Malignant Glioma, Recurrent Glioblastoma
Conditions
Brief summary
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.
Detailed description
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.
Interventions
BIOLOGICALDurvalumab
Given IV
OTHERLaboratory Biomarker Analysis
Correlative Studies
PROCEDURESurgical Procedure
Undergo surgical tumor resection
BIOLOGICALTremelimumab
Given IV
Sponsors
AstraZeneca
MedImmune LLC
National Cancer Institute (NCI)
Northwestern University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have a grade III or IV glioma that has progressed after standard radiotherapy (RT) and temozolomide (TMZ) (Note: Pathology will need to be reviewed locally but registration can occur based on pathology report) * Patients must have had radiographic evidence of tumor progression by brain MRI or computed tomography (CT) scan with contrast * Patients must be \> 12 weeks from completion of radiation therapy unless there is tissue confirmation of tumor recurrence or there is progression outside the radiation treatment field * 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 occurs remote from the treated site * Patients must be surgical candidates * Patients must have had no more than 3 prior lines of chemotherapy; this includes the initial treatment and two relapses; concurrent and adjuvant TMZ-based chemotherapy, including the combination of TMZ with another agent, is considered one line of chemotherapy; for clarification, please contact the principle investigator (PI), Dr. Jeffrey Raizer, at (312) 695-0990 * Patients must be \>= * 4 weeks from TMZ * 6 weeks from a nitrosoureas * 3 weeks from a biologic or targeted agent (i.e. small molecule) * 4 weeks for a vascular endothelial growth factor (VEGF) inhibitor (i.e. bevacizumab) * Patients must exhibit a Karnofsky performance status (KPS) \>= 70 * Life expectancy of \>= 12 weeks (per treating investigator's discretion) * Patients must be on a stable or decreasing dose of corticosteroids within 5 days prior to CT scan or MRI (which is done to determine eligibility); the goal should be dexamethasone 4 mg or less at the time of starting treatment; if patient requires \> 4mg of steroid, please check with the principle investigator (PI); requirement for greater than 10mg of steroid will make the patient ineligible * Leukocytes \>= 3,000/mcL * Absolute neutrophil count \>= 1,500/mcL * Platelets \>= 100,000/mcl * Hemoglobin (Hb) \> 10.0 g/dL (can be transfused to this level) * International Normalized Ratio (INR), prothrombin time (PT), or activated partial thromboplastin time (aPTT) as follows: * In the absence of therapeutic intent to anticoagulate the patient: INR \< 1.5 or PT \< 1.5 x upper normal limit (ULN) or aPTT \< 1.5 x ULN * In the presence of therapeutic intent to anticoagulate the patient: INR or PT and aPTT within therapeutic limits (according to the medical standard in the institution) and the patient has been on a stable dose of anticoagulants for at least 2 weeks before registration * Total bilirubin =\< 1.5 x ULN (except in patients with Gilbert's disease) * Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT)/ alanine aminotransferase (ALT) serum glutamic pyruvic transaminase (SPGT) =\< 2.5 X institutional upper limit of normal (ULN) * Serum creatinine \< 1.5 x ULN * Serum creatinine clearance (CL) \> 40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance * Females of child-bearing potential (FOCBP) and males must agree to use adequate contraception (e.g. hormonal or barrier method of birth control prior to registration, for the duration of study participation, and for 180 days after the last dose of MEDI4736 + tremelimumab combination therapy or 90 days after the last dose of MEDI4736 or tremelimumab monotherapy; should a female patient become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately NOTE: A FOCBP is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets both of the following criteria: * Has not undergone a hysterectomy or bilateral oophorectomy * Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for \> 12 months) * FOCBP must have a negative pregnancy test (serum or urine) within 7 days prior to registration on study * Patients must have the ability to understand and the willingness to sign a written informed consent prior to registration on study * Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up * Malignancy treated with curative intent and with no known active disease \>=3 years before the first dose of study drug and of low potential risk for recurrence; NOTE: the exceptions to this requirement include adequately treated non-melanoma skin cancer or lentigo maligna or carcinoma in situ without evidence of disease * Patients can only be on non-enzyme inducing anti-convulsants; if they are on an enzyme inducing anti-convulsant, they may be converted to a non-enzyme inducing anti-convulsants but they will need a 2 week wash out period from time of drug discontinuation until day 1 of study treatment * Patients must have given written, signed and dated informed consent prior to registration on the study; NOTE: no study-specific screening procedures may be performed until consent has been given
Exclusion criteria
* Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site); previous enrolment or randomization in the present study * Has received prior therapy with an anti-programmed cell death protein 1 (PD-1), anti-programmed cell death ligand 2 (PD-L2), anti-cluster of differentiation (CD)137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) * Has known active hepatitis B (e.g., hepatitis B virus antigen \[HBsAg\] reactive) or hepatitis C (e.g., hepatitis c virus \[HCV\] ribonucleic acid \[RNA\] \[qualitative\] is detected) * Known active human immunodeficiency virus (HIV1/2 antibodies) * Patient has history of primary immunodeficiency OR has received any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment, excluding intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses; attempts should be made to have patient on lowest possible dose of steroids (acceptable range 4-10mg, please contact PI if dose is \>4 mg) and weaned to off as is feasible * Patients receiving any other investigational chemotherapeutic agents within 30 days prior to the first dose of trial treatment * Mean QT interval corrected for heart rate (QTc) \>= 470 ms calculated from an electrocardiograms (ECGs) using Bazett's Correction; if first ECG is abnormal, then the mean will be calculated from 3 consecutive ECGs (taken 2-5 minutes apart); please contact the PI for further clarification * Active or prior documented history of immunologic disorder including autoimmune disease within the past 2 years NOTE: Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded * Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis) * History of allogeneic organ transplant * Uncontrolled intercurrent illness including, but not limited to, * Ongoing or active infection, * Symptomatic congestive heart failure, * Uncontrolled hypertension (defined as \> 150/90) * Unstable angina pectoris, * Cardiac arrhythmia, * Active peptic ulcer disease or gastritis, * Active bleeding diatheses * Psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent * Known history of previous clinical diagnosis of tuberculosis * History of leptomeningeal carcinomatosis * Receipt of live attenuated vaccination within 30 days prior to study entry (or due to receive one within 30 days of receiving either MEDI4736 or tremelimumab) * Female subjects who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control * Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results * Subjects with uncontrolled seizures * Patients who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to MEDI3475 are not eligible
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| T-cell (Immunologic) Changes in Blood | 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) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| MRI Changes | Baseline and 3 days after surgery | 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. |
| Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | 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 | 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. |
| Overall Survival | 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 | 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 to Progression | 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 | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| T-cell Changes | Up to 2 years | Immunologic changes of T-cells will be correlated to survival outcomes. T-cell changes will be measured from blood samples. |
| PDL1 Expression | Up to 2 years | Immunologic changes of PDL1 levels will be correlated to survival outcomes. PDL1 levels will be measured from blood samples. |
Countries
United States
Participant flow
Recruitment details
The study opened to accrual on September 13th, 2016 with an accrual goal of 36 patients. The first patient was enrolled onto the study and started treatment on November 1st, 2016. The accrual goal was met on April 5th, 2018. The study intended to increase the accrual goal, but the funding sponsor did not approve additional funding. The study closed permanently to further enrollment of participants on January 22nd, 2019.
Participants by arm
| Arm | Count |
|---|---|
| Arm 1: Tremelimumab Only * Pre-Surgery (14 days +/-3 days prior to surgery): One dose of tremelimumab IV, 75 mg.
* Post-surgical MRI of brain will be done 72 hours after surgery.
* Post-Surgery (14 days after surgery): Tremelimumab IV, 5 mg, every 4 weeks for up to 24 months until disease progression or unacceptable toxicity.
* Contrast-enhanced MRI or CT scan will be done approximately every 2 cycles or 8 weeks. | 12 |
| Arm 2: MEDI4736 Only * Pre-Surgery (14 days +/-3 days prior to surgery): One dose of MEDI4736, 750 mg IV
* Post-surgical MRI of brain will be done within 72 hours after surgery.
* Post-Surgery (14 days after surgery): MEDI4736, 750 mg IV every 2 weeks for up to 24 months until disease progression or unacceptable toxicity.
* Contrast-enhanced MRI or CT scan will be done approximately every 2 cycles or 8 weeks | 12 |
| Arm 3: Tremelimumab + MEDI4736 * Pre-Surgery (14 days +/-3 days prior to surgery): One dose of tremelimumab IV, 75 mg, one dose of MEDI4736, 750 mg IV
* Post-surgical MRI of brain will be done within 72 hours after surgery.
* Post-Surgery (14 days after surgery): Tremelimumab IV, 75 mg, every 4 weeks (for up to 7 doses), MEDI4736 IV, 750 mg, every 2 weeks (for up to 14 doses).
* Starting C7D1 (week 25): Tremelimumab IV, 75 mg, every 12 weeks and MEDI4736 IV, 750mg, every 2 weeks, for up to 24 months until disease progression or unacceptable toxicity.
* On days when tremelimubab and MEDI4736 are given on the same day, tremilimumab is administered first, then MED14736 infused after a gap of 1 hour for the first cycle. If tolerated, then can be given one after the other for subsequent infusions.
