GBM AGILE: A Trial to Evaluate Multiple Regimens in Newly Diagnosed and Recurrent Glioblastoma

Sponsor

Global Coalition for Adaptive Research (Other)

Overall Status

Recruiting

CT.gov ID

NCT03970447

Collaborator

Bayer (Industry), Kazia Therapeutics Limited (Industry), Kintara Therapeutics, Inc. (Industry), Biohaven Pharmaceuticals, Inc. (Industry), Vigeo Therapeutics, Inc. (Industry)

1,030

Enrollment

Locations

Arms

106.1

Anticipated Duration (Months)

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Condition or Disease	Intervention/Treatment	Phase
Glioblastoma	Drug: Temozolomide Drug: Lomustine Drug: Regorafenib Radiation: Radiation Drug: Paxalisib Drug: VAL-083 Drug: VT1021 Drug: Troriluzole Drug: VT1021	Phase 2/Phase 3

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

1030 participants

Allocation:

Randomized

Intervention Model:

Sequential Assignment

Intervention Model Description:

GBM AGILE is a multi-arm, platform trial. The evaluation of each therapy in GBM AGILE proceeds in 2 possible stages. A therapy's Stage 1 is an adaptively randomized Screening stage for evaluating the therapy within patient signatures compared against a common control. A therapy in Stage 1 will stop accruing patients if it reaches its maximal sample size, drops for futility, or evinces inadequate safety. If a therapy reaches an efficacy threshold for graduation from Stage 1, it will move into Stage 2 within one of the prospectively defined signatures. The maximum sample size in Stage 1 is 150 patients. For a therapy graduating to Stage 2 there is a fixed randomization, expansion cohort. The maximum sample size in Stage 2 is 50 experimental patients in the graduating signature. The primary analysis of a regimen's effect on OS uses all patients in both its stages and all control patients in the trial in the graduating signature, suitably adjusted for any possible time trends.GBM AGILE is a multi-arm, platform trial. The evaluation of each therapy in GBM AGILE proceeds in 2 possible stages. A therapy's Stage 1 is an adaptively randomized Screening stage for evaluating the therapy within patient signatures compared against a common control. A therapy in Stage 1 will stop accruing patients if it reaches its maximal sample size, drops for futility, or evinces inadequate safety. If a therapy reaches an efficacy threshold for graduation from Stage 1, it will move into Stage 2 within one of the prospectively defined signatures. The maximum sample size in Stage 1 is 150 patients. For a therapy graduating to Stage 2 there is a fixed randomization, expansion cohort. The maximum sample size in Stage 2 is 50 experimental patients in the graduating signature. The primary analysis of a regimen's effect on OS uses all patients in both its stages and all control patients in the trial in the graduating signature, suitably adjusted for any possible time trends.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

GBM AGILE: Global Adaptive Trial Master Protocol: An International, Seamless Phase II/III Response Adaptive Randomization Platform Trial Designed To Evaluate Multiple Regimens In Newly Diagnosed and Recurrent GBM

Actual Study Start Date :

Jul 30, 2019

Anticipated Primary Completion Date :

Jun 1, 2026

Anticipated Study Completion Date :

