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History of Changes for Study: NCT04145115
A Study Testing the Effect of Immunotherapy (Ipilimumab and Nivolumab) for People With Recurrent Glioblastoma With Elevated Mutational Burden
Latest version (submitted August 4, 2022) on ClinicalTrials.gov
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Study Record Versions
Version A B Submitted Date Changes
1 October 29, 2019 None (earliest Version on record)
2 November 6, 2019 Study Status
3 December 5, 2019 Study Description and Study Status
4 December 9, 2019 Study Status
5 January 10, 2020 Study Status and Study Identification
6 January 20, 2020 Study Status
7 February 3, 2020 Conditions and Study Status
8 April 15, 2020 Study Status
9 April 16, 2020 Oversight and Study Status
10 May 2, 2020 Study Status
11 June 16, 2020 Oversight and Study Status
12 June 24, 2020 Study Status
13 July 18, 2020 Study Status
14 October 16, 2020 Study Status, Eligibility and Study Description
15 October 24, 2020 Study Status
16 November 6, 2020 Recruitment Status, Study Status and Contacts/Locations
17 November 7, 2020 Study Status and Contacts/Locations
18 November 10, 2020 Contacts/Locations and Study Status
19 November 18, 2020 Contacts/Locations and Study Status
20 December 1, 2020 Contacts/Locations and Study Status
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24 December 30, 2020 Contacts/Locations and Study Status
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29 January 14, 2021 Contacts/Locations and Study Status
30 January 15, 2021 Contacts/Locations and Study Status
31 January 19, 2021 Contacts/Locations, Arms and Interventions and Study Status
32 January 21, 2021 Contacts/Locations and Study Status
33 January 23, 2021 Contacts/Locations and Study Status
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37 January 30, 2021 Contacts/Locations and Study Status
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40 February 11, 2021 Contacts/Locations and Study Status
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48 March 25, 2021 Contacts/Locations and Study Status
49 April 2, 2021 Study Status
50 April 3, 2021 Contacts/Locations and Study Status
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60 May 25, 2021 Contacts/Locations and Study Status
61 May 27, 2021 Contacts/Locations and Study Status
62 May 29, 2021 Contacts/Locations and Study Status
63 June 8, 2021 Contacts/Locations, Arms and Interventions and Study Status
64 June 11, 2021 Contacts/Locations and Study Status
65 June 12, 2021 Contacts/Locations and Study Status
66 June 25, 2021 Contacts/Locations and Study Status
67 June 26, 2021 Contacts/Locations and Study Status
68 July 6, 2021 Contacts/Locations and Study Status
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70 July 23, 2021 Contacts/Locations and Study Status
71 July 24, 2021 Contacts/Locations and Study Status
72 July 27, 2021 Contacts/Locations and Study Status
73 August 4, 2021 Contacts/Locations and Study Status
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76 August 11, 2021 Contacts/Locations and Study Status
77 August 24, 2021 Contacts/Locations and Study Status
78 August 26, 2021 Contacts/Locations and Study Status
79 August 27, 2021 Contacts/Locations and Study Status
80 September 14, 2021 Contacts/Locations, Eligibility and Study Status
81 September 22, 2021 Study Status
82 September 25, 2021 Contacts/Locations and Study Status
83 September 30, 2021 Contacts/Locations and Study Status
84 October 2, 2021 Contacts/Locations and Study Status
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86 October 14, 2021 Contacts/Locations and Study Status
87 October 16, 2021 Contacts/Locations and Study Status
88 October 19, 2021 Contacts/Locations and Study Status
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90 October 28, 2021 Contacts/Locations and Study Status
91 October 30, 2021 Contacts/Locations and Study Status
92 November 4, 2021 Contacts/Locations and Study Status
93 November 5, 2021 Contacts/Locations and Study Status
94 November 9, 2021 Contacts/Locations and Study Status
95 December 8, 2021 Contacts/Locations, Oversight and Study Status
96 December 11, 2021 Contacts/Locations and Study Status
97 December 15, 2021 Contacts/Locations and Study Status
98 December 16, 2021 Study Status
99 December 18, 2021 Contacts/Locations and Study Status
100 December 21, 2021 Contacts/Locations and Study Status
101 December 22, 2021 Contacts/Locations and Study Status
102 December 23, 2021 Contacts/Locations and Study Status
103 December 29, 2021 Contacts/Locations and Study Status
104 January 4, 2022 Contacts/Locations and Study Status
105 January 11, 2022 Contacts/Locations and Study Status
106 January 18, 2022 Contacts/Locations and Study Status
107 January 20, 2022 Contacts/Locations and Study Status
108 January 27, 2022 Contacts/Locations and Study Status
109 January 28, 2022 Contacts/Locations and Study Status
110 February 3, 2022 Contacts/Locations and Study Status
111 February 8, 2022 Contacts/Locations and Study Status
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116 February 18, 2022 Contacts/Locations and Study Status
117 March 1, 2022 Contacts/Locations and Study Status
118 March 5, 2022 Contacts/Locations and Study Status
119 March 11, 2022 Contacts/Locations and Study Status
120 March 16, 2022 Contacts/Locations and Study Status
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122 March 19, 2022 Contacts/Locations and Study Status
123 March 29, 2022 Contacts/Locations and Study Status
124 March 31, 2022 Contacts/Locations and Study Status
125 April 5, 2022 Study Status
126 April 8, 2022 Contacts/Locations and Study Status
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129 April 30, 2022 Contacts/Locations and Study Status
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133 May 18, 2022 Contacts/Locations and Study Status
134 June 2, 2022 Study Status
135 June 7, 2022 Arms and Interventions and Study Status
136 June 10, 2022 Contacts/Locations and Study Status
137 June 14, 2022 Contacts/Locations and Study Status
138 June 23, 2022 Contacts/Locations, Study Identification, Eligibility, Conditions, Study Description and Study Status
139 June 25, 2022 Contacts/Locations and Study Status
140 June 29, 2022 Study Status and Arms and Interventions
141 July 5, 2022 Contacts/Locations and Study Status
142 July 7, 2022 Contacts/Locations and Study Status
143 July 19, 2022 Contacts/Locations and Study Status
144 July 21, 2022 Contacts/Locations and Study Status
145 July 23, 2022 Contacts/Locations and Study Status
146 July 26, 2022 Contacts/Locations and Study Status
147 August 4, 2022 Contacts/Locations and Study Status
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Study NCT04145115
Submitted Date:  October 29, 2019 (v1)

