Tremelimumab and Durvalumab in Combination or Alone in Treating Patients with Recurrent Glioblastoma

Inclusion Criteria

• Patients must have a prior diagnosis of grade IV glioma (glioblastoma) per 2016 World Health Organization (WHO) criteria, 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
• 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 resection 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 principal investigator (PI), Dr. Karan Dixit, at (312) 503-4724
• 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); patients must be on no more than 8 mg a day but an attempt should be made to keep the dose at 4 mg or less; please contact the PI if doses of > 4 mg are needed
• Leukocytes >= 3,000/mcL (within 14 days prior to registration)
• Absolute neutrophil count >= 1,500/mcL (within 14 days prior to registration)
• Platelets >= 100,000/mcl (within 14 days prior to registration)
• Hemoglobin (Hb) > 10.0 g/dL (can be transfused to this level) (within 14 days prior to registration)
• International normalized ratio (INR), prothrombin time (PT), or activated partial thromboplastin time (aPTT) as follows (within 14 days prior to registration): * 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) (within 14 days prior to registration)
• 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) (within 14 days prior to registration)
• Serum creatinine < 1.5 x ULN (within 14 days prior to registration)
• 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 (within 14 days prior to registration)
• 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
• 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-PD-1, PD-L2, anti-CD137, 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 surface 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)
• Treatment with radiation therapy within 12 weeks prior to the first dose of study treatment, unless there is tissue confirmation of tumor recurrence or there is progression outside the treatment field
• Administration of any of the following within the specified timeframe prior to the first dose of study drug: * 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 VEGF inhibitor (i.e. bevacizumab)
• 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 4-8 mg, please contact PI if dose is > 4 mg) and weaned to off as is feasible
• Patients receiving any other investigational chemotherapeutic agents within 28 days prior to the first dose of trial treatment
• Patients on an enzyme-inducing anti-convulsant who cannot be switched to a non-enzyme-inducing anti-convulsant with a 2 week wash-out period from time of drug discontinuation until day 1 of study 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 * Unstable angina pectoris, * Cardiac arrhythmia, * Active peptic ulcer disease or gastritis, * Active bleeding diatheses or * 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
• Patients with a history of active malignancy within 3 years prior to registration; note: exceptions to this requirement include adequately treated non-melanoma skin cancer or lentigo maligna or carcinoma in situ without evidence of disease or prostate cancers with a Gleason score < 8 and with prostatectomy and no lymph node involvement
• 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