A Trial to Evaluate Multiple Regimens in Newly Diagnosed and Recurrent Glioblastoma
- Conditions
- Glioblastoma
- Interventions
- Registration Number
- NCT03970447
- Lead Sponsor
- Global Coalition for Adaptive Research
- Brief Summary
Glioblastoma (GBM) adaptive, global, innovative learning environment (GBM AGILE) is an international, seamless Phase II/III response adaptive randomization platform trial designed to evaluate multiple therapies in newly diagnosed (ND) and recurrent GBM.
- Detailed Description
Glioblastoma (GBM) adaptive, global, innovative learning environment (GBM AGILE) is an international, seamless Phase II/III response adaptive randomization platform trial designed to evaluate multiple therapies in newly diagnosed (ND) and recurrent GBM. Its goals are to identify effective therapies for glioblastoma and match effective therapies with patient subtypes. Bayesian response adaptive randomization is used within subtypes of the disease to assign participants to Arms based on their performance. The primary endpoint is overall survival (OS).
GBM AGILE is designed to efficiently evaluate therapies. The trial will be conducted under a single Master Investigational New Drug Application/Clinical Trial Application and Master Protocol, allowing multiple drugs and drug combinations from different pharmaceutical companies to be evaluated simultaneously. The plan is to add experimental therapies as new information about promising new drugs are identified and remove therapies as they complete their evaluation.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 1030
- Age ≥ 18 years.
- Histologically confirmed Grade IV GBM, inclusive of gliosarcoma (WHO criteria; IDH wild-type by immunohistochemistry [IHC] or sequencing for IDH) established following either a surgical resection or biopsy. An MRI scan with the required imaging sequences performed within 21 days prior to randomization preferably. The post-operative MRI scan performed within 96 hours of surgery or the MRI scan performed for radiation therapy planning may serve as the MRI scan performed during screening if all required imaging sequences were obtained.
- Karnofsky performance status ≥ 60% performed within a 14-day window prior to randomization.
- Availability of tumor tissue representative of GBM from definitive surgery or biopsy.
Recurrent Inclusion Criteria:
- Age ≥ 18 years.
- Histologically confirmed Grade IV GBM, inclusive of gliosarcoma (WHO criteria; IDH wild-type by immunohistochemistry [IHC] or sequencing for IDH) at first or second recurrence after initial standard, control or experimental therapy that includes at a minimum radiation therapy (RT).
- Evidence of recurrent disease demonstrated by disease progression using slightly modified Response Assessment in Neuro-Oncology (RANO) criteria.
- Two scans to confirm progression are required: at least 1 scan at the time of progression and 1 scan prior to the time of progression.
- Karnofsky performance status ≥ 70% performed within a 14-day window prior to randomization.
- Availability of tumor tissue representative of GBM from initial definitive surgery and/or, recurrent surgery, if performed.
Newly Diagnosed
- Received any prior treatment for glioma including: a. Prior prolifeprospan 20 with carmustine wafer. b. Prior intracerebral, intratumoral, or cerebral spinal fluid (CSF) agent. c. Prior radiation treatment for GBM or lower-grade glioma. d. Prior chemotherapy or immunotherapy for GBM or lower-grade glioma. Receiving additional, concurrent, active therapy for GBM outside of the trial.
- Extensive leptomeningeal disease.
- QTc > 450 msec if male and QTc > 470 msec if female.
- History of another malignancy in the previous 2 years, with a disease-free interval of < 2 years. Patients with prior history of in situ cancer or basal or squamous cell skin cancer are eligible.
Recurrent Exclusion Criteria:
- Early disease progression prior to 3 months (12 weeks) from the completion of RT.
- More than 2 prior lines for chemotherapy administration. (NOTE: In the 1st line adjuvant setting, combination of temozolomide (TMZ) with an experimental agent, is considered one line of chemotherapy.)
- Received any prior treatment with lomustine, agents part of any of the experimental arms, and bevacizumab or other vascular endothelial growth factor (VEGF) or VEGF receptor-mediated targeted agent.
- Any prior treatment with prolifeprospan 20 with carmustine wafer.
- Any prior treatment with an intracerebral agent.
- Receiving additional, concurrent, active therapy for GBM outside of the trial
- Extensive leptomeningeal disease.
- QTc > 450 msec if male and QTc > 470 msec if female.
