Clinical Trials /

Immunotherapy (Nivolumab and Ipilimumab) Before and After Surgery for the Treatment of Recurrent or Progressive High Grade Glioma in Children and Young Adults

NCT04323046

Description:

This phase I trial studies the side effects of nivolumab and ipilimumab before and after surgery in treating children and young adults with high grade glioma that has come back (recurrent) or is increasing in scope or severity (progressive). Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Related Conditions:
  • Malignant Glioma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Immunotherapy (Nivolumab and Ipilimumab) Before and After Surgery for the Treatment of Recurrent or Progressive High Grade Glioma in Children and Young Adults
  • Official Title: A Randomized, Double-Blinded, Pilot Trial of Neoadjuvant Checkpoint Inhibition Followed by Combination Adjuvant Checkpoint Inhibition in Children and Young Adults With Recurrent or Progressive High Grade Glioma (HGG)

Clinical Trial IDs

  • ORG STUDY ID: 190815
  • SECONDARY ID: NCI-2020-01502
  • SECONDARY ID: PNOC 0019
  • NCT ID: NCT04323046

Conditions

  • Glioblastoma
  • Malignant Glioma
  • Recurrent Glioblastoma
  • Recurrent Malignant Glioma
  • Recurrent Grade III Glioma
  • Grade III Glioma

Interventions

DrugSynonymsArms
IpilimumabAnti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, YervoyGroup A (neoadjuvant nivolumab and placebo)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoGroup A (neoadjuvant nivolumab and placebo)
Placebo AdministrationGroup A (neoadjuvant nivolumab and placebo)

Purpose

This phase I trial studies the side effects of nivolumab and ipilimumab before and after surgery in treating children and young adults with high grade glioma that has come back (recurrent) or is increasing in scope or severity (progressive). Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To measure the relative changes in cell cycle-related genetic signature of the tumor
      microenvironment post administration of neoadjuvant nivolumab and placebo, ipilimumab and
      placebo, and nivolumab and ipilimumab in children and young adults with recurrent or
      progressive high grade glioma (HGG) when compared to a cohort of archived non-treated
      recurrent pediatric HGG samples.

      II. To characterize the safety and tolerability of neoadjuvant nivolumab and placebo,
      neoadjuvant ipilimumab and placebo, and neoadjuvant ipilimumab and nivolumab followed by
      adjuvant ipilimumab and nivolumab in children and young adults with recurrent or progressive
      HGG.

      SECONDARY OBJECTIVES:

      I. To determine the 6 month and 12 month overall survival (OS) in children and young adults
      with recurrent or progressive HGG treated with neoadjuvant nivolumab and placebo, ipilimumab
      and placebo, or nivolumab and ipilimumab followed by adjuvant nivolumab and ipilimumab.

      II. To determine the 6 month and 12 month progression-free survival (PFS) in children and
      young adults with recurrent or progressive HGG treated with neoadjuvant nivolumab and
      placebo, ipilimumab and placebo, or nivolumab and ipilimumab followed by adjuvant nivolumab
      and ipilimumab.

      EXPLORATORY OBJECTIVES:

      I. To measure relative changes in interferon gamma associated genetic signature within the
      tumor microenvironment post administration of neoadjuvant nivolumab and placebo, ipilimumab
      and placebo, or nivolumab and ipilimumab in children and young adults with recurrent or
      progressive HGG compared to archived non-treated recurrent pediatric HGG samples.

      II. To explore the correlation of interferon-gamma-associated genetic signature, cell
      cycle-related genetic signature and infiltrating T lymphocyte (TIL) density and clonality
      with clinical responses for each treatment arm.

      III. To measure TIL density post administration of neoadjuvant nivolumab and placebo compared
      to neo-adjuvant ipilimumab and placebo, and neoadjuvant nivolumab and ipilimumab in children
      and young adults with recurrent or progressive HGG.

