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

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ClinicalTrials.gov Identifier: NCT03970447
Recruitment Status : Recruiting
First Posted : May 31, 2019
Last Update Posted : November 25, 2021
Sponsor:
Collaborators:
Bayer
Kazia Therapeutics Limited
Kintara Therapeutics, Inc.
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Glioblastoma Drug: Temozolomide Drug: Lomustine Drug: Regorafenib Radiation: Radiation Drug: Paxalisib Drug: VAL-083 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.

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Study Type : Interventional  (Clinical Trial)
Estimated 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.

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 : July 30, 2019
Estimated Primary Completion Date : December 2023
Estimated Study Completion Date : June 2024

Resource links provided by the National Library of Medicine


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 Name: 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: 30 mg/m2 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 Name: Dianhydrogalactitol




Primary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: 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 :
  1. Progression-free survival (PFS) [ Time Frame: 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.

  2. Tumor Response [ Time Frame: 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.

  3. Duration of Response (CR + PR) [ Time Frame: 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03970447


Contacts
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Contact: Patient Information 310-598-3199 patientinfo@gcaresearch.org
Contact: Rachel Rosenstein-Sisson RRosenstein.Sisson@GCAResearch.org

Locations
Show Show 43 study locations
Sponsors and Collaborators
Global Coalition for Adaptive Research
Bayer
Kazia Therapeutics Limited
Kintara Therapeutics, Inc.
Investigators
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Principal Investigator: Tim Cloughesy, MD GCAR CMO and GBM AGILE Global PI
Additional Information:
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Responsible Party: Global Coalition for Adaptive Research
ClinicalTrials.gov Identifier: NCT03970447    
Other Study ID Numbers: GCAR-7213
First Posted: May 31, 2019    Key Record Dates
Last Update Posted: November 25, 2021
Last Verified: August 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: Global Coalition for Adaptive Research (GCAR) is in the planning stages at this time.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Global Coalition for Adaptive Research:
Glioblastoma
Newly diagnosed
recurrent
O6-methylguanine-DNA-methyltransferase (MGMT) methylated
MGMT unmethylated
isocitrate dehydrogenase (IDH) wild-type
Bayesian
adaptive randomization
Master Protocol
Platform Trial
Phase 2
Phase 3
Additional relevant MeSH terms:
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Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Temozolomide
Lomustine
Dianhydrogalactitol
GDC-0084
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors