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Testing the Use of the Immunotherapy Drugs Ipilimumab and Nivolumab Plus Radiation Therapy Compared to the Usual Treatment (Temozolomide and Radiation Therapy) for Newly Diagnosed MGMT Unmethylated Glioblastoma

NCT04396860

Description:

This phase II/III trial compares the usual treatment with radiation therapy and temozolomide to radiation therapy plus immunotherapy with ipilimumab and nivolumab in treating patients with newly diagnosed MGMT unmethylated glioblastoma. Radiation therapy uses high energy photons to kill tumor and shrink tumors. Chemotherapy drugs, 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. 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 radiation therapy with ipilimumab and nivolumab lengthen the time without brain tumor from returning or growing and extend patients life compared to usual treatment of radiation therapy and chemotherapy.

Related Conditions:
  • Glioblastoma
  • Gliosarcoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2/Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Testing the Use of the Immunotherapy Drugs Ipilimumab and Nivolumab Plus Radiation Therapy Compared to the Usual Treatment (Temozolomide and Radiation Therapy) for Newly Diagnosed MGMT Unmethylated Glioblastoma
  • Official Title: A Randomized Phase II/III Open-Label Study of Ipilimumab and Nivolumab Versus Temozolomide in Patients With Newly Diagnosed MGMT (Tumor O-6-Methylguanine DNA Methyltransferase) Unmethylated Glioblastoma

Clinical Trial IDs

  • ORG STUDY ID: NCI-2020-03404
  • SECONDARY ID: NCI-2020-03404
  • SECONDARY ID: NRG-BN007
  • SECONDARY ID: NRG-BN007
  • SECONDARY ID: U10CA180868
  • NCT ID: NCT04396860

Conditions

  • Gliosarcoma
  • MGMT-Unmethylated Glioblastoma

Interventions

DrugSynonymsArms
IpilimumabAnti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, YervoyArm II (radiation therapy, ipilimumab, nivolumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoArm II (radiation therapy, ipilimumab, nivolumab)
TemozolomideCCRG-81045, Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-, M & B 39831, M and B 39831, Methazolastone, RP-46161, SCH 52365, Temcad, Temodal, Temodar, Temomedac, TMZArm I (radiation therapy, temozolomide)

Purpose

This phase II/III trial compares the usual treatment with radiation therapy and temozolomide to radiation therapy plus immunotherapy with ipilimumab and nivolumab in treating patients with newly diagnosed MGMT unmethylated glioblastoma. Radiation therapy uses high energy photons to kill tumor and shrink tumors. Chemotherapy drugs, 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. 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 radiation therapy with ipilimumab and nivolumab lengthen the tiem without brain tumor from returning or growing and extend patients life compared to usual treatment of radiation therapy and chemotherapy.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine if adding ipilimumab and nivolumab to radiotherapy significantly prolongs
      progression-free survival (PFS) versus adding temozolomide to radiotherapy in patients with
      newly diagnosed glioblastoma (GBM) without MGMT promoter methylation. (Phase II) II. To
      determine if adding ipilimumab and nivolumab to radiotherapy significantly prolongs overall
      survival (OS) versus adding temozolomide to radiotherapy in patients with newly diagnosed GBM
      without MGMT promoter methylation. (Phase III)

      SECONDARY OBJECTIVES:

      I. To determine if adding ipilimumab and nivolumab to radiotherapy significantly prolongs PFS
      versus adding temozolomide to radiotherapy in patients with newly diagnosed GBM without MGMT
      promoter methylation for the phase III part of the study.

      II. To determine if adding ipilimumab and nivolumab to radiotherapy significantly increases
      the 2-year overall survival (OS) rate versus adding temozolomide to radiotherapy in patients
      with newly diagnosed GBM without MGMT promoter methylation.

      III. To evaluate the safety of adding ipilimumab and nivolumab to radiotherapy via
      comparative frequency between arms of specific adverse events of interest and frequency
      summaries for all adverse event types.