- History of another malignancy in the previous 2 years, with a disease-free interval of < 2 years. Patients with prior history of in situ cancer or basal or squamous cell skin cancer are eligible.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Control Arm Radiation Newly Diagnosed GBM: Radiation therapy (XRT) 60 Gy for 6 weeks. Temozolomide 75 mg/m2 orally daily during radiation therapy. Rest Period 2-6 weeks from the last day of radiation, and the start of the first cycle of Maintenance Therapy 2-6 weeks after the last day of radiotherapy. The start of all subsequent maintenance therapy cycles (2-12) every 4 weeks + 7 days after the first daily dose of temozolomide of the preceding cycle. Total number of cycles should comply with institutional or country standards. During maintenance therapy, the first cycle of temozolomide will be at 150 mg/m2 for Days 1-5 of a 28-day cycle. Second and subsequent cycles of maintenance therapy will be at 200 mg/m2 for Days 1-5 of a 28-day cycle. Recurrent GBM: Lomustine started at 110 mg/m2/day on Day 1 of a 42-day cycle as per local standards. Treatment will continue for up to 6 total cycles. VAL-083 Treatment Arm VAL-083 Newly Diagnosed MGMT Methylated and Unmethylated GBM: XRT 60 Gy for 6 weeks. Temozolomide 75 mg/m2 orally daily during radiation therapy. Rest Period 4 weeks from the last day of radiation. Maintenance period: VAL-083 (Dosage Form: Infusion for intravenous administration; Strength: 30 mg/m2) on Day 1, 2 and 3 of 21-day cycle. Recurrent GBM: VAL-083 (Dosage Form: Infusion for intravenous administration; Strength: 30 mg/m2) on Day 1, 2 and 3 of 21-day cycle. Troriluzole Treatment Arm - Enhanced Safety Management (ESM) Troriluzole Newly diagnosed MGMT Methylated and Unmethylated GBM and Recurrent GBM: Supplemental safety assessments including bi-weekly collection of adverse events, dose modification profile, hematology, serum chemistry and coagulation panels. ESM will continue until the Data Safety Monitoring Board (DSMB) suspends collection of additional data. VT1021 Treatment Arm - Enhanced Safety Management (ESM) VT1021 Experimental: VT1021 Treatment Arm - Enhanced Safety Management (ESM) Newly diagnosed MGMT Methylated and Unmethylated GBM: Supplemental safety assessments including bi-weekly collection of adverse events, dose modification profile, hematology, serum chemistry and coagulation panels. PK and PD assessments are done for patients as a part of ESM. ESM will continue until the Data Safety Monitoring Board (DSMB) suspends collection of additional data. Recurrent GBM: ESM is not applicable for patients with Recurrent GBM in the VT1021 treatment arm. VT1021 Treatment Arm - Dose Finding Phase VT1021 Newly diagnosed MGMT Methylated and Unmethylated GBM: Rolling 6 design. Treatment as outlined in section "Experimental: VT1021 Treatment Arm" with the first 6 patients receiving VT1021 at 12 mg/kg twice weekly in combination with temozolomide and radiation therapy. If there are two dose limiting toxicities reported, the dose will be de-escalated to 9 mg/kg two times a week. 6 patients will then be receiving 9 mg/kg two times a week and observed for DLTs for 4 weeks. Recurrent GBM: Dose Finding Phase is not applicable for patients with Recurrent GBM in the VT1021 treatment arm. VT1021 Treatment Arm VT1021 Newly diagnosed MGMT Methylated and Unmethylated GBM: XRT 60 Gy for 6 weeks. Temozolomide 75 mg/m2 orally daily and VT1021 (Dosage Form: Infusion for intravenous administration; Strength: 10 mg/mL; Dose: As confirmed through the dose finding phase) twice weekly during radiation therapy. Rest period: 2-6 weeks from last day of radiation. VT1021 dosing will continue during the rest period. Maintenance period: The first cycle of temozolomide will be at 150 mg/m2 for days 1-5 of a 28-day cycle. Second and subsequent cycles of maintenance therapy will be at 200 mg/m2 for days 1-5 of a 28-day cycle. Temozolomide will be administered for up to 6 cycles in the maintenance phase in combination with VT1021. After 6 cycles, VT1021 only. Recurrent GBM: VT1021 (Dosage Form: Infusion for intravenous administration; Strength: 10 mg/mL; Dose: 12mg/kg) twice weekly. Control Arm Temozolomide Newly Diagnosed GBM: Radiation therapy (XRT) 60 Gy for 6 weeks. Temozolomide 75 mg/m2 orally daily during radiation therapy. Rest Period 2-6 weeks from the last day of