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

Summary

This study is a response adaptive randomization platform trial designed to evaluate multiple therapies in people with newly diagnosed and recurrent IDH-wildtype GBM. Its goals are to identify effective therapies for overall survival for different patient subtypes.

Inclusion Criteria

Newly diagnosed GBM:

  1. Age ≥ 18 years.
  2. 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.
  3. 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.
  4. Post-operative MRI should be ideally within 96 hours of surgery. This eligibility criterion is not applicable if the patient underwent a biopsy only and no post-operative MRI was required.
  5. Use of dexamethasone 4 mg or less per day within 5 days prior to randomization.
  6. Karnofsky performance status ≥ 60% performed within a 14-day window prior to randomization.
  7. Administration of any non-cytotoxic potential anti-tumor agent (eg, interferon, tamoxifen, thalidomide, cis-retinoic acid) and/or herbal preparations/medications have been stopped at least 7 days prior to starting therapy. The use of tetrahydrocannabinol/cannabidiol is strongly discouraged during study treatment.
  8. Have undergone recent surgery or biopsy provided that:
    1. Craniotomy or intracranial biopsy site must be adequately healed and free of drainage or cellulitis, and the underlying cranioplasty must appear intact at the time of randomization.
    2. Initiation of study treatment is at least 14 days from prior surgery/biopsy for glioblastoma.
    3. Laser interstitial thermal therapy (LITT) is allowed for newly diagnosed patients. Study treatment needs to be initiated at least 7 days after the LITT.
  9. For any women (any individual assigned female at birth) who are not postmenopausal or surgically sterile and who are sexually active, agreement to use a highly effective method of contraception during the Treatment period and for at least 7 months after the last dose of study treatment. Such methods include combined oral, intravaginal or transdermal hormonal contraception; progestogen-only oral, injectable, or implantable hormonal contraception; intrauterine device (IUD) or intrauterine hormone-releasing system (IUS).
  10. Male patients (any individual assigned male at birth) of reproductive potential must avoid pregnancy in partners who are women of childbearing potential, and such partners should not consider getting pregnant during the study and for at least 7 months after treatment is discontinued or longer if requested by local authorities. Male patients are considered to be of reproductive potential unless permanently sterile by bilateral orchidectomy or vasectomized with appropriate post-vasectomy documentation of absence of sperm in ejaculate. Male patients must not donate semen for 6 months after the last dose of study treatment.
  11. Patients with type I diabetes mellitus, poorly controlled type II diabetes mellitus, hypothyroidism only requiring hormone replacement, isolated autoimmune skin disorders not requiring systemic treatment (eg, vitiligo, psoriasis, or alopecia), or conditions not expected to recur in the absence of an external trigger are eligible to participate.
  12. Availability of tumor tissue representative of glioblastoma from definitive surgery or biopsy.
  13. Provide written informed consent and comply with the study protocol as judged by the Investigator. Of note, If the patient has an impairment that prevents him/her from providing written consent, the site may follow local institutional procedures for obtaining consent.

Recurrent GBM:

  1. Age ≥ 18 years.
  2. 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).
  3. Evidence of recurrent disease demonstrated by disease progression using slightly modified Response Assessment in Neuro-Oncology (RANO) criteria, defined by any of the following:
    1. ≥ 25% increase in sum of products of perpendicular diameters of measurable enhancing lesions, compared with the smallest tumor measurement obtained either at the post-chemoradiation baseline (if no decrease) or best response (on stable or increasing steroid dose).
    2. Any new measurable (> 1 × 1 cm) enhancing lesions after the post-chemoradiation scan.
  4. Three scans to confirm progression are required: (1) the pre progression scan, (2) the progression scan that indicates tumor growth prior to the study, and (3) a baseline screening scan (if different from progression scan)
  5. Baseline MRI performed within 14 days prior to randomization.
  6. Use of dexamethasone 4 mg per day or less within 5 days prior to randomization.
  7. Karnofsky performance status ≥ 70% performed within a 14-day window prior to randomization.
  8. Administration of the following prior therapy, with a minimum time of:
    1. 28 days or 5 half-lives, whichever is shorter, elapsed from the administration of any experimental agent prior to initiation of study treatment.
    2. 28 days elapsed from the administration of any prior cytotoxic agents prior to initiation of study treatment. However, 14 days should have elapsed from the administration of vincristine and ≥ 21 days from procarbazine and TMZ.
  9. Administration of any non-cytotoxic potential anti-tumor agent (eg, interferon, tamoxifen, thalidomide, cis-retinoic acid) and/or herbal medicine has been stopped at least 7 days prior to randomization.
  10. Patients who have undergone recent surgery for recurrent or progressive brain tumor are eligible provided that:
    1. Prior to surgery there was imaging evidence of measurable progressive disease as described above.
    2. Craniotomy or intracranial biopsy site must be adequately healed and free of drainage or cellulitis, and the underlying cranioplasty must appear intact at the time of randomization.
    3. Initiation of study treatment is at least 14 days from prior surgery/biopsy.
  11. Patients are on a stable or decreasing dose of corticosteroids within 5 days prior to randomization.
    12. Prior therapy with gamma knife or other focal high-dose radiotherapy is allowed, but the patient must have subsequent histologic documentation of recurrence, unless the recurrence is a new lesion outside the irradiated field.
  12. For any women (any individual assigned female at birth) who are not postmenopausal or surgically sterile and who are sexually active, agreement to use a highly effective method of contraception during the Treatment period and for at least 7 months after the last dose of study treatment. Such methods include combined oral, intravaginal or transdermal hormonal contraception; progestogen-only oral, injectable, or implantable hormonal contraception; intrauterine device (IUD) or intrauterine hormone-releasing system (IUS).
  13. Male patients (any individual assigned male at birth) of reproductive potential must avoid pregnancy in partners who are women of childbearing potential, and such partners should not consider getting pregnant during the study and for at least 7 months after treatment is discontinued or longer if requested by local authorities. Male patients are considered to be of reproductive potential unless permanently sterile by bilateral orchidectomy or vasectomized with appropriate post-vasectomy documentation of absence of sperm in ejaculate. Male patients must not donate semen for 6 months after the last dose of study treatment.
  14. Patients with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, isolated autoimmune skin disorders not requiring systemic treatment, (eg,vitiligo, psoriasis, or alopecia), or conditions not expected to recur in the absence of an external trigger are eligible to participate.
  15. Availability of tumor tissue representative of GBM from initial definitive surgery and/or, recurrent surgery, if performed.
  16. Provide written informed consent and comply with the study protocol as judged by the Investigator. If the patient has an impairment that prevents him/her from providing written consent, the site may follow local institutional procedures for obtaining consent.

For the most up-to-date list of criteria, please visit clinicaltrials.gov.

Exclusion Criteria

Newly diagnosed GBM:

  1. Received any prior treatment for glioma including:
    1. Prior prolifeprospan 20 with carmustine wafer.
    2. Prior intracerebral, intratumoral, or cerebral spinal fluid (CSF) agent.
    3. Prior radiation treatment for GBM or lower-grade glioma.
    4. Prior chemotherapy or immunotherapy for GBM or lower-grade glioma.
  2. Receiving additional, concurrent, active therapy (including experimental) for GBM outside of the trial.
  3. Extensive leptomeningeal disease. Leptomeningeal disease in the region of the primary tumor and confined to the supratentorial area is allowed.
  4. Candidate for urgent palliative intervention for primary disease (eg, impending herniation) as judged by the Investigator.
  5. History of allergy or hypersensitivity to any of the study treatments or any of their excipients.
  6. Laboratory results must be obtained within 28 days prior to randomization AND 7 days prior to the start of study treatment. Results that meet the following parameters are exclusionary:
    1. Absolute neutrophil count (ANC) less than 1.5 × 109/L
    2. Platelet count less than 100 × 109/L
    3. Hemoglobin (Hb) less than 9.0 g/dL. The use of transfusion or other intervention to achieve adequate Hb levels is acceptable.
    4. Total bilirubin ≥ 1.5 × upper limit of normal (ULN); except in patients diagnosed with Gilbert’s disease for which bilirubin must be ≤ 2.0 × ULN.
    5. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) or alanine aminotransferase (ALT)/serum glutamic-pyruvic transaminase ≥ 3 × ULN.
    6. Alkaline phosphatase (ALP) ≥ 2.5 × ULN.
    7. Persistent ≥ Grade 3 lipase (> 2.0 to 5.0 x ULN with signs or symptoms;> 5.0 × ULN and asymptomatic).
    8. Serum creatinine > 1.5 × ULN or calculated creatinine clearance (CrCl) 60 mL/min (using Cockcroft and Gault).
    9. Persistent ≥ Grade 3 proteinuria (dipstick ≥ 4+, urine protein ≥ 3.5 g/24 hours, or nephrotic syndrome).
  7. International normalized ratio (INR), prothrombin time (PT), or activated partial thromboplastin time (aPTT) as follows:
    1. In the absence of therapeutic intent to anticoagulate the patient
      1. INR > 1.5 × ULN.
      2. PT > 1.5 × ULN.
      3. aPTT > 1.5 × ULN.
    2. In the presence of therapeutic intent to anticoagulate the patient:
      1. INR or PT and aPTT not within therapeutic limits (according to the medical standard in the institution).
      2. Patient has not been on a stable dose of anticoagulants for at least 2 weeks prior to randomization or a thromboembolic event > Grade 2 at the time of randomization.
    3. Use of warfarin sodium (Coumadin®), or any other warfarin-derivative anticoagulant, is not permitted at any dose
  8. QTc > 450 msec if male and QTc > 470 msec if female.
  9. Pregnant or lactating (or a positive serum β-HCG pregnancy test 3 to 7 days prior to randomization)
  10. Unable or unwilling to undergo brain MRI scans with intravenous gadolinium.
  11. 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.
  12. Serious non-healing wound, ulcer, bone fracture, or abscess.
  13. Any cerebrovascular accident (including transient ischemic attacks) within the last 6 months prior to initiation of study treatment.
  14. Any hemorrhage or bleeding event that is ≥ Grade 3 based on the National Cancer Institute Common Terminology Criteria for Adverse Event (CTCAE) or Grade 2 intracranial hemorrhage within 4 weeks prior to the start of study treatment.
  15. Uncontrolled or severe cardiac disease (eg, history of unstable angina, myocardial infarction, coronary stenting, or bypass surgery within the last 6 months prior to initiation of study treatment), symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia (including atrial flutter/fibrillation), requirement for ionotropic support or use of devices for cardiac conditions (eg, pacemakers/defibrillators), or hypertension (systolic blood pressure [BP] of > 160 mm Hg or diastolic BP of > 100 mm Hg despite optimal medical management).
  16. History of interstitial lung disease, history of slowly progressive dyspnea and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary hypersensitivity pneumonitis, or symptomatic pleural effusion.
  17. Active, known, or suspected uncontrolled autoimmune disease, which required therapy in the past 2 years, including but not limited to systemic lupus erythematosus, Hashimoto's thyroiditis, scleroderma, polyarteritis nodosa, or autoimmune hepatitis.
  18. Known history of hepatitis B, human immunodeficiency virus (HIV), or active hepatitis C infection requiring treatment with antiviral therapy. HIV testing is not required in the absence of clinical suspicion.
  19. History of bleeding diathesis (irrespective of severity) in the absence of therapeutic anticoagulation.
  20. Uncontrolled intercurrent illness including (eg, symptomatic ascites), but not limited to ongoing or active infection.
  21. Any condition that could make the patient noncompliant with the study procedures and/or study requirements, as judged by the Investigator (eg, cognitive impairment, psychiatric illness).

Recurrent GBM:

  1. Early disease progression prior to 3 months (12 weeks) from the completion of radiation therapy.
  2. 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.)
  3. 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.
  4. Any prior treatment with prolifeprospan 20 with carmustine wafer.
  5. Any prior treatment with an intracerebral agent.
  6. Receiving additional, concurrent, active therapy for GBM outside of the trial.
  7. Extensive leptomeningeal disease.
  8. Candidate for urgent palliative intervention for primary disease (eg, impending herniation) as judged by the Investigator.
  9. History of allergy or hypersensitivity to any of the study treatments or any of their excipients.
  10. Laboratory results must be obtained within 28 days prior to randomization AND 7 days prior to the start of study treatment. Results that meet the following parameters are exclusionary:
    1. ANC less than 1.5 × 109/L
    2. Platelet count less than 100 × 109/L
    3. Hb 9.0 g/dL within 7 days prior to enrollment. The use of transfusion or other intervention to achieve acceptable Hb levels is acceptable.
    4. Total bilirubin ≥ 1.5 × ULN (except in patients diagnosed with Gilbert’s disease)
    5. AST/SGOT or ALT/SGPT ≥ 3 × ULN.
    6. ALP ≥ 2.5 × ULN.
    7. Persistent ≥ Grade 3 lipase (> 2.0 to 5.0 x ULN with signs or symptoms;> 5.0 x ULN and asymptomatic).
    8. Serum creatinine > 1.5 × ULN or calculated CrCl 60 mL/min (using Cockcroft and Gault).
    9. Persistent ≥ Grade 3 proteinuria (dipstick ≥ 4+, urine protein ≥ 3.5 g/24 hours, or nephrotic syndrome).
  11. INR, PT, or aPTT as follows:
    1. In the absence of therapeutic intent to anticoagulate the patient:
      1. INR > 1.5 × ULN.
      2. PT > 1.5 × ULN.
      3. aPTT > 1.5 × ULN.
    2. In the presence of therapeutic intent to anticoagulate the patient:
      1. INR or PT and aPTT not within therapeutic limits (according to the medical standard in the institution).
      2. Patient has not been on a stable dose of anticoagulants for at least 2 weeks prior to randomization or a thromboembolic event > Grade 2 at the time of randomization.
    3. Use of warfarin sodium (Coumadin®), or any other warfarin-derivative anticoagulant, is not permitted at any dose
  12. QTc > 450 msec if male and QTc > 470 msec if female.
  13. People who are pregnant or lactating (or received a positive serum β-HCG pregnancy test 3 to 7 days prior to randomization)
  14. Unable or unwilling to undergo brain MRI scans with IV gadolinium.
  15. 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.
  16. Serious non-healing wound, ulcer, bone fracture, or abscess.
  17. Any cerebrovascular accident (including transient ischemic attacks) within the last 6 months prior to initiation of study treatment.
  18. Any hemorrhage or bleeding event that is ≥ Grade 3 based on the National Cancer Institute Common Terminology Criteria for Adverse Event (CTCAE) or Grade 2 intracranial hemorrhage within 4 weeks prior to the start of study treatment.
  19. Uncontrolled or severe cardiac disease (eg, history of unstable angina, myocardial infarction, coronary stenting, or bypass surgery within the last 6 months prior to initiation of study treatment), symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia (including atrial flutter/fibrillation), requirement for ionotropic support or use of devices for cardiac conditions (eg, pacemakers/defibrillators), or hypertension (systolic blood pressure [BP] of > 160 mm Hg or diastolic BP of > 100 mm Hg despite optimal medical management).
  20. History of interstitial lung disease, history of slowly progressive dyspnea and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary hypersensitivity pneumonitis, or symptomatic pleural effusion.
  21. Active, known, or suspected uncontrolled autoimmune disease, which required therapy in the past 2 years, including but not limited to systemic lupus erythematosus, Hashimoto's thyroiditis, scleroderma, polyarteritis nodosa, or autoimmune hepatitis.
  22. Known history of hepatitis B, HIV, or active hepatitis C infection requiring treatment with antiviral therapy. HIV testing is not required in the absence of clinical suspicion.
  23. History of bleeding diathesis (irrespective of severity) in the absence of therapeutic anticoagulation.
  24. Uncontrolled intercurrent illness including (eg, symptomatic ascites), but not limited to ongoing or active infection.
  25. Any condition that could make the patient noncompliant with the study procedures and/or study requirements, as judged by the Investigator (eg, cognitive impairment, psychiatric illness).

For the most up-to-date list of criteria, please visit clinicaltrials.gov.

Investigator(s)

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