Description:
This phase II trial studies the effect of immunotherapy drugs (ipilimumab and nivolumab) in
treating patients with glioblastoma that has come back (recurrent) and carries a high number
of mutations. Cancer is caused by changes (mutations) to genes that control the way cells
function. Tumors with high number of mutations may respond well to immunotherapy.
Immunotherapy with monoclonal antibodies such as ipilimumab and nivolumab may help the body's
immune system attack the cancer and may interfere with the ability of tumor cells to grow and
spread. Giving ipilimumab and nivolumab may lower the chance of recurrent glioblastoma with
high number of mutations from growing or spreading compared to usual care (surgery or
chemotherapy).
Title
- Brief Title: A Study Testing the Effect of Immunotherapy (Ipilimumab and Nivolumab) in Patients With Recurrent Glioblastoma With Elevated Mutational Burden
- Official Title: A Phase II Study of Checkpoint Blockade Immunotherapy in Patients With Somatically Hypermutated Recurrent Glioblastoma
Clinical Trial IDs
- ORG STUDY ID:
NCI-2019-07242
- SECONDARY ID:
NCI-2019-07242
- SECONDARY ID:
A071702
- SECONDARY ID:
A071702
- SECONDARY ID:
U10CA180821
- NCT ID:
NCT04145115
Conditions
- Recurrent Glioblastoma
- Secondary Glioblastoma
Interventions
| Drug | Synonyms | Arms |
|---|
| Ipilimumab | Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, Ipilimumab Biosimilar CS1002, MDX-010, MDX-CTLA4, Yervoy | Treatment (nivolumab, ipilimumab) |
| Nivolumab | BMS-936558, CMAB819, MDX-1106, NIVO, Nivolumab Biosimilar CMAB819, ONO-4538, Opdivo | Treatment (nivolumab, ipilimumab) |
Purpose
This phase II trial studies the effect of immunotherapy drugs (ipilimumab and nivolumab) in
treating patients with glioblastoma that has come back (recurrent) and carries a high number
of mutations. Cancer is caused by changes (mutations) to genes that control the way cells
function. Tumors with high number of mutations may respond well to immunotherapy.
Immunotherapy with monoclonal antibodies such as ipilimumab and nivolumab may help the body's
immune system attack the cancer and may interfere with the ability of tumor cells to grow and
spread. Giving ipilimumab and nivolumab may lower the chance of recurrent glioblastoma with
high number of mutations from growing or spreading compared to usual care (surgery or
chemotherapy).
Detailed Description
PRIMARY OBJECTIVE:
I. To determine whether the combination of ipilimumab and nivolumab increases the tumor
response rate assessed by modified Response Assessment in Neuro-Oncology (RANO) Criteria in
patients with hypermutated recurrent glioblastoma.
SECONDARY OBJECTIVES:
I. Estimate the overall survival distribution, median survival, and one-year survival rate of
patients with hypermutated, recurrent glioblastoma who are treated with ipilimumab and
nivolumab.
II. Estimate the progression-free survival distribution and median progression-free survival
of patients with hypermutated, recurrent glioblastoma who are treated with ipilimumab and
nivolumab.
III. Determine the adverse event profile of patients with hypermutated, recurrent
glioblastoma who are treated with ipilimumab and nivolumab.
EXPLORATORY OBJECTIVES:
I. Test whether PD-L1 or immunologic infiltrate in the tumor microenvironment are associated
with objective tumor response, overall survival, progression-free survival, tumor mutational
burden, or rates of grade 3 or higher adverse events.
II. Test whether MGMT status, microsatellite instability (MSI) status, mutational signatures,
or amount of tumor mutational burden (TMB) including germline analysis are associated with
objective tumor response, overall survival, progression-free survival, or rates of grade 3 or
higher adverse events.
III. Evaluate associations between exome and transcriptome gene levels with objective tumor
response, overall survival, progression-free survival, rates of grade 3 or higher adverse
events.
IV. Evaluate associations between the gut microbiome and objective tumor response.
V. Response rate using immunotherapy (i)RANO.
OUTLINE:
Patients receive nivolumab intravenously (IV) over 30 minutes and ipilimumab IV over 30
minutes on day 1. Treatment repeats every 3 weeks for 4 cycles in the absence of disease
progression or unacceptable toxicity. Patients then receive nivolumab IV over 30 minutes on
day 1. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable
toxicity.