radiation, and the start of the first cycle of Maintenance Therapy 2-6 weeks after the last day of radiotherapy. The start of all subsequent maintenance therapy cycles (2-12) every 4 weeks + 7 days after the first daily dose of temozolomide of the preceding cycle. Total number of cycles should comply with institutional or country standards. During maintenance therapy, the first cycle of temozolomide will be at 150 mg/m2 for Days 1-5 of a 28-day cycle. Second and subsequent cycles of maintenance therapy will be at 200 mg/m2 for Days 1-5 of a 28-day cycle. Recurrent GBM: Lomustine started at 110 mg/m2/day on Day 1 of a 42-day cycle as per local standards. Treatment will continue for up to 6 total cycles. Control Arm Lomustine Newly Diagnosed GBM: Radiation therapy (XRT) 60 Gy for 6 weeks. Temozolomide 75 mg/m2 orally daily during radiation therapy. Rest Period 2-6 weeks from the last day of radiation, and the start of the first cycle of Maintenance Therapy 2-6 weeks after the last day of radiotherapy. The start of all subsequent maintenance therapy cycles (2-12) every 4 weeks + 7 days after the first daily dose of temozolomide of the preceding cycle. Total number of cycles should comply with institutional or country standards. During maintenance therapy, the first cycle of temozolomide will be at 150 mg/m2 for Days 1-5 of a 28-day cycle. Second and subsequent cycles of maintenance therapy will be at 200 mg/m2 for Days 1-5 of a 28-day cycle. Recurrent GBM: Lomustine started at 110 mg/m2/day on Day 1 of a 42-day cycle as per local standards. Treatment will continue for up to 6 total cycles. Regorafenib Treatment Arm Regorafenib Newly Diagnosed MGMT Unmethylated GBM: XRT 60 Gy for 6 weeks. Temozolomide 75 mg/m2 orally daily during radiation therapy. Rest Period 4 weeks from the last day of radiation. Maintenance period: Regorafenib (Dosage Form: Tablet for oral administration; Strength: 40 mg) 160 mg orally (PO) every day (QD) for 3 weeks of every 4 week cycle (i.e., 3 weeks on, 1 week off). Recurrent GBM: Regorafenib (Dosage Form: Tablet for oral administration; Strength: 40 mg) 160 mg orally (PO) every day (QD) for 3 weeks of every 4 week cycle (i.e., 3 weeks on, 1 week off). ADI-PEG 20 Treatment Arm - Enhanced Safety Management (ESM) ADI-PEG 20 Newly diagnosed MGMT Methylated and Unmethylated GBM: ESM is not applicable for newly diagnosed patients on the ADI-PEG 20 treatment arm. Recurrent GBM: Supplemental safety assessments including bi-weekly collection of adverse events, dose modification profile, hematology, serum chemistry and coagulation panels. ESM will continue until the Data Safety Monitoring Board (DSMB) suspends collection of additional data. Troriluzole Treatment Arm - Dose Finding Phase Troriluzole Newly diagnosed MGMT Methylated and Unmethylated GBM: Rolling 6 design. The first 6 patients will receive troriluzole at 100 mg BID for the first two weeks followed by 200 mg BID for the next two weeks in combination with temozolomide and radiation therapy. If there are two dose limiting toxicities (DLTs) reported, the dose will be de-escalated to 100 mg in the morning and followed by 200 mg in the evening. 6 patients will receive this dose and observed for 4 weeks. If there are two DLTs reported, then this dose will be de-escalated to 100 mg BID. 6 patients will then be receiving this dose and observed for DLTs for 4 weeks. Recurrent GBM: Rolling 6 design. The first 6 patients receiving troriluzole 100 mg twice a day (BID) for the first two weeks followed by 200 mg BID for the next two weeks in combination with lomustine. The dose de-escalation is similar to that of newly diagnosed patients during the rolling 6 design. Troriluzole Treatment Arm Troriluzole Newly diagnosed MGMT Methylated and Unmethylated GBM: XRT 60 Gy for 6 weeks. Temozolomide 75 mg/m2 orally daily and troriluzole (Dosage Form: Capsule for oral administration; Strength: 100 mg; Dose: As confirmed by dose finding phase) BID. Rest period: 2-6 weeks from last day of radiation. Troriluzole dosing will continue during the rest period. Maintenance period: The first cycle of temozolomide will be at 150 mg/m2 for days 1-5 of a 28-day cycle. Second and subsequent cycles of maintenance therapy will be at 200 mg/m2 for days 1-5 of a 28-day cycle. Temozolomide will be administered for up to 6 cycles in the maintenance phase in combination with troriluzole. After 6 cycles, troriluzole only. Recurrent GBM: Lomustine 100 mg/m2 orally on day 1 of a 42-day cycle in combination with troriluzole (Dosage Form: Capsule for oral administration; Strength: 100 mg; Dose: As confirmed by dose finding phase) BID. After 6 cycles, troriluzole only. ADI-PEG 20 Treatment Arm - Dose Finding Phase ADI-PEG 20 Newly diagnosed MGMT Methylated and Unmethylated GBM: Dose Finding Phase is not applicable for newly diagnosed patients on the ADI-PEG 20 treatment arm. Recurrent GBM: Rolling 6 design. The first 6 patients will receive ADI-PEG 20 at 36 mg/m2 once a week in combination with lomustine 100 mg/m2 orally on day 1 of a 42-day cycle. 6 patients will receive this dose and be observed for 4 weeks. If there are two dose limiting toxicities (DLTs) reported, the dose will be de-escalated to 18 mg/m2 once a week. 6 patients will receive this dose and be observed for 4 weeks. ADI-PEG 20 Treatment Arm ADI-PEG 20 Newly diagnosed MGMT Methylated and Unmethylated GBM: XRT 60 Gy over 6 weeks. Temozolomide (75 mg/m2 orally daily and ADI-PEG 20 (Dosage Form: Solution for intramuscular injection; Strength: 11.5 ± 1.0 mg/ml; Dose: 36 mg/m2) once a week. Rest period: 2-6 weeks from last day of radiation. ADI-PEG 20 dosing will continue during rest period. Maintenance period: The first cycle of temozolomide will be at 150 mg/m2 for days 1-5 of a 28-day cycle. Subsequent cycles will be at 200 mg/m2 for days 1-5 of a 28-day cycle. Temozolomide will be administered for up to 6 cycles in the maintenance phase in combination with ADI-PEG 20. After 6 cycles, ADI-PEG 20 only for up to 104 weeks of total treatment. Recurrent GBM: Lomustine 100 mg/m2 orally on day 1 of a 42-day cycle in combination with ADI-PEG 20 (Dosage Form: Solution for IM injection; Strength: 11.5 ± 1.0 mg/ml; Dose: As confirmed by dose finding phase, once a week. After 6 cycles, ADI-PEG 20 only for up to 104 weeks of total treatment. Paxalisib Treatment Arm Paxalisib Newly Diagnosed MGMT Unmethylated GBM: XRT 60 Gy for 6 weeks. Temozolomide 75 mg/m2 orally daily during radiation therapy. Rest Period 4 weeks from the last day of radiation. Maintenance period: Paxalisib (Dosage Form: Tablet for oral administration; Strength: 15 mg per tablet) 45 mg orally (PO) every day for 28 days for the first cycle. If tolerated, increase dose to 60 mg orally (PO) every day for 28 days for all subsequent cycles. Recurrent GBM: Paxalisib (Dosage Form: Tablet for oral administration; Strength: 15 mg per tablet) 45 mg orally (PO) every day for 21 days for the first cycle. If tolerated, increase dose to 60 mg orally (PO) every day for 21 days for all subsequent cycles.
- Primary Outcome Measures
Name Time Method Overall Survival (OS) From date of randomization until the date of death from any cause, or until 12 months following last patient randomization (approximately 2 years), whichever comes first. Overall survival is defined from the time of randomization to death from any cause. Patients still alive at the time of an analysis will be considered censored at their date of last contact.
- Secondary Outcome Measures
Name Time Method Progression-free survival (PFS) From date of randomization to date of clinically determined progression or date of death from any cause, or until 12 months following last patient randomization (approximately 2 years), whichever comes first. Progression-free survival is defined as the time from randomization to clinically determined progression or death from any cause. All participants will be included in the analysis of PFS.
Tumor Response From initiation of study treatment to date of disease progression, or until 12 months following last patient randomization (approximately 2 years), whichever comes first. Tumor response is categorized by Complete Response (CR), Partial Response (PR), Stable Disease (SD), and Progressive Disease (PD). Response captured from initiation of study treatment until disease progression.
Duration of Response (CR + PR) From date of response to date of clinically determined disease progression or date of death from any cause, or until 12 months following last patient randomization (approximately 2 years), whichever comes first. Duration of response (CR+PR) is defined as time from date of response to date of clinically determined disease progression or death from any cause.