Open or close this module Study Identification
Unique Protocol ID: NCI-2019-07242
Brief Title: A Study Testing the Effect of Immunotherapy (Ipilimumab and Nivolumab) for People With Recurrent Glioblastoma With Elevated Mutational Burden
Official Title: A Phase II Study of Checkpoint Blockade Immunotherapy in Patients With Somatically Hypermutated Recurrent Glioblastoma
Secondary IDs: NCI-2019-07242 [Registry Identifier: CTRP (Clinical Trial Reporting Program)]
A071702 [Alliance for Clinical Trials in Oncology]
A071702 [CTEP]
U10CA180821 [U.S. NIH Grant/Contract]
Open or close this module Study Status
Record Verification: October 2019
Overall Status: Not yet recruiting
Study Start: April 4, 2020
Primary Completion: May 31, 2023 [Anticipated]
Study Completion: May 31, 2023 [Anticipated]
First Submitted: October 29, 2019
First Submitted that
Met QC Criteria:
October 29, 2019
First Posted: October 30, 2019 [Actual]
Last Update Submitted that
Met QC Criteria:
October 29, 2019
Last Update Posted: October 30, 2019 [Actual]
Open or close this module Sponsor/Collaborators
Sponsor: National Cancer Institute (NCI)
Responsible Party: Sponsor
Collaborators:
Open or close this module Oversight
U.S. FDA-regulated Drug: Yes
U.S. FDA-regulated Device: No
Data Monitoring:
Open or close this module Study Description
Brief Summary: This phase II trial studies how well immunotherapy (ipilimumab and nivolumab) works in treating patients with glioblastoma that has come back (recurrent) and has a high mutational burden. 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 from growing or spreading compared to standard surgery or chemotherapy.
Detailed Description:

PRIMARY OBJECTIVE:

I. To determine whether the combination of ipilimumab and nivolumab increases the tumor response rate assessed by the Response Assessment in Neuro-Oncology Criteria (RANO) 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.

Open or close this module Conditions
Conditions: Glioblastoma, IDH-Mutant
Recurrent Glioblastoma
Keywords:
Open or close this module Study Design
Study Type: Interventional
Primary Purpose: Treatment
Study Phase: Phase 2
Interventional Study Model: Single Group Assignment
Number of Arms: 1
Masking: None (Open Label)
Allocation: N/A
Enrollment: 37 [Anticipated]
Open or close this module Arms and Interventions
Arms Assigned Interventions
Experimental: Treatment (nivolumab, ipilimumab)
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.
Biological: Ipilimumab
Given IV
Other Names:
  • Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
  • BMS-734016
  • MDX-010
  • MDX-CTLA4
  • Yervoy
Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo
Open or close this module Outcome Measures
Primary Outcome Measures:
1. Overall response rate
[ Time Frame: Up to 32 months ]

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:
1. Overall survival (OS)
[ Time Frame: From the time of treatment initiation until death from any cause, assessed up to 3 years ]

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.
2. 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 ]

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.
3. Incidence of adverse events (AEs)
[ Time Frame: Up to 3 years ]

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.
Open or close this module Eligibility
Minimum Age: 18 Years
Maximum Age:
Sex: All
Gender Based:
Accepts Healthy Volunteers: No
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
  • 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
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 or Karnofsky performance status (KPS) >= 70
  • 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
Open or close this module Contacts/Locations
Study Officials: Gavin P Dunn
Principal Investigator
Alliance for Clinical Trials in Oncology
Locations:
Open or close this module IPDSharing
Plan to Share IPD: Yes
NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page
Supporting Information:
Time Frame:
Access Criteria:
URL: https://grants.nih.gov/policy/sharing.htm
Open or close this module References
Citations:
Links:
Available IPD/Information:

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