      IV. To evaluate the effect of adding ipilimumab and nivolumab to radiotherapy versus adding
      temozolomide to radiotherapy on patient reported outcomes (PROs), as measured by the MD
      Anderson Symptom Inventory - Brain Tumor (MDASI-BT) in patients with newly diagnosed GBM
      without MGMT promoter methylation.

      V. To evaluate the effect of adding ipilimumab and nivolumab to radiotherapy versus adding
      temozolomide to radiotherapy on selected Patient Reported Outcomes-Common Terminology
      Criteria for Adverse Events (PRO-CTCAE) items in patients with newly diagnosed GBM without
      MGMT promoter methylation.

      VI. To evaluate the impact of adding ipilimumab and nivolumab to radiotherapy versus adding
      temozolomide to radiotherapy on neurocognitive function (NCF) in patients with newly
      diagnosed GBM without MGMT promoter methylation.

      VII. To explore whether detection of human telomerase gene (TERT) promoter mutations in
      peripheral blood plasma correlates with OS, PFS, and 2-year OS rate.

      EXPLORATORY OBJECTIVES:

      I. To explore biomarkers in pre-treatment archival tumor tissue that may predict efficacy of
      ipilimumab and nivolumab as measured by OS, PFS, and 2-year OS rate, such as but not limited
      to:

      Ia. PDL1 expression Ib. Mutational burden II. To explore (in the two treatment separately)
      whether the MGMT protein expression correlates with clinical outcomes including OS, PFS, and
      2-year OS rate.

      III. To evaluate if MGMT protein expression may be predictive of differential treatment
      effects between the two treatment arms.

      IV. To explore whether changes in peripheral blood immunologic profiles correlate with
      efficacy (as measured by OS, PFS, and 2-year OS rate) or toxicity.

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM 1: Patients undergo radiation therapy over 30 fractions for 5 days per week
      (Monday-Friday) and receive temozolomide orally (PO) daily for 6 weeks. After radiation,
      patients may wear the Optune device at the discretion of the patient and their treating
      physician. Beginning 1 month after radiation therapy, patients receive temozolomide on days
      1-5. Treatment repeats every 28 days for up to 12 cycles at the discretion of the treating
      investigator in the absence of disease progression or unacceptable toxicity.

      ARM 2: Patients undergo radiation therapy over 30 fractions for 5 days per week
      (Monday-Friday) for 6 weeks. Starting on the first day of radiation, patients also receive
      ipilimumab intravenously (IV) over 90 minutes once every 4 weeks (Q4W) for 4 doses and
      nivolumab IV over 30 minutes every 2 weeks until disease progression.

      After completion of study treatment, patients are followed up every 3 months for year 1, then
      every 4 months for year 2, and then every 6 months thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (radiation therapy, temozolomide)Active ComparatorPatients undergo radiation therapy over 30 fractions for 5 days per week (Monday-Friday) and receive temozolomide PO daily for 6 weeks. After radiation, patients may wear the Optune device at the discretion of the patient and their treating physician. Beginning 1 month after radiation therapy, patients receive temozolomide on days 1-5. Treatment repeats every 28 days for up to 12 cycles at the discretion of the treating investigator in the absence of disease progression or unacceptable toxicity.
  • Temozolomide
Arm II (radiation therapy, ipilimumab, nivolumab)ExperimentalPatients undergo radiation therapy over 30 fractions for 5 days per week (Monday-Friday) for 6 weeks. Starting on the first day of radiation, patients also receive ipilimumab IV over 90 minutes Q4W for 4 doses and nivolumab IV over 30 minutes every 2 weeks until disease progression.
  • Ipilimumab
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  PRIOR TO STEP 1 REGISTRATION:

          -  No known IDH mutation. (If tested before step 1 registration, patients known to have
             IDH mutation in the tumor on local or other testing are ineligible and should not be
             registered)

          -  Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue block and
             hematoxylin & eosin (H&E) stained slide to be sent for central pathology review for
             confirmation of histology and MGMT promoter methylation status. Note that tissue for
             central pathology review and central MGMT assessment must be received by the NRG
             Oncology biospecimen bank on or before postoperative calendar day 23. If tissue cannot
             be received by postoperative calendar day 23, then patients may NOT enroll on this
             trial as central pathology review and stratification will not be complete in time for
             the patient to start treatment no later than 6 weeks following surgery. Results of
             central pathology review and central MGMT analysis will generally be conveyed to NRG
             Oncology within 10 business days of receipt of tissue

          -  Contrast-enhanced brain MRI within 72 hours after surgery

               -  Magnetic resonance imaging (MRI) with Axial T2 weighted FLAIR {preferred} or T2
                  turbo spin echo (TSE)/fast spin echo (FSE) and 3-dimensional (3D)
                  contrast-enhanced T1 sequences are required

               -  3D pre contrast-enhanced T1 sequences are strongly suggested

          -  Women of childbearing potential (WOCBP) and men who are sexually active with WOCBP
             must be willing to use an adequate method of contraception hormonal or barrier method
             of birth control; or abstinence during and after treatment

          -  The patient or a legally authorized representative must provide study-specific
             informed consent prior to study entry

          -  PRIOR TO STEP 2 REGISTRATION:

          -  Histopathologically proven diagnosis of glioblastoma (or gliosarcoma as a subtype of
             glioblastoma) confirmed by central pathology review

          -  MGMT promoter without methylation confirmed by central pathology review. Note:
             Patients with tissue that is insufficient or inadequate for analysis, fails MGMT
             testing, or has indeterminate or methylated MGMT promoter are excluded

          -  IDH mutation testing by at least one method (such as immunohistochemistry for IDH1
             R132H) must be performed as part of standard of care and no mutation must be found
             (i.e IDH wildtype). (If a mutation is identified then the patient will be ineligible
             and must be registered as ineligible at step 2.)

          -  History/physical examination within 28 days prior to step 2 registration

          -  Karnofsky Performance Status (KPS) >= 70 within 28 days prior to step 2 registration

          -  Neurologic function assessment within 28 days prior to step 2 registration

          -  Hemoglobin >= 10 g/dl (Note: the use of transfusion or other intervention to achieve
             Hgb >= 10.0 g/dl is acceptable) (within 7 days prior to Step 2 registration)

          -  Leukocytes >= 2,000/mm^3 (within 7 days prior to Step 2 registration)

          -  Absolute neutrophil count >= 1,500/mm^3 (within 7 days prior to Step 2 registration)

          -  Platelets >= 100,000/mm^3 (within 7 days prior to Step 2 registration)

          -  Total bilirubin =< 1.5 x institutional/lab upper limit of normal (ULN) (within 7 days
             prior to Step 2 registration)

          -  Aspartate transaminase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) =< 2.5 x
             ULN (within 7 days prior to Step 2 registration)

          -  Alanine transferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN
             (within 7 days prior to Step 2 registration)

          -  Serum creatinine =< 1.5 x ULN OR creatinine clearance (CrCl) >= 50mL/min (if using the
             Cockcroft-Gault formula) (within 7 days prior to Step 2 registration)

          -  For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
             load must be undetectable on suppressive therapy, if indicated. Patients with a
             history of hepatitis C virus (HCV) infection must have been treated and cured. For
             patients with HCV infection who are currently on treatment, they are eligible if they
             have an undetectable HCV viral load

          -  For women of childbearing potential (WOCBP), negative serum or urine pregnancy test
             within 7 days prior to step 2 registration. Note that it may need to be repeated if
             not also within 72 hours prior to treatment start

               -  Women of childbearing potential (WOCBP) is defined as any female who has
                  experienced menarche and who has not undergone surgical sterilization
                  (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause
                  is defined clinically as 12 months of amenorrhea in a woman over 45 in the
                  absence of other biological or physiological causes