Trial Locations
- Locations (62)
University of California, Los Angeles
🇺🇸Los Angeles, California, United States
St. Joseph Hospital
🇺🇸Orange, California, United States
University of California, San Francisco
🇺🇸San Francisco, California, United States
Stanford Cancer Center
🇺🇸Stanford, California, United States
Yale Cancer Center / Smilow Cancer Hospital
🇺🇸New Haven, Connecticut, United States
University of Colorado Denver
🇺🇸Aurora, Colorado, United States
University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States
Cedars Sinai - Samuel Oschin Comprehensive Cancer Institute
🇺🇸Los Angeles, California, United States
University of California, San Diego
🇺🇸La Jolla, California, United States
Mayo Clinic Cancer Center
🇺🇸Jacksonville, Florida, United States
Sylvester Comprehensive Cancer Center
🇺🇸Miami, Florida, United States
Moffitt Cancer Center
🇺🇸Tampa, Florida, United States
Piedmont Atlanta Hospital
🇺🇸Atlanta, Georgia, United States
Winship Cancer Institute of Emory University
🇺🇸Atlanta, Georgia, United States
Uniklinik Koeln - Zentrum fuer Neurologie und Psychiatrie
🇩🇪Cologne, Germany
LSU Health Sciences Center - New Orleans
🇺🇸New Orleans, Louisiana, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Dana Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Henry Ford Health System
🇺🇸Detroit, Michigan, United States
Abbott Northwestern Hospital
🇺🇸Minneapolis, Minnesota, United States
Mayo Clinic Cancer Center - Rochester
🇺🇸Rochester, Minnesota, United States
University of Mississippi Medical Center
🇺🇸Jackson, Mississippi, United States
Washington University School of Medicine - Siteman Cancer Center
🇺🇸Saint Louis, Missouri, United States
Perlmutter Cancer Center, NYU Langone Health
🇺🇸New York, New York, United States
Icahn School of Medicine at Mount Sinai
🇺🇸New York, New York, United States
Columbia University Medical Center
🇺🇸New York, New York, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
Comprehensive Cancer Center of Wake Forest
🇺🇸Winston-Salem, North Carolina, United States
University Hospitals Cleveland Medical Center
🇺🇸Cleveland, Ohio, United States
Princess Margaret Cancer Centre
🇨🇦Toronto, Ontario, Canada
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
Ohio State University Cancer Center
🇺🇸Columbus, Ohio, United States
University of Pennsylvania - Perelman Center for Advanced Medicine
🇺🇸Philadelphia, Pennsylvania, United States
Allegheny General Hospital
🇺🇸Pittsburgh, Pennsylvania, United States
University of Pittsburgh Medical Center - Hillman Cancer Center
🇺🇸Pittsburgh, Pennsylvania, United States
Medical University of South Carolina - Hollings Cancer Center
🇺🇸Charleston, South Carolina, United States
Texas Oncology - Austin
🇺🇸Austin, Texas, United States
University of Texas Southwestern Medical Center
🇺🇸Dallas, Texas, United States
University of Texas - MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
University of Utah - Huntsman Cancer Institute
🇺🇸Salt Lake City, Utah, United States
University of Virginia Health
🇺🇸Charlottesville, Virginia, United States
University of Washington Medical Center
🇺🇸Seattle, Washington, United States
Froedtert Hospital/Medical College of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
Northern Sydney Cancer Centre/Royal North Shore Hospital
🇦🇺St Leonards, New South Wales, Australia
Calvary Mater Newcastle
🇦🇺Waratah, New South Wales, Australia
Royal Brisbane and Women's Hospital
🇦🇺Herston, Queensland, Australia
Flinders Medical Centre
🇦🇺Bedford Park, South Australia, Australia
Austin Health
🇦🇺Heidelberg, Victoria, Australia
Peter MacCallum Cancer Centre
🇦🇺Melbourne, Victoria, Australia
Sunnybrook Health Sciences Centre
🇨🇦Toronto, Ontario, Canada
Montreal Neurological Institute and Hospital, McGill University
🇨🇦Montréal, Quebec, Canada
Université de Sherbrooke
🇨🇦Sherbrooke, Quebec, Canada
Centre Hospitalier Lyon Sud / Hôpital Neurologique P. Wertheimer
🇫🇷Bron, France
Hopital de la Timone
🇫🇷Marseille, France
Hopital Piti-Salpetriere
🇫🇷Paris, France
Dr. Senckenbergisches Institut für Neuroonkologie
🇩🇪Frankfurt, Germany
Universitätsklinik Heidelberg
🇩🇪Heidelberg, Germany
Universitätsklinikum Regensburg
🇩🇪Regensburg, Germany
Universitätsklinikum Tübingen
🇩🇪Tübingen, Germany
Centre Hospitalier Universitaire Vaudois Lausanne
🇨🇭Lausanne, Vaud, Switzerland
University Hospital Zurich
🇨🇭Zürich, Switzerland