Jun 1, 2028

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Control Arm 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.	Drug: Temozolomide Dosage Form: Capsule for oral administration Strengths: 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, or 250 mg Other Names: Temodar Temodal Temcad Drug: Lomustine Dosage Form: Capsule for oral administration Strength: 5 mg, 10 mg, 40 mg, and 100 mg Other Names: CCNU CeeNU Gleostine Radiation: Radiation 60 Gy
Experimental: Regorafenib Treatment Arm 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).	Drug: Regorafenib Dosage Form: Tablet for oral administration Strength: 40 mg Standard Regimen: 160 mg orally (PO) every day (QD) for 3 weeks of every 4 week cycle (i.e., 3 weeks on, 1 week off) Other Names: Stivarga BAY 73-4506
Experimental: Paxalisib Treatment Arm 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.	Drug: Paxalisib Dosage Form: Tablet for oral administration Strength: 15 mg Standard Regimen: 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 Other Names: GDC-0084
Experimental: VAL-083 Treatment Arm 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.	Drug: VAL-083 Dosage Form: Infusion for intravenous administration Strength: 40 mg per vial Standard Regimen: 30 mg/m2 on Day 1, 2 and 3 of 21-day cycle. The drug is available in powder form. It is reconstituted with 5 mL of 0.9% Sodium Chloride for Injection, USP. This will produce a solution of 40 mg VAL-083 in 5 mL. The required volume of reconstituted VAL-083 for the patient is then calculated at the rate of 30 mg/m2. The corresponding volume is further diluted into 250 mL of 0.9% Sodium Chloride for Injection, USP, prior to intravenous administration. Other Names: Dianhydrogalactitol
Experimental: VT1021 Treatment Arm - Dose Finding Phase 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.	Drug: VT1021 Dosage form: Infusion for intravenous administration Strength: 10 mg/mL Standard Regimen Newly Diagnosed: Dose as confirmed through the dose finding phase, administered twice weekly (Mon and Thurs or Tues and Fri or Mon and Fri). Standard Regimen Recurrent: 12 mg/kg administered twice weekly (Mon and Thurs or Tues and Fri or Mon and Fri). The drug is available as a sterile solution of the acetate salt formulated with phosphate-buffered saline, mannitol, and 2.5% polysorbate 80. The required volume stock solution for the patient is calculated. The corresponding volume is diluted in 500 mL of either 0.9% saline or D5W, prior to intravenous administration.
Experimental: VT1021 Treatment Arm - Enhanced Safety Management (ESM) 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.	Drug: VT1021 Dosage form: Infusion for intravenous administration Strength: 10 mg/mL Standard Regimen Newly Diagnosed: Dose as confirmed through the dose finding phase, administered twice weekly Standard Regimen Recurrent: 12 mg/kg administered twice weekly.
Experimental: VT1021 Treatment Arm Newly diagnosed MGMT Methylated and Unmethylated GBM: XRT 60 Gy for 6 weeks. Temozolomide 75 mg/m2 orally daily and VT1021 (Dosage from: 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 from: Infusion for intravenous administration; Strength: 10 mg/mL; Dose: 12mg/kg) twice weekly.	Drug: VT1021 Dosage form: Infusion for intravenous administration Strength: 10 mg/mL Standard Regimen Newly Diagnosed: Dose as confirmed through the dose finding phase, administered twice weekly Standard Regimen Recurrent: 12 mg/kg administered twice weekly.
Experimental: Troriluzole Treatment Arm - Dose Finding Phase 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.	Drug: Troriluzole Dosage from: Capsule for oral administration Strength: 100 mg Standard Regimen: Dose as confirmed through the dose finding phase orally BID. Other Names: BHV-4157
Experimental: Troriluzole Treatment Arm - Enhanced Safety Management (ESM) 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.	Drug: Troriluzole Dosage from: Capsule for oral administration Strength: 100 mg Standard Regimen: Dose as confirmed through the dose finding phase orally BID. Other Names: BHV-4157
Experimental: Troriluzole Treatment Arm Newly diagnosed MGMT Methylated and Unmethylated GBM: XRT 60 Gy for 6 weeks. Temozolomide 75 mg/m2 orally daily and troriluzole (Dosage from: 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 from: Capsule for oral administration; Strength: 100 mg; Dose: As confirmed by dose finding phase) BID. After 6 cycles, troriluzole only.	Drug: Troriluzole Dosage from: Capsule for oral administration Strength: 100 mg Standard Regimen: Dose as confirmed through the dose finding phase orally BID. Other Names: BHV-4157

Outcome Measures

Primary Outcome Measures

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

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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Newly Diagnosed 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) 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 Exclusion Criteria:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35249
2	University of California, San Diego	La Jolla	California	United States	92093
3	Cedars Sinai - Samuel Oschin Comprehensive Cancer Institute	Los Angeles	California	United States	90048
4	University of California, Los Angeles	Los Angeles	California	United States	90095
5	St. Joseph Hospital	Orange	California	United States	92868
6	University of California, San Francisco	San Francisco	California	United States	94143
7	Stanford Cancer Center	Stanford	California	United States	94305
8	University of Colorado Denver	Aurora	Colorado	United States	80045
9	Yale Cancer Center / Smilow Cancer Hospital	New Haven	Connecticut	United States	06511
10	Mayo Clinic Cancer Center	Jacksonville	Florida	United States	32224
11	Sylvester Comprehensive Cancer Center	Miami	Florida	United States	33136
12	Moffitt Cancer Center	Tampa	Florida	United States	33612
13	Piedmont Atlanta Hospital	Atlanta	Georgia	United States	30309
14	Winship Cancer Institute of Emory University	Atlanta	Georgia	United States	30322
15	LSU Health Sciences Center - New Orleans	New Orleans	Louisiana	United States	70112
16	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
17	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02115
18	Henry Ford Health System	Detroit	Michigan	United States	48202
19	Abbott Northwestern Hospital	Minneapolis	Minnesota	United States	55407
20	Mayo Clinic Cancer Center - Rochester	Rochester	Minnesota	United States	55905
21	University of Mississippi Medical Center	Jackson	Mississippi	United States	39213
22	Washington University School of Medicine - Siteman Cancer Center	Saint Louis	Missouri	United States	63110
23	Perlmutter Cancer Center, NYU Langone Health	New York	New York	United States	10016
24	Icahn School of Medicine at Mount Sinai	New York	New York	United States	10029
25	Columbia University Medical Center	New York	New York	United States	10032
26	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
27	Duke University Medical Center	Durham	North Carolina	United States	27710
28	Comprehensive Cancer Center of Wake Forest	Winston-Salem	North Carolina	United States	272157
29	University Hospitals Cleveland Medical Center	Cleveland	Ohio	United States	44106
30	Cleveland Clinic	Cleveland	Ohio	United States	44195
31	Ohio State University Cancer Center	Columbus	Ohio	United States	43210
32	University of Pennsylvania - Perelman Center for Advanced Medicine	Philadelphia	Pennsylvania	United States	19104
33	Allegheny General Hospital	Pittsburgh	Pennsylvania	United States	15212
34	University of Pittsburgh Medical Center - Hillman Cancer Center	Pittsburgh	Pennsylvania	United States	15232
35	Medical University of South Carolina - Hollings Cancer Center	Charleston	South Carolina	United States	29425
36	Texas Oncology - Austin	Austin	Texas	United States	78705
37	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390
38	University of Texas - MD Anderson Cancer Center	Houston	Texas	United States	77030
39	University of Utah - Huntsman Cancer Institute	Salt Lake City	Utah	United States	84112
40	University of Virginia Health	Charlottesville	Virginia	United States	22908
41	University of Washington Medical Center	Seattle	Washington	United States	98101
42	Froedtert Hospital/Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
43	Sunnybrook Health Sciences Centre	Toronto	Ontario	Canada	M4N 3M5
44	Princess Margaret Cancer Centre	Toronto	Ontario	Canada	M5G 2C1
45	Montreal Neurological Institute and Hospital, McGill University	Montréal	Quebec	Canada	H3A 2B4
46	Université de Sherbrooke	Sherbrooke	Quebec	Canada	J1H 5H3
47	Centre Hospitalier Lyon Sud / Hôpital Neurologique P. Wertheimer	Bron		France	69677
48	Universitätsspital Basel	Basel		Switzerland	CH-4031
49	University Hospital Zurich	Zürich		Switzerland