Tremelimumab and Durvalumab in Combination or Alone in Treating Patients With Recurrent Malignant Glioma
Condition: Malignant Glioma; Recurrent Glioblastoma
MeSH terms: Glioblastoma; Glioma; Recurrence
Intervention: Durvalumab; Laboratory Biomarker Analysis; Surgical Procedure; Tremelimumab
Intervention description: Given IV; Correlative Studies; Undergo surgical tumor resection; Given IV
Intervention MeSH terms: Durvalumab; Ipilimumab; Tremelimumab; Immunoglobulins; Antibodies, Monoclonal; Immunoglobulin G
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 36.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

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.
    

Eligibility criteria:

        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