3 years.)
- Overall Response Rate in phase 1 participants with recurrent GBM/GS(Until study stops or death; up to approximately 3 years.)
- Adverse events associated with treatment in newly diagnosed phase 1 participants(Up to 28 days following completion of MMF with adjuvant temozolomide (up to ~15 months))
- Adverse events associated with treatment in all Phase 1 Participants(Up to 28 days following completion of MMF + RT (up to ~9 weeks))
- Median Overall Survival (OS) in phase 1 participants with recurrent GBM/GS(Until study stops or death; up to approximately 3 years.)
- Median Freedom from Local Progression (FFLP) in phase 1 participants with recurrent GBM/GS(Until study stops or death; up to approximately 3 years.)
- Concentrations of Guanosine Triphosphate (GTP) in Tumor Tissue in Phase 0 Participants(After one week of MMF administration)
- Adverse Events Associated With Treatment in All Phase 1 Participants(Up to 28 days following completion of MMF + RT (up to ~9 weeks))
- Adverse Events Associated With Treatment in Newly Diagnosed Phase 1 Participants(Up to 28 days following completion of MMF with adjuvant temozolomide (up to ~15 months))
- Overall Response Rate in Phase 1 Participants With Recurrent GBM/GS(Until study stops or death; up to approximately 3 years.)
- Median Progression Free Survival (PFS) in Phase 1 Participants With Recurrent GBM/GS(Until study stops or death; up to approximately 3 years.)
- Median Freedom From Local Progression (FFLP) in Phase 1 Participants With Recurrent GBM/GS(Until study stops or death; up to approximately 3 years.)
- Median Overall Survival (OS) in Phase 1 Participants With Recurrent GBM/GS(Until study stops or death; up to approximately 3 years.)