      IV. To estimate the objective response rate (ORR) in children and young adults with recurrent
      or progressive HGG treated with neoadjuvant nivolumab and placebo, neoadjuvant ipilimumab and
      placebo, or neoadjuvant ipilimumab and nivolumab followed by adjuvant ipilimumab and
      nivolumab.

      V. To evaluate the association between advanced magnetic resonance imaging (MRI) parameters
      (apparent diffusion coefficient (ADC) on diffusion weighted imaging (DWI), relative cerebral
      blood volume (rCBV) on dynamic susceptibility contrast (DSC) perfusion MRI, pre-contrast T1
      shortening on T1-weighed images, and/or magnetization transfer ratio with asymmetric analysis
      (MTRasym) on pH-weighted amine chemical exchange saturation transfer (CEST)-echo planar
      imaging (EPI)) and tumor and peripheral blood immune responses.

      VI. To measure relative change in peripheral T-cell response and post administration of
      neo-adjuvant nivolumab and placebo, ipilimumab and placebo, or nivolumab and ipilimumab in
      children and young adults with recurrent or progressive HGG.

      VII. To measure PD-1 and PDL-1 expression by immunohistochemistry for children and young
      adults with recurrent or progressive HGG post neoadjuvant nivolumab and placebo, neoadjuvant
      ipilimumab and placebo, or neoadjuvant ipilimumab and nivolumab, and evaluate the differences
      between the three arms as well as between each group and archived non-treated recurrent
      pediatric HGG samples.

      VIII. To explore the correlation of tumor mutational load with clinical response for children
      and young adults with recurrent or progressive HGG treated with neoadjuvant nivolumab and
      placebo, neoadjuvant ipilimumab and placebo, or neoadjuvant ipilimumab and nivolumab followed
      by adjuvant ipilimumab and nivolumab.

      IX. To assess quality of life (QOL) and cognitive measures in children and young adults with
      recurrent or progressive HGG treated with neoadjuvant nivolumab and placebo, neoadjuvant
      ipilimumab and placebo, or neoadjuvant ipilimumab and nivolumab followed by adjuvant
      ipilimumab and nivolumab.

      OUTLINE: Patients are randomized to 1 of 3 groups.

      GROUP A:

      NEOADJUVANT: Patients receive nivolumab intravenously (IV) over 30 minutes and placebo IV
      over 30 minutes 14 days before undergoing standard of care surgical resection.

      ADJUVANT COMBINATION INFUSION: After recovery from surgery (no more than 35 days afterwards),
      patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1.
      Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or
      unacceptable toxicity.

      ADJUVANT MAINTENANCE: After completion of combination infusion, patients receive nivolumab IV
      over 30 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease
      progression or unacceptable toxicity.

      GROUP B:

      NEOADJUVANT: Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes
      14 days before undergoing standard of care surgical resection.

      ADJUVANT COMBINATION INFUSION: After recovery from surgery (no more than 35 days afterwards),
      patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1.
      Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or
      unacceptable toxicity.

      ADJUVANT MAINTENANCE: After completion of combination infusion, patients receive nivolumab IV
      over 30 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease
      progression or unacceptable toxicity.

      GROUP C:

      NEOADJUVANT: Patients receive placebo IV over 30 minutes and ipilimumab IV over 30 minutes 14
      days before undergoing standard of care surgical resection.

      ADJUVANT COMBINATION INFUSION: After recovery from surgery (no more than 35 days afterwards),
      patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1.
      Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or
      unacceptable toxicity.

      ADJUVANT MAINTENANCE: After completion of combination infusion, patients receive nivolumab IV
      over 30 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease
      progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days and then every 2
      months for up to 24 months.
    

Trial Arms

NameTypeDescriptionInterventions
Group A (neoadjuvant nivolumab and placebo)ExperimentalNEOADJUVANT: Patients receive nivolumab IV over 30 minutes and placebo IV over 30 minutes 14 days before undergoing standard of care surgical resection. ADJUVANT COMBINATION INFUSION: After recovery from surgery (no more than 35 days afterwards), patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. ADJUVANT MAINTENANCE: After completion of combination