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A Study Testing the Effect of Immunotherapy (Ipilimumab and Nivolumab) in Patients with Recurrent Glioblastoma with Elevated Mutational Burden

Status
Active
Cancer Type
Brain & Spinal Cord Tumor
Trial Phase
Phase II
Eligibility
18 Years and older, Male and Female
Study Type
Treatment
NCT ID
NCT04145115
Protocol IDs
A071702 (primary)
A071702
NCI-2019-07242
Study Sponsor
Alliance for Clinical Trials in Oncology

Summary

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).

Objectives

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.

Eligibility

  1. PRE-REGISTRATION:
  2. Histologically confirmed glioblastoma (World Health Organization [WHO] grade IV) presenting at first or second recurrence including secondary glioblastoma
  3. 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
  4. Tissue available from surgical resection or biopsy of recurrent tumor =< 28 days prior to pre-registration, or planned surgery or biopsy of recurrent tumor =< 28 days after pre-registration
  5. Does not require > 4 mg dexamethasone beyond the perioperative period defined as the time =< 2 weeks after surgical procedure
  6. No prior treatment with laser ablation at the time of recurrent tumor tissue sampling. Patients who have previously undergone laser ablation >= 4 months prior to recurrent tumor tissue sampling can be included
  7. Age >= 18 years
  8. Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  9. Able to undergo brain MRI with contrast
  10. Absolute neutrophil count >= 1500/mm^3
  11. Platelet count >= 100,000/mm^3
  12. Total bilirubin =< 1.5 x upper limit of normal (ULN) * If Gilbert syndrome, then total bilirubin =< 3 x ULN
  13. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.0 x ULN
  14. Creatinine =< 1.5 x ULN OR creatinine clearance (CrCl) >= 50 mL/min (if using the Cockcroft-Gault formula)
  15. History of active malignancy (outside of the patient's glioblastoma) that has required treatment within the previous 2 years. Participant with prior history of in situ cancer or basal or squamous cell skin cancer are eligible
  16. REGISTRATION ELIGIBILITY CRITERIA: Tissue obtained from biopsy or resection at first or second recurrence exhibits TMB >= 10 on FoundationOne CDx testing
**Clinical trials are research studies that involve people. These studies test new ways to prevent, detect, diagnose, or treat diseases. People who take part in cancer clinical trials have an opportunity to contribute to scientists’ knowledge about cancer and to help in the development of improved cancer treatments. They also receive state-of-the-art care from cancer experts... Click here to learn more about clinical trials.
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