Newly Diagnosed Astrocytoma, Grade IV, Newly Diagnosed Glioblastoma, Newly Diagnosed Gliosarcoma, Recurrent Astrocytoma, Grade IV, Recurrent Glioblastoma, Recurrent Gliosarcoma
Conditions
Keywords
recurrent Glioblastoma, recurrent Gliosarcoma, newly diagnosed Glioblastoma, newly diagnosed Gliosarcooma, Recurrent Astrocytoma, Grade IV, Newly Diagnosed Astrocytoma, Grade IV
Brief summary
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.
Detailed description
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.
Interventions
DRUGMycophenolate Mofetil
500-2000mg orally twice daily, one week prior to re-resection (2 participants at each of 4 dose levels: 500mg, 1000mg, 1500mg and 2000mg)
RADIATIONRadiation Therapy
40.5 Gy in 15 fractions
PROCEDURERe-resection (as part of standard of care)
Re-resection or biopsy of tumor as part of standard of care
DRUGTemozolomide
Temozolomide capsules are an approved oral chemotherapeutic drug for the treatment of adult patients with newly diagnosed GBM/GS concomitantly with radiotherapy and then as adjuvant treatment. The dosing and timing of temozolomide therapy will be determined as per standard-of-care for the individual patient by the treating oncologist.
Sponsors
University of Michigan Rogel Cancer Center
National Cancer Institute (NCI)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase 0 will include 8 participants; eligible participants from phase 0 may continue on to phase 1.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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.
Exclusion criteria
* 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Concentration of Mycophenolic Acid (MPA) in Tumor Tissue in Phase 0 Participants | 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 | 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 | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Concentrations of Guanosine Triphosphate (GTP) in Tumor Tissue in Phase 0 Participants | After one week of MMF administration | The concentrations of GTP in tumor tissue, measured by mass spectrometry on a continuous scale. This measure includes all phase 0 participants. |
| Adverse Events Associated With Treatment in All Phase 1 Participants | Up to 28 days following completion of MMF + RT (up to ~9 weeks) | Toxicities at each dose level will be tabulated, categorized by grade and attribution. This measure includes all phase 1 participants. |
| 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) | Toxicities at each dose level will be tabulated, categorized by grade and attribution. This measure includes only newly diagnosed phase 1 participants. |
| Overall Response Rate in Phase 1 Participants With Recurrent GBM/GS | Until study stops or death; up to approximately 3 years. | Determined by modified Response Assessment for Neuro-Oncology (mRANO) criteria. The number and proportion of patients with progressive disease, stable disease, partial and complete response will be calculated for each dose level and overall. This measure includes only phase 1 participants with recurrent GBM/GS. |
| Median Progression Free Survival (PFS) in Phase 1 Participants With Recurrent GBM/GS | Until study stops or death; up to approximately 3 years. | PFS defined as time from date of registration to the date of documented progressive disease, other disease related therapy or death. Determined by mRANO criteria. This measure includes only phase 1 participants with recurrent GBM/GS. |
| Median Freedom From Local Progression (FFLP) in Phase 1 Participants With Recurrent GBM/GS | Until study stops or death; up to approximately 3 years. | FFLP defined as time from date of registration to the date of documented local progressive disease. Determined by mRANO criteria. This measure includes only phase 1 participants with recurrent GBM/GS. |
| Median Overall Survival (OS) in Phase 1 Participants With Recurrent GBM/GS | Until study stops or death; up to approximately 3 years. | OS defined as time from date of registration to date of death or last follow up. Determined by Kaplan Meier method. This measure includes only phase 1 participants with recurrent GBM/GS. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORNathan Clarke, MD
University of Michigan Rogel Cancer Center
Participant flow
Pre-assignment details
1 subject was enrolled into Phase 1- Recurrent, but chose to not start study treatment. 2 Subjects were enrolled into Phase 1- Newly diagnosed, but did not start treatment.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 23 Participants |
| Age, Categorical Between 18 and 65 years | 42 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 60 Participants |
| Region of Enrollment United States | 2 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 2 | 1 / 2 | 0 / 2 | 1 / 2 | 2 / 3 | 4 / 4 | 12 / 19 | 2 / 4 | 8 / 11 | 11 / 16 |
| other Total, other adverse events | 2 / 2 | 0 / 2 | 2 / 2 | 2 / 2 | 3 / 3 | 4 / 4 | 16 / 19 | 4 / 4 | 10 / 11 | 16 / 16 |
| serious Total, serious adverse events | 1 / 2 | 0 / 2 | 0 / 2 | 0 / 2 | 0 / 3 | 2 / 4 | 2 / 19 | 1 / 4 | 4 / 11 | 9 / 16 |
Outcome results
None listed