Ipilimumab and/or Nivolumab in Combination With Temozolomide in Treating Patients With Newly Diagnosed Glioblastoma or Gliosarcoma



Status:Active, not recruiting
Conditions:Brain Cancer
Therapuetic Areas:Oncology
Healthy:No
Age Range:18 - Any
Updated:3/9/2019
Start Date:April 16, 2015

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Phase I Study of Ipilimumab, Nivolumab, and the Combination in Patients With Newly Diagnosed Glioblastoma

This phase I trial studies the safety and best dose of ipilimumab, nivolumab, or both in
combination with temozolomide in treating patients with newly diagnosed glioblastoma or
gliosarcoma. Monoclonal antibodies, such as ipilimumab and nivolumab, may block tumor growth
in different ways by targeting certain cells. Drugs used in chemotherapy, such as
temozolomide, work in different ways to stop the growth of tumor cells, either by killing the
cells, by stopping them from dividing, or by stopping them from spreading. It is not yet
known which combination is a better treatment for glioblastoma or gliosarcoma.

PRIMARY OBJECTIVES:

I. Determine the maximum safe dose of single-agent treatment with ipilimumab, nivolumab and
the combination when given with temozolomide during maintenance treatment for newly diagnosed
glioblastoma.

SECONDARY OBJECTIVES:

I. Collect and record the side effect profiles for single-agent treatment with ipilimumab,
nivolumab, and the combination when given with temozolomide during the maintenance phase for
newly diagnosed glioblastoma.

II. Perform pilot studies of immune cells within tumor samples, e.g. phenotyping tumor
infiltrating lymphocytes (TILs) by interrogating tumor tissues from diagnostic tumor blocks.

III. Report the number of patients alive at 1 and 2 years after the start of single-agent
treatment with ipilimumab, nivolumab, and the combination when given with temozolomide during
the maintenance phase for newly diagnosed glioblastoma.

OUTLINE: Patients are randomized to 1 of 3 treatment arms.

ARM I: Within 5 weeks after completion of chemoradiation, patients receive temozolomide
orally (PO) on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence
of disease progression or unacceptable toxicity. Patients also receive ipilimumab
intravenously (IV) over 90 minutes once every 4 weeks for 4 courses and then beginning 3
months after course 4 once every 3 months for 4 courses in the absence unacceptable toxicity.

ARM II: Within 5 weeks after completion of chemoradiation, patients receive temozolomide PO
on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease
progression or unacceptable toxicity. Patients also receive nivolumab IV over 60 minutes once
every 2 weeks for 16 weeks and then once every 2 weeks for 48 weeks in the absence
unacceptable toxicity.

ARM III: Within 5 weeks after completion of chemoradiation, patients receive temozolomide PO
on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease
progression or unacceptable toxicity. Patients also receive ipilimumab IV over 90 minutes
once every 4 weeks for 4 courses and nivolumab IV over 60 minutes once every 2 weeks for 64
weeks in the absence unacceptable toxicity.

After completion of study treatment, patients are followed up at 1 month, and then every 3
months for 1 year, every 4 months for 1 year, and then every 6 months thereafter.

Inclusion Criteria:

- Histopathologically proven diagnosis of glioblastoma or gliosarcoma prior to
registration by pathology report

- The tumor must be unifocal, confined to the supratentorial compartment and have
undergone a gross total or near gross total resection; this will increase the
likelihood that the patient will not require corticosteroids or develop
pseudoprogression

- The formalin-fixed, paraffin-embedded (FFPE) tumor tissue block must be available to
be sent for retrospective central pathology review after registration

- Patients must be registered within 35 days of completion of chemoradiation

- History/physical examination within 7 days prior to registration

- Patients must have undergone an evaluation by magnetic resonance imaging (MRI) within
35 days of completing radiation and must also be within 7 days prior to registration;
MRI must NOT demonstrate tumor progression, but patients with imaging changes
consistent with pseudo-progression, stable neurologic function and not needing
corticosteroid treatment are eligible

- Karnofsky performance status >= 70 within 7 days prior to registration

- Absolute neutrophil count >= 1,500 cells/mm^3

- Platelet count >= 100,000 cells/mm^3

- Hemoglobin (Hgb) > 9 g/dL (can be achieved with transfusion)

- Blood urea nitrogen (BUN) =< 30 mg/dl

- Serum creatinine =< 1.7 mg/dl

- Total bilirubin (except patients with Gilbert's syndrome, who are eligible for the
study but exempt from the total bilirubin eligibility criterion) =< 2.0 mg/dl

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x upper
limit of normal (ULN)

- The patient must have completed chemoradiation (all cohorts) within standards of care
established by prior Radiation Therapy Oncology Group (RTOG)/Network Radiotherapy
Group (NRG) Oncology studies as follows:

- Radiation therapy

- Modality: either 3-dimensional (3D) or intensity-modulated radiation therapy
(IMRT), or proton therapy is allowed

- Time to initiation: radiotherapy must be initiated within or equal to 42
days after surgery

- Target volumes: target volume definition will be based upon
postoperative-enhanced MRI; preoperative imaging should be used for
correlation and improved identification, as necessary

- Dose guidelines: the initial target volume will be treated to 46 Gray (Gy)
in 23 fractions; after 46 Gy, the cone-down or boost volume will be treated
to a total of 60 Gy, with seven additional fractions of 2 Gy each (14 Gy
boost dose)

- Temozolomide during concomitant radiation therapy

- Temozolomide must have been administered continuously from day 1 of
radiotherapy to the last day of radiation (+/- 3 days to take into
consideration holidays) at a daily oral dose of 75 mg/m^2 for a maximum of
49 days (except missed doses due to toxicity)

- The patient must not be on a corticosteroid dose greater than physiologic replacement
dosing defined as 30 mg of cortisone per day or its equivalent

- The patient must provide study-specific informed consent prior to study entry

- Echocardiogram (ECHO) cardiogram and cardiology consultation required within 7 days
prior to registration for patients with a history of congestive heart failure or
cardiovascular disease or history of exposure to cardiotoxic agents who are not
already excluded

Exclusion Criteria:

- Definitive clinical or radiologic evidence of progressive disease

- Prior placement of Gliadel wafer or local brachytherapy

- Use of an immunotherapy such as a vaccine therapy, dendritic cell vaccine or
intracavitary or convectional enhanced delivery of therapy

- Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free
for a minimum of 3 years

- Unstable angina within the last 6 months prior to registration

- Transmural myocardial infarction within the last 6 months prior to registration

- Evidence of recent myocardial infarction or ischemia by the findings of S-T elevations
of >= 2 mm using the analysis of an electrocardiogram (EKG) performed within 7 days
prior to registration

- New York Heart Association grade II or greater congestive heart failure requiring
hospitalization within 12 months prior to registration

- History of stroke, cerebral vascular accident (CVA) or transient ischemic attack
within 6 months prior to registration

- Serious and inadequately controlled cardiac arrhythmia

- Significant vascular disease (e.g., aortic aneurysm, history of aortic dissection) or
clinically significant peripheral vascular disease

- Evidence of bleeding diathesis or coagulopathy

- Serious or non-healing wound, ulcer, or bone fracture or history of abdominal fistula,
gastrointestinal perforation, intra-abdominal abscess major surgical procedure, open
biopsy, or significant traumatic injury within 28 days prior to registration, with the
exception of the craniotomy for tumor resection

- Acute bacterial or fungal infection requiring intravenous antibiotics at the time of
registration

- Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy at the time of registration

- Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note,
however, that laboratory tests for additional liver function tests and coagulation
parameters are not required for entry into this protocol

- Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease
Control and Prevention (CDC) definition; note, however, that human immunodeficiency
virus (HIV) testing is not required for entry into this protocol

- Active connective tissue disorders, such as lupus or scleroderma, which in the opinion
of the treating physician may put the patient at high risk for immunologic toxicity

- Patients with active autoimmune disease or history of autoimmune disease that might
recur, which may affect vital organ function or require immune suppressive treatment
including systemic corticosteroids, should be excluded; these include but are not
limited to patients with a history of immune related neurologic disease, multiple
sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome or chronic
inflammatory demyelinating polyneuropathy (CIDP), myasthenia gravis; systemic
autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue
diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis,
hepatitis; and patients with a history of toxic epidermal necrolysis (TEN),
Stevens-Johnson syndrome, or phospholipid syndrome should be excluded

- Of note, patients with vitiligo, endocrine deficiencies including thyroiditis
managed with replacement hormones including physiologic corticosteroids are
eligible; patients with rheumatoid arthritis and other arthropathies, Sjogren's
syndrome and psoriasis controlled with topical medication and patients with
positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies
should be evaluated for the presence of target organ involvement and potential
need for systemic treatment but should otherwise be eligible

- Any other major medical illnesses or psychiatric impairments that in the
investigator's opinion will prevent administration or completion of protocol therapy

- Pregnancy or lactating females; women of childbearing potential must have a negative
serum pregnancy test within 7 days prior to registration

- History of severe hypersensitivity reaction to any monoclonal antibody
We found this trial at
11
sites
10900 Euclid Ave
Cleveland, Ohio 44106
216-368-2000
Principal Investigator: Lisa R. Rogers
Phone: 800-641-2422
Case Western Reserve Univ Continually ranked among America's best colleges, Case Western Reserve University has...
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22 South Greene Street
Baltimore, Maryland 21201
410-328-7904
Principal Investigator: Edward A. Sausville
Phone: 800-888-8823
University of Maryland Greenebaum Cancer Center The University of Maryland Marlene and Stewart Greenebaum Cancer...
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Baltimore, MD
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9000 Rockville Pike
Bethesda, Maryland 20892
301-496-2563
Principal Investigator: Mark R. Gilbert
Phone: 800-411-1222
National Institutes of Health Clinical Center The National Institutes of Health (NIH) Clinical Center in...
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450 Brookline Ave
Boston, Massachusetts 2215
617-632-3000
Principal Investigator: Patrick Y. Wen
Phone: 877-442-3324
Dana-Farber Cancer Institute Since it’s founding in 1947, Dana-Farber has been committed to providing adults...
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18101 Lorain Avenue
Cleveland, Ohio 44111
216.476.7000
Principal Investigator: Mark R. Gilbert
Phone: 301-402-6298
Cleveland Clinic Cancer Center at Fairview Hospital Fairview Hospital is a 488-bed hospital located at...
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2049 E 100th St
Cleveland, Ohio 44106
(216) 444-2200
Principal Investigator: Manmeet S. Ahluwalia
Phone: 866-223-8100
Cleveland Clinic Foundation The Cleveland Clinic (formally known as The Cleveland Clinic Foundation) is a...
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Columbus, Ohio 43210
Principal Investigator: Raju R. Raval
Phone: 800-293-5066
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Houston, Texas 77030
Principal Investigator: John F. de Groot
Phone: 713-792-3245
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Houston, TX
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San Francisco, California 94143
Principal Investigator: Nicholas A. Butowski
Phone: 877-827-3222
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San Francisco, CA
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