* Contrast-enhanced MRI or CT scan will be done approximately every 2 cycles or 8 weeks | 12 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Follow-up Period (up to 2 Years) | Death | 12 | 10 | 10 |
| Post-Surgery Treatment (Adjuvant) | Adverse Event | 0 | 1 | 1 |
| Post-Surgery Treatment (Adjuvant) | Progressive Disease | 10 | 6 | 10 |
| Post-Surgery Treatment (Adjuvant) | Protocol Violation | 1 | 0 | 0 |
| Post-Surgery Treatment (Adjuvant) | Withdrawal by Subject | 1 | 4 | 0 |
| Pre-Surgical Treatment | Progressive Disease | 0 | 1 | 0 |
| Pre-Surgical Treatment | Withdrawal by Subject | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Arm 1: Tremelimumab Only | Arm 2: MEDI4736 Only | Arm 3: Tremelimumab + MEDI4736 | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 2 Participants | 4 Participants | 7 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 10 Participants | 8 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 1 Participants | 1 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 11 Participants | 11 Participants | 31 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 11 Participants | 12 Participants | 33 Participants |
| Region of Enrollment United States | 12 participants | 12 participants | 12 participants | 36 participants |
| Sex: Female, Male Female | 4 Participants | 3 Participants | 5 Participants | 12 Participants |
| Sex: Female, Male Male | 8 Participants | 9 Participants | 7 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 12 / 12 | 10 / 11 | 10 / 11 |
| other Total, other adverse events | 12 / 12 | 11 / 11 | 11 / 11 |
| serious Total, serious adverse events | 9 / 12 | 10 / 12 | 8 / 12 |
Outcome results
Primary
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)
Population: Blood samples were collected from patients and shipped to an outside organization. The PI has contacted the outside organization to request T-cell data to be collected from blood samples and followed up multiple times. Outside organization has been unresponsive. There is no data collected from blood samples and will not be any data generated in the future from bloods samples for this endpoint. We have no data to report for this endpoint
Secondary
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: Tremelimumab Only | MRI Changes | 1410 milimeters squared | Standard Deviation 4290 |
| Arm 2: MEDI4736 Only | MRI Changes | 1720 milimeters squared | Standard Deviation 2730 |
| Arm 3: Tremelimumab + MEDI4736 | MRI Changes | 3020 milimeters squared | Standard Deviation 7320 |
Secondary
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
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm 1: Tremelimumab Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Acute Encephalopathy | 1 Participants |
| Arm 1: Tremelimumab Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Pulmonary Embolism | 1 Participants |
| Arm 1: Tremelimumab Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Hydrocephalus | 0 Participants |
| Arm 1: Tremelimumab Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Viral meningitis | 0 Participants |
| Arm 1: Tremelimumab Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Wound dehiscence | 0 Participants |
| Arm 1: Tremelimumab Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Intraparenchymal hemorrhage | 0 Participants |
| Arm 1: Tremelimumab Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Back Pain | 0 Participants |
| Arm 1: Tremelimumab Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 5 Intracranial hemorrhage | 1 Participants |
| Arm 1: Tremelimumab Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Encephalopathy | 0 Participants |
| Arm 1: Tremelimumab Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Weakness | 0 Participants |
| Arm 1: Tremelimumab Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Left-sided Weakness | 1 Participants |
| Arm 1: Tremelimumab Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Stroke | 0 Participants |
| Arm 1: Tremelimumab Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 4 Encephalopathy | 1 Participants |
| Arm 1: Tremelimumab Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 5 Disease Progression | 5 Participants |
| Arm 1: Tremelimumab Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Wound Infection | 0 Participants |
| Arm 1: Tremelimumab Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 4 Seizures | 1 Participants |
| Arm 1: Tremelimumab Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 UTI | 2 Participants |
| Arm 1: Tremelimumab Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 4 Sepsis | 0 Participants |
| Arm 1: Tremelimumab Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Seizures | 1 Participants |
| Arm 1: Tremelimumab Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Colitis | 0 Participants |
| Arm 1: Tremelimumab Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Clinical decline | 2 Participants |
| Arm 1: Tremelimumab Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Fall | 1 Participants |
| Arm 1: Tremelimumab Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Gait imbalance | 0 Participants |
| Arm 2: MEDI4736 Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 4 Seizures | 0 Participants |
| Arm 2: MEDI4736 Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 UTI | 0 Participants |
| Arm 2: MEDI4736 Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Pulmonary Embolism | 0 Participants |
| Arm 2: MEDI4736 Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Fall | 0 Participants |
| Arm 2: MEDI4736 Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 5 Intracranial hemorrhage | 0 Participants |
| Arm 2: MEDI4736 Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 4 Encephalopathy | 1 Participants |
| Arm 2: MEDI4736 Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Clinical decline | 0 Participants |
| Arm 2: MEDI4736 Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Acute Encephalopathy | 0 Participants |
| Arm 2: MEDI4736 Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Viral meningitis | 1 Participants |
| Arm 2: MEDI4736 Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Back Pain | 1 Participants |
| Arm 2: MEDI4736 Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Weakness | 1 Participants |
| Arm 2: MEDI4736 Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Encephalopathy | 1 Participants |
| Arm 2: MEDI4736 Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Intraparenchymal hemorrhage | 1 Participants |
| Arm 2: MEDI4736 Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Hydrocephalus | 1 Participants |
| Arm 2: MEDI4736 Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Gait imbalance | 1 Participants |
| Arm 2: MEDI4736 Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Colitis | 0 Participants |
| Arm 2: MEDI4736 Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 4 Sepsis | 0 Participants |
| Arm 2: MEDI4736 Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Wound Infection | 0 Participants |
| Arm 2: MEDI4736 Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Stroke | 0 Participants |
| Arm 2: MEDI4736 Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Wound dehiscence | 0 Participants |
| Arm 2: MEDI4736 Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 5 Disease Progression | 4 Participants |
| Arm 2: MEDI4736 Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Left-sided Weakness | 0 Participants |
| Arm 2: MEDI4736 Only | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Seizures | 4 Participants |
| Arm 3: Tremelimumab + MEDI4736 | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Gait imbalance | 0 Participants |
| Arm 3: Tremelimumab + MEDI4736 | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Seizures | 2 Participants |
| Arm 3: Tremelimumab + MEDI4736 | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Pulmonary Embolism | 0 Participants |
| Arm 3: Tremelimumab + MEDI4736 | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Colitis | 1 Participants |
| Arm 3: Tremelimumab + MEDI4736 | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 4 Seizures | 0 Participants |
| Arm 3: Tremelimumab + MEDI4736 | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Left-sided Weakness | 1 Participants |
| Arm 3: Tremelimumab + MEDI4736 | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 4 Sepsis | 1 Participants |
| Arm 3: Tremelimumab + MEDI4736 | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 4 Encephalopathy | 0 Participants |
| Arm 3: Tremelimumab + MEDI4736 | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 5 Disease Progression | 2 Participants |
| Arm 3: Tremelimumab + MEDI4736 | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Wound Infection | 1 Participants |
| Arm 3: Tremelimumab + MEDI4736 | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 5 Intracranial hemorrhage | 0 Participants |
| Arm 3: Tremelimumab + MEDI4736 | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Weakness | 0 Participants |
| Arm 3: Tremelimumab + MEDI4736 | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Back Pain | 0 Participants |
| Arm 3: Tremelimumab + MEDI4736 | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 UTI | 1 Participants |
| Arm 3: Tremelimumab + MEDI4736 | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Encephalopathy | 1 Participants |
| Arm 3: Tremelimumab + MEDI4736 | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Viral meningitis | 0 Participants |
| Arm 3: Tremelimumab + MEDI4736 | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Stroke | 1 Participants |
| Arm 3: Tremelimumab + MEDI4736 | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Intraparenchymal hemorrhage | 0 Participants |
| Arm 3: Tremelimumab + MEDI4736 | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Acute Encephalopathy | 0 Participants |
| Arm 3: Tremelimumab + MEDI4736 | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Fall | 0 Participants |
| Arm 3: Tremelimumab + MEDI4736 | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Hydrocephalus | 0 Participants |
| Arm 3: Tremelimumab + MEDI4736 | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Clinical decline | 0 Participants |
| Arm 3: Tremelimumab + MEDI4736 | Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 | Grade 3 Wound dehiscence | 1 Participants |
Secondary
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: Tremelimumab Only | Overall Survival | 7.246 months |
| Arm 2: MEDI4736 Only | Overall Survival | 11.71 months |
| Arm 3: Tremelimumab + MEDI4736 | Overall Survival | 7.703 months |
Secondary
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: Tremelimumab Only | Time to Progression | 2.746 months |
| Arm 2: MEDI4736 Only | Time to Progression | 4.356 months |
| Arm 3: Tremelimumab + MEDI4736 | Time to Progression | 4.913 months |
Other Pre-specified
PDL1 Expression
Immunologic changes of PDL1 levels will be correlated to survival outcomes. PDL1 levels will be measured from blood samples.
Time frame: Up to 2 years
Other Pre-specified
T-cell Changes
Immunologic changes of T-cells will be correlated to survival outcomes. T-cell changes will be measured from blood samples.
Time frame: Up to 2 years