The main purpose of this trial is to investigate the effects of a new class of drugs that help the patient's immune system attack their tumor (glioblastoma multiforme - GBM). These drugs have already shown benefit in some other cancer types and are now being explored in GBM. Both tremelimumab and durvalumab (MEDI4736) are "investigational" drugs, which means that the drugs are not approved by the Food and Drug Administration (FDA). Both drugs are antibodies (proteins used by the immune system to fight infections and cancers). Durvalumab attaches to a protein in tumors called PD-L1. It may prevent cancer growth by helping certain blood cells of the immune system get rid of the tumor. Tremelimumab stimulates (wakes up) the immune system to attack the tumor by inhibiting a protein molecule called CTLA-4 on immune cells. Combining the actions of these drugs may result in better treatment options for patients with glioblastoma.
PRIMARY OBJECTIVES: I. To determine the T-cell changes that occur in glioblastoma (GBM) treated with tremelimumab and durvalumab (MEDI4736) as single agents and in combination. SECONDARY OBJECTIVES: I. To evaluate the safety of either tremelimumab or MEDI4736 alone and in combination in patients with GBM. II. To determine the time to progression for patients treated with either tremelimumab or MEDI4736 alone and in combination of both, post-surgery. III. To determine the overall survival for patients treated with tremelimumab or MEDI4736 alone and in combination of both post-surgery. IV. To assess magnetic resonance imaging (MRI) changes in patients treated with either tremelimumab or MEDI4736 alone and in combination of both post-surgery. TERTIARY OBJECTIVES: I. To correlate T-cell changes and programmed death ligand 1 (PDL1) expression with patient outcomes. OUTLINE: Patients are randomized to 1 of 3 arms. ARM 1: Patients receive tremelimumab intravenously (IV) over 1 hour on day 1. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. ARM 2: Patients receive durvalumab IV over 1 hour on days 1 and 15. Courses repeat every 2 weeks in the absence of disease progression or unacceptable toxicity. ARM 3: Patients receive tremelimumab IV over 1 hour on day 1 then, after a gap of 1 hour for the first cycle, durvalumab IV over 1 hour on days 1 and 15. Courses repeat every 4 weeks with tremelimumab for up to 7 courses and every 2 weeks with durvalumab for up to 14 courses. Patients then receive both tremelimumab and durvalumab IV over 1 hour every 12 weeks in the absence of disease progression or unacceptable toxicity. All patients undergo surgical tumor resection on day 14. After completion of study treatment, patients are followed up every 8-16 weeks for 2 years.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
36
Given IV
Correlative Studies
Undergo surgical tumor resection
Given IV
Northwestern University
Chicago, Illinois, United States
T-cell (Immunologic) Changes in Blood
To determine the T-cell changes that occur in glioblastoma treated with tremelimumab and MEDI4736 as single agents and in combination. The changes from baseline will be assessed in blood samples and tissue samples before pre-surgery treatment with MEDI4736 and/or tremelimumab, day of surgery, and during adjuvant treatment, for all patients in the 3 arms.
Time frame: From baseline up to end of treatment, where all patients received at least 1 dose pre-surgery, and range of cycles attempted post-surgery was 0-16 (1 Cycle = 4 weeks)
MRI Changes
To assess MRI changes in lesion size in patients treated with either Tremelimumab or MEDI4736 alone and in combination of both post surgery. Only patients who have been administered at least one dose of investigational drug, undergone surgery, and have undergone at least one post-surgery disease assessment will be evaluable for this endpoint. Changes will be summarized using means. MRI changes below show the changes from baseline to after surgery.
Time frame: Baseline and 3 days after surgery
Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5
Toxicity, both frequency and severity, will continue to be measured by monitoring the occurrence of adverse events. Adverse events will be defined as those included in CTCAE v 4.03. AEs graded 3, 4, 5 (regardless of attribution to the study drug) are included here. Grade 1 (mild): the event causes discomfort without disruption of normal daily activities. Grade 2 (moderate): the event causes discomfort that affects normal daily activities. Grade 3 (severe): the event makes the patient unable to perform normal daily activities or significantly affects his/her clinical status. Grade 4 (Life-threatening): the patient was at risk of death at the time of the event. Grade 5 (fatal): the event caused death.
Time frame: From baseline, pre-surgery treatment period (2 weeks prior to surgery), and post-surgery treatement, where the range of cycles attempted post-surgery was 0-16 (1 Cycle = 4 weeks), to 90 days post treatment discontinuation
Overall Survival
To determine post-surgery the overall survival for patients treated with Tremelimumab or MEDI4736 alone and in combination. This will be defined as the number of months surviving from the time of first dose of study treatment until death by any cause. Only patients who have been administered at least one dose of investigational drug and undergone surgery will be evaluable for this endpoint.
Time frame: From the start of treatment (pre-surgery treatment period = 2 weeks), to surgery, to post-surgery treatment, where range of cycles attempted was 0-16 (1 Cycle = 4 weeks), to 2 years post treatment discontinuation
Time to Progression
To the time to progression (per Modified RANO criteria and iRANO criteria) for patients treated with either Tremelimumab or MEDI4736 alone and in combination. This will be defined as the number of months from the time of first dose of study treatment until progression of disease (PD) or death from any cause. Only patients who have been administered at least one dose of investigational drug and undergone surgery will be evaluable for this endpoint. Definition of PD per RANO criteria: New contrast-enhancing lesion outside of radiation field on decreasing, stable, or increasing doses of corticosteroids; Increase by \> 50% (modified from \>25% according to published RANO criteria) enhancement from the first post-surgical scan, or a subsequent scan with smaller tumor size, and the scan 8 weeks or later on stable or increasing doses of corticosteroids; Clinical deterioration not attributable to concurrent medication or comorbid conditions.
Time frame: From start of treatment (pre-surgery treatment period = 2 weeks), to surgery, to post-surgery treatment where range of cycles attempted was 0-16 (1 Cycle = 4 weeks), and up to 2 years of follow-up after treatment discontinuation
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