        Exclusion Criteria:

          -  Prior therapy for tumor except for biopsy or resection. For example, prior
             chemotherapy, immunotherapy, or targeted therapy for GBM or lower grade glioma is
             disallowed (including but not limited to temozolomide, lomustine, bevacizumab, any
             viral therapy, ipilimumab or other CTLA-4 antibody, PD-1 antibody, CD-137 agonist,
             CD40 antibody, PDL-1 or 2 antibody, vaccine therapy, polio or similar viral injection
             as treatment for the tumor, and/or any other antibody or drug specifically targeting
             T-cell co-stimulation or immune checkpoint pathways) as is prior Laser interstitial
             thermal therapy (LITT), Gliadel wafer, radiotherapy, radiosurgery, gamma knife, cyber
             knife, vaccine or other immunotherapy, brachytherapy, or convection enhanced delivery;

               -  Note that 5-aminolevulinic acid (ALA)-mediated fluorescent guided resection (FGR)
                  photodynamic therapy (PDT) or fluorescein administered prior to/during surgery to
                  aid resection is not exclusionary and is not considered a chemotherapy or
                  intracerebral agent

          -  Current or planned treatment with any other investigational agents for the study
             cancer

          -  Definitive clinical or radiologic evidence of metastatic disease outside the brain

          -  Prior invasive malignancy (except non-melanomatous skin cancer, cervical cancer in
             situ and melanoma in situ) unless disease free for a minimum of 2 years

          -  Prior radiotherapy to the head or neck that would result in overlap of radiation
             therapy fields

          -  Pregnancy and nursing females due to the potential teratogenic effects and potential
             risk for adverse events in nursing infants

          -  History of severe hypersensitivity reaction to any monoclonal antibody

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to ipilimumab, nivolumab, or temozolomide

          -  On any dose of any systemically administered (oral, rectal, intravenous)
             corticosteroid within 3 days prior to step 2 registration. Inhaled, topical, and
             ocular corticosteroids are allowed without limitation but must be recorded. Note that
             treatment with systemically administered corticosteroid after initiating study
             treatment is allowed as needed

          -  Patients with known immune impairment who may be unable to respond to anti-CTLA 4
             antibody

          -  History of interstitial lung disease including but not limited to sarcoidosis or
             pneumonitis

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, defined as New York Heart Association
             functional classification III/IV (Note: Patients with known history or current
             symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should
             have a clinical risk assessment of cardiac function using the New York Heart
             Association functional classification), unstable angina pectoris, cardiac arrhythmia,
             or psychiatric illness/social situations that would limit compliance with study
             requirements

          -  Known history of testing positive for human immunodeficiency virus (HIV) or known
             acquired immunodeficiency syndrome (AIDS)

          -  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, are excluded. These include but are not limited
             to: patients with a history of immune-related neurologic disease, central nervous
             system (CNS) or motor neuropathy, multiple sclerosis, autoimmune (demyelinating)
             neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease
             such as autoimmune vasculitis [e.g., Wegener's Granulomatosis]), systemic lupus
             erythematosus (SLE), connective tissue diseases (e.g., systemic progressive
             sclerosis), 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, Hashimoto's thyroiditis,
             autoimmune hepatitis are excluded because of the risk of recurrence or exacerbation of
             disease

               -  Exceptions: patients with a history of the following conditions are not excluded:

                    -  Vitiligo

                    -  Endocrine deficiencies including thyroiditis managed with replacement
                       hormones including physiologic corticosteroids

                    -  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

          -  Patients who have evidence of active or acute diverticulitis, intra-abdominal abscess,
             gastrointestinal (GI) obstruction and abdominal carcinomatosis which are known risk
             factors for bowel perforation are also excluded

          -  Current or planned therapy with warfarin
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival (PFS) (Phase II)
Time Frame:From randomization to disease progress or death, assessed up to 4 years
Safety Issue:
Description:PFS will be defined as time from randomization to disease progress or death. This analysis will be performed on the intent-to-treat basis. PFS distributions for each treatment group will be estimated via the Kaplan-Meier survival function. Will utilize the "PFS resolution" guidance provided in the ALLIANCE A071102 study, the updated Response Assessment in Neuro-Oncology Criteria (RANO) criteria.

Secondary Outcome Measures

Measure:PFS for the entire cohort (Phase II/III)
Time Frame:At 2 year
Safety Issue:
Description:PFS curves will be estimated via the Kaplan-Meier method and a stratified log-rank test.
Measure:OS proportion
Time Frame:At 2 years
Safety Issue:
Description:2-year OS will be compared between treatment arms, to determine whether the proportion surviving to this landmark is increased in the experimental (ipilimumab [ipi] + nivolumab [nivo]) arm. Estimates will be obtained from the Kaplan Meier curves, and a test comparing the proportion surviving with an appropriate variance term that accounts for censoring (Greenwood's formula) will be used.
Measure:Comparative frequency of specific adverse events of interest
Time Frame:Up to 4 years
Safety Issue:
Description:Adverse events (AEs) will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 and Patient Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE).
Measure:Frequency summaries for all adverse event types
Time Frame:Up to 4 years
Safety Issue:
Description:Adverse events will be graded according to CTCAE v5.0 and PRO-CTCAE. Comprehensive summaries of all AEs by treatment arm will be generated and examined. Counts and frequencies of worst (highest score) AE per patient will be presented overall and by AE type category, separately by assigned treatment group. Complementing physician-assessed AEs will be selected PRO-CTCAE symptom items that have demonstrated sensitivity to immunotherapy-related toxicities but do not overlap with MDASI-BT. The following PRO-CTCAE symptom items will be monitored: rash, itching, muscle pain, joint pain, headache, chills, mouth/throat sores, skin dryness, hair loss, cough, taste changes, dizziness, swelling, hot flashes.
Measure:Patient reported symptom burden
Time Frame:Up to 4 years
Safety Issue:
Description:Will be assessed using the MD Anderson Symptom Inventory - Brain Tumor (MDASI-BT)-modified. The MDASI-BT consists of 23 symptoms rated on an 11-point ordinal scale (0 to 10) to indicate the presence and severity of the symptom in the last 24 hours, with 0 being "not present" and 10 being "as bad as you can imagine." These interference items include: general activity, mood, work (includes both work outside the home and housework), relations with other people, walking, and enjoyment of life. Complementing MDASI-BT will be selected PRO-CTCAE symptom items that have demonstrated sensitivity to immunotherapy-related toxicities but do not overlap with MDASI-BT.
Measure:Neurocognitive function (NCF)
Time Frame:Up to 4 years
Safety Issue:
Description:
Measure:Patient-reported toxicity outcomes
Time Frame:Up to 4 years
Safety Issue:
Description:Will utilize the PRO-CTCAE to assess the following items: abdominal pain, rash, itching, muscle pain, joint pain, pain and swelling at injection site, headache, chills, mouth/throat sores, skin dryness, hair loss, cough, taste changes, dizziness, swelling, and hot flashes. Statistical models will be used to estimate treatment effects adjusting for patient and tumor characteristics that may be imbalanced by arm, or suggest a differential treatment effect by characteristic (e.g., treatment-covariate interactions). The Cox proportional hazards regression model will be the principal approach, however, in the case that the proportional hazards assumption is inadequately met, other modeling approaches will be applied as appropriate.
Measure:Serial Liquid biopsy of TERT
Time Frame:At baseline and before odd numbered cycles
Safety Issue:
Description:Will be assessed to detect progression. Response is assessed by on changes in contrast enhancement and/or T2/fluid attenuated inversion recovery (FLAIR) hyperintensity on magnetic resonance imaging (MRI) which can reflect changes that are not specific for tumor progression

Details

Phase:Phase 2/Phase 3
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

May 20, 2020