Ipilimumab and/or Nivolumab in Combination With Temozolomide in Treating Patients With Newly Diagnosed Glioblastoma or Gliosarcoma
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| ClinicalTrials.gov Identifier: NCT02311920 |
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Recruitment Status :
Completed
First Posted : December 9, 2014
Last Update Posted : January 10, 2023
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Gliosarcoma Supratentorial Glioblastoma | Biological: Ipilimumab Other: Laboratory Biomarker Analysis Biological: Nivolumab Drug: Temozolomide | Phase 1 |
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.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 32 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Phase I Study of Ipilimumab, Nivolumab, and the Combination in Patients With Newly Diagnosed Glioblastoma |
| Actual Study Start Date : | April 16, 2015 |
| Actual Primary Completion Date : | December 31, 2017 |
| Actual Study Completion Date : | December 22, 2022 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Arm I (temozolomide and ipilimumab)
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 then beginning 3 months after course 4 once every 3 months for 4 courses in the absence unacceptable toxicity.
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Biological: Ipilimumab
Given IV
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies Drug: Temozolomide Given PO
Other Names:
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Experimental: Arm II (temozolomide and nivolumab)
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.
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Other: Laboratory Biomarker Analysis
Correlative studies Biological: Nivolumab Given IV
Other Names:
Drug: Temozolomide Given PO
Other Names:
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Experimental: Arm III (temozolomide, nivolumab, ipilimumab)
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.
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Biological: Ipilimumab
Given IV
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies Biological: Nivolumab Given IV
Other Names:
Drug: Temozolomide Given PO
Other Names:
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- Immune-related dose-limiting toxicities for the single-agent treatment with ipilimumab [ Time Frame: Up to 8 weeks ]The frequency and severity of toxicities will be reported.
- Immune-related dose-limiting toxicities for the single-agent treatment with nivolumab [ Time Frame: Up to 8 weeks ]The frequency and severity of toxicities will be reported.
- Immune-related dose-limiting toxicities for the combination of ipilimumab and nivolumab when given with temozolomide [ Time Frame: Up to 8 weeks ]The frequency and severity of toxicities will be reported.
- Incidence of adverse events, graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 1 month post-treatment ]Will 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.
- Biomarker analysis of immune cells within tumor samples using standard immunohistochemistry [ Time Frame: Up to 1 month post-treatment ]The results of this battery of assays will be used to obtain pilot data and an assessment of feasibility in obtaining reproducible results in preparation for a subsequent randomized, statistically powered comparative clinical trial.
- Number of patients who are alive [ Time Frame: 1 year after the start of immunotherapy treatment ]The number of patients who are alive at 1 year will be reported.
- Number of patients who are alive [ Time Frame: 2 years after the start of immunotherapy treatment ]The number of patients who are alive at 2 years will be reported.
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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)
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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:
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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)
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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)
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- 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
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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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02311920
| United States, California | |
| UCSF Medical Center-Parnassus | |
| San Francisco, California, United States, 94143 | |
| United States, Georgia | |
| Emory University Hospital/Winship Cancer Institute | |
| Atlanta, Georgia, United States, 30322 | |
| United States, Maryland | |
| University of Maryland/Greenebaum Cancer Center | |
| Baltimore, Maryland, United States, 21201 | |
| National Institutes of Health Clinical Center | |
| Bethesda, Maryland, United States, 20892 | |
| United States, Massachusetts | |
| Dana-Farber Cancer Institute | |
| Boston, Massachusetts, United States, 02215 | |
| United States, New York | |
| NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center | |
| New York, New York, United States, 10032 | |
| United States, Ohio | |
| Case Western Reserve University | |
| Cleveland, Ohio, United States, 44106 | |
| Cleveland Clinic Cancer Center/Fairview Hospital | |
| Cleveland, Ohio, United States, 44111 | |
| Cleveland Clinic Foundation | |
| Cleveland, Ohio, United States, 44195 | |
| Ohio State University Comprehensive Cancer Center | |
| Columbus, Ohio, United States, 43210 | |
| United States, Texas | |
| M D Anderson Cancer Center | |
| Houston, Texas, United States, 77030 | |
| Principal Investigator: | Mark R Gilbert | NRG Oncology |
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT02311920 |
| Other Study ID Numbers: |
NCI-2014-02404 NCI-2014-02404 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) NRG-BN002 PNRG-BN002_R05PAPP02 NRG-BN002 ( Other Identifier: NRG Oncology ) NRG-BN002 ( Other Identifier: CTEP ) U10CA180868 ( U.S. NIH Grant/Contract ) |
| First Posted: | December 9, 2014 Key Record Dates |
| Last Update Posted: | January 10, 2023 |
| Last Verified: | January 2023 |
|
Glioblastoma Gliosarcoma Astrocytoma Glioma Neoplasms, Neuroepithelial Neuroectodermal Tumors Neoplasms, Germ Cell and Embryonal Neoplasms by Histologic Type Neoplasms Neoplasms, Glandular and Epithelial |
Neoplasms, Nerve Tissue Nivolumab Ipilimumab Temozolomide Antineoplastic Agents, Immunological Antineoplastic Agents Immune Checkpoint Inhibitors Molecular Mechanisms of Pharmacological Action Antineoplastic Agents, Alkylating Alkylating Agents |