Tremelimumab and Durvalumab in Combination or Alone in Treating Patients With Recurrent Malignant Glioma

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.

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