After completion of study treatment, patients without disease progression are followed every
8 weeks until disease progression, then every 3 months for up to 3 years. Patients with
disease progression after completion of study treatment are followed every 3 months for up to
3 years.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| Treatment (nivolumab, ipilimumab) | Experimental | Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive nivolumab IV over 30 minutes on day 1. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. | |
Eligibility Criteria
Inclusion Criteria:
- PRE-REGISTRATION:
- Histologically confirmed glioblastoma (World Health Organization [WHO] grade IV)
presenting at first or second recurrence including secondary glioblastoma
- Presence of measurable disease, as defined by a bidimensionally measurable lesion on
magnetic resonance imaging (MRI) with a minimum diameter of 10 mm in both dimensions,
prior to resection or biopsy of recurrent tumor
- Tissue available from surgical resection or biopsy of recurrent tumor =< 14 days prior
to pre-registration, or planned surgery or biopsy of recurrent tumor =< 14 days after
pre-registration
- Does not require > 4 mg dexamethasone beyond the perioperative period defined as the
time =< 2 weeks after surgical procedure
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- Able to undergo brain MRI with contrast
- Absolute neutrophil count >= 1500/mm^3
- Platelet count >= 100,000/mm^3
- Total bilirubin =< 1.5 x upper limit of normal (ULN)
- If Gilbert syndrome, then total bilirubin =< 3 x ULN
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.0 x ULN
- Creatinine =< 1.5 x ULN OR creatinine clearance (CrCl) >= 50 mL/min (if using the
Cockcroft-Gault formula)
- REGISTRATION:
- Tissue obtained from biopsy or resection at first or second recurrence exhibits TMB >=
20 on FoundationOne CDx testing
Exclusion Criteria:
- No active autoimmune disease or history of autoimmune disease
- These include but are not limited to patients with a history of immune related
neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy,
Guillain-Barre syndrome, 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 because of the risk of
recurrence or exacerbation of disease
- 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
- No prior treatment with checkpoint blockade therapies (anti-CTLA4, anti-PD1/PD-L1) or
bevacizumab
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Overall response rate |
| Time Frame: | Up to 32 months |
| Safety Issue: | |
| Description: | Assessed by the Response Assessment in Neuro-Oncology Criteria (RANO). The proportion of patients who have a confirmed tumor response will be computed as the number of patients with a confirmed complete response (CR) or confirmed partial response (PR) as determined by RANO criteria divided by the number of evaluable patients, which are eligible patients who have measurable disease and completed one cycle of treatment. Will be estimated with a binomial point estimate that will be computed as the number of responses divided by the number of evaluable patients. Exact 95% binomial confidence intervals will be generated and reported. |
Secondary Outcome Measures
| Measure: | Overall survival (OS) |
| Time Frame: | From the time of treatment initiation until death from any cause, assessed up to 3 years |
| Safety Issue: | |
| Description: | Will be summarized using Kaplan-Meier (KM) estimators. Survival curves will be generated from the KM estimators. KM estimates will be determined for the median OS as well as the 12-month OS rates. Confidence intervals will be provided for the median values as well as the one-year rates. |
| Measure: | Progression-free survival (PFS) |
| Time Frame: | From the time of treatment initiation until disease progression as measured using RANO criteria or death, whichever occurs first, assessed up to 3 years |
| Safety Issue: | |
| Description: | Will be summarized using KM estimators. Survival curves will be generated from the KM estimators. KM estimates will be determined for the median PFS as well as the 12-month PFS rates. Confidence intervals will be provided for the median values as well as the one-year rates. |
| Measure: | Incidence of adverse events (AEs) |
| Time Frame: | Up to 3 years |
| Safety Issue: | |
| Description: | The AEs will be summarized by the frequency and relative frequency of the maximum grade experienced by the patients for all recorded AEs. Adverse event data will be summarized by each observed AE with the number of patients who reported the AE as well as the proportion of patients with the AE. |
Details
| Phase: | Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | National Cancer Institute (NCI) |
Last Updated
August 30, 2021
