IRB Study Number 19-1299
Status Recruiting
Phases Phase 2, Phase 3
Institute Taussig Cancer Institute
Description
Primary Objectives
To identify experimental therapies that improve OS for GBM patients in the Screening stage (Stage 1), determining if predefined patient subtypes or associated biomarkers uniquely benefit from the treatment.
To confirm identified efficacious experimental therapies and associated biomarker signatures in an expansion stage (Stage 2) designed to support a new drug application.
Secondary Objectives
To evaluate PFS by each biomarker/therapeutic combination.
To evaluate OS by each biomarker/therapeutic combination.
To determine short- and long-term safety signals and QOL measures of an experimental Arm in GBM patients versus standard of care.
Inclusion Criteria
Age ≥ 18 years.
Histologically confirmed Grade IV GBM/gliosarcoma (WHO criteria; non-IDH R132H mutant by immunohistochemistry [IHC] or sequencing for IDH) established following either a surgical resection or biopsy. This includes:
a. Treatment naïve (chemotherapy and RT) patients with prior diagnosis of lower-grade astrocytoma from a biopsy that has been upgraded to a histologically verified glioblastoma after a subsequent definitive surgery.
NOTE: Known isocitrate dehydrogenase (NADP+), mitochondrial (IDH2) or other known isocitrate dehydropgenase (NADP+), soluable (IDH1) variants are to be excluded.
MRI within 21 days prior to randomization.
Post-operative MRI within 96 hours of surgery.
Corticosteroid use of dexamethasone 4 mg or less per day within 5 days prior to randomization.
Karnofsky performance status ≥ 60% performed within a 14-day window prior to randomization.
Administration of any non-cytotoxic agent (e.g., interferon, tamoxifen, thalidomide, cis-retinoic acid, and herbal medicine) has elapsed for 7 days.
Have undergone recent surgery provided that:
a. Prior to surgery there was imaging evidence of measurable disease.
b. 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.
c. Initiation of study treatment is at least 14 days from prior surgery/biopsy for glioblastoma.
For women who are not postmenopausal (i.e., < 2 years after last menstruation) or surgically sterile (absence of ovaries and/or uterus) and who are sexually active: agreement to use an adequate method of contraception (oral contraceptives, intrauterine contraceptive device, or barrier method of contraception in conjunction with spermicidal jelly) during the Treatment period and for at least 6 months after the last dose of study drug.
For male patients who are partners of premenopausal women: agreement to use a barrier method of contraception during the Treatment period and for at least 6 months after the last dose of study drug.
Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are eligible to participate.
Availability of tumor tissue representative of glioblastoma from definitive surgery or biopsy.
Willingness and ability to provide written informed consent and to comply with the study protocol as judged by the Investigator.
For investigational Arm-specific criteria, see Appendix B (control) or Appendix C (study treatment).
Exclusion Criteria
- Received any prior treatment for glioma including:
a. Prior prolifeprospan 20 with carmustine wafer.
b. Prior intracerebral agent.
c. Prior radiation treatment for GBM or lower-grade glioma.
d. Prior chemotherapy or immunotherapy for GBM or lower-grade glioma.
NOTE: 5-aminolevulinic acid-mediated photodynamic therapy administered prior to surgery to aid in optimal surgical resection is not considered a chemotherapy agent.
Receiving additional, concurrent, active therapy for GBM outside of the trial.
Have extensive leptomeningeal disease.
Candidate for urgent palliative intervention for primary disease (e.g., impending herniation) as judged by the Investigator.
History of allergy or hypersensitivity to any of the study treatments or any of their excipients.
Laboratory testing for organ function. Laboratory results must be obtained within 28 days prior to randomization and repeated before treatment initiation if > 7 days have elapsed from when samples were obtained to when testing was performed. These include the following:
a. Absolute neutrophil count (ANC) < 1.5 × 109/L.
b. Platelet count < 100 × 109/L.
c. Hemoglobin (Hb) < 9.0 g/dL (NOTE: The use of transfusion or other intervention to achieve Hb ≥ 9 g/dL is acceptable).
d. 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.
e. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) or alanine aminotransferase (ALT)/serum glutamic-pyruvic transaminase ≥ 3 × ULN.
f. Alkaline phosphatase (ALP) ≥ 2.5 × ULN.
g. Persistent Grade 3 lipase (> 2.0 to 5.0 x ULN with signs or symptoms; > 5.0 x ULN and asymptomatic).
h. Serum creatinine > 1.5 × ULN or calculated creatinine clearance (CrCl) < 60 mL/min (using Cockcroft and Gault).
i. Persistent Grade 3 proteinuria (dipstick ≥ 4+, urine protein ≥ 3.5 g/24 hours, or nephrotic syndrome).
- International normalized ratio (INR), prothrombin time (PT), or activated partial thromboplastin time (aPTT) as follows:
a. In the absence of therapeutic intent to anticoagulate the patient:
i. INR > 1.5.
ii. PT > 1.5 × ULN.
iii. aPTT > 1.5 ×ULN.
b. In the presence of therapeutic intent to anticoagulate the patient:
i. INR or PT and aPTT not within therapeutic limits (according to the medical standard in the institution).
ii. Participant has not been on a stable dose of anticoagulants for at least 2 weeks prior to randomization.
NOTE: Per American Society of Clinical Oncology (ASCO) guidelines, use of low-molecular-weight heparin (LMWH) should be the preferred approach.
QTc > 450 msec if male and QTc > 470 msec if female.
Pregnant or lactating (or a positive pregnancy test within 14 days prior to randomization).
Unable or unwilling to undergo brain MRI scans with intravenous (IV) gadolinium.
History of another malignancy in the previous 3 years, with a disease-free interval of < 3 years. Patients with prior history of in situ cancer or basal or squamous cell skin cancer are eligible.
Serious, non-healing wound, ulcer, bone fracture, or abscess.
Any cerebrovascular accident (including transient ischemic attacks) within the last 6 months prior to initiation of study treatment.
Any hemorrhage or bleeding event that is ≥ Grade 3 based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE), Grade 2 intracranial hemorrhage, or persistent thrombotic/embolic event within 4 weeks prior to the start of study medication.
Uncontrolled or severe cardiac disease (e.g., 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 inotropic support or use of devices for cardiac conditions (e.g., pacemakers/defibrillators), or hypertension (participants with systolic blood pressure [BP] of > 160 mmHg or diastolic BP of > 100 mmHg despite optimal medical management are to be excluded).
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.
Active, known, or suspected auto-immune disease, including systemic lupus erythematosus, Hashimotos thyroiditis, scleroderma, polyarteritis nodosa, or auto-immune hepatitis.
Known history of hepatitis B, human immunodeficiency virus (HIV), or active hepatitis C infection requiring treatment with antiviral therapy.
Note: HIV testing is not required in the absence of clinical suspicion.
History of bleeding diathesis (irrespective of severity).
Uncontrolled intercurrent illness including (e.g., symptomatic ascites), but not limited to ongoing or active infection.
Uncontrolled psychiatric illness or any condition that could make the subject noncompliant with the study procedures and/or study requirements.
For investigational Arm-specific criteria, see Appendix B (control) or Appendix C (study treatment).
