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

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

Overview

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. All institutions are enrolling Newly Diagnosed participants. Institutions also enrolling Recurrent participants are marked with an asterisk (\*).

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.

Interventions

• Drug Temozolomide
  Dosage Form: Capsule for oral administration Strengths: 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, or 250 mg
• Drug Lomustine
  Dosage Form: Capsule for oral administration Strength: 5 mg, 10 mg, 40 mg, and 100 mg
• 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)
• Radiation Radiation
  60 Gy
• 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
• 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 Inje
• 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 vol
• Drug Troriluzole
  Dosage Form: Capsule for oral administration Strength: 100 mg Standard Regimen: Dose as confirmed through the dose finding phase orally BID.
• Biological ADI-PEG 20
  Dosage Form: Solution for intramuscular injection Strength: 11.5 ± 1.0 mg/ml Standard Regimen: For newly diagnosed patients, 36mg/m2. For recurrent disease patients, dose as confirmed through the dose finding phase intramuscularly once a week
• Drug AZD1390
  Standard Regimen Newly Diagnosed: Given once daily on days of radiation and once daily for 14 consecutive days after completion of radiation.

Primary outcome measures

• 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.]

Secondary outcome measures (3)

• 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.]
• 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.]
• 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.]

Eligibility 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 > 470 msec
• 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 > 470 msec
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 42 centers

• University of Alabama at Birmingham — Birmingham
• University of California, San Diego — La Jolla
• Cedars Sinai - Samuel Oschin Comprehensive Cancer Institute — Los Angeles
• University of California, Los Angeles — Los Angeles
• St. Joseph Hospital — Orange
• University of California, San Francisco — San Francisco
• Stanford Cancer Center — Stanford
• University of Colorado Denver — Aurora
• … and 34 more centers

Australia · 6 centers

• Northern Sydney Cancer Centre/Royal North Shore Hospital — St Leonards
• Calvary Mater Newcastle — Waratah
• Royal Brisbane and Women's Hospital — Herston
• Flinders Medical Centre — Bedford Park
• Austin Health — Heidelberg
• Peter MacCallum Cancer Centre — Melbourne

Germany · 6 centers

• Uniklinik Koeln - Zentrum fuer Neurologie und Psychiatrie — Cologne
• Dr. Senckenbergisches Institut für Neuroonkologie — Frankfurt
• Universitätsklinik Heidelberg — Heidelberg
• Universitaetsklinikum Heidelberg - Neurologische Klinik — Mannheim
• Universitätsklinikum Regensburg — Regensburg
• Universitätsklinikum Tübingen — Tübingen

Canada · 4 centers

• Sunnybrook Health Sciences Centre — Toronto
• Princess Margaret Cancer Centre — Toronto
• Montreal Neurological Institute and Hospital, McGill University — Montreal
• Université de Sherbrooke — Sherbrooke

France · 3 centers

• Centre Hospitalier Lyon Sud / Hôpital Neurologique P. Wertheimer — Bron
• Hopital de la Timone — Marseille
• Hopital Piti-Salpetriere — Paris

Switzerland · 2 centers

• Centre Hospitalier Universitaire Vaudois Lausanne — Lausanne
• University Hospital Zurich — Zurich

Publications

• Wen PY, Berry DA, Buxton MB, Colman H, de Groot J, Lim M, Mellinghoff I, Perry JR, Weller M, Blondin NA, Butt OH, Damek DM, de la Fuente MI, Drappatz J, Dunbar E, Giglio P, Hyddmark EV, Iwamoto F, Jaeckle KA, Kim L, Kling HM, Lee EQ, Mantica M, Mikkelsen T, Nabors B, Newton HB, Olson JJ, Schiff D, Walbert T, Weathers SP, Cloughesy T, Lassman AB; GBM AGILE Regorafenib Study Group. Evaluation of Reg PMID 41980234
• Chen JJ, Vincent MY, Shepard D, Peereboom D, Mahalingam D, Battiste J, Patel MR, Juric D, Wen PY, Bullock A, Selfridge JE, Pant S, Liu J, Li W, Fyfe S, Wang S, Zota V, Mahoney J, Watnick RS, Cieslewicz M, Watnick J. Phase 1 dose expansion and biomarker study assessing first-in-class tumor microenvironment modulator VT1021 in patients with advanced solid tumors. Commun Med (Lond). 2024 May 21;4(1): PMID 38773224

Identifiers

NCT: NCT03970447 · GCAR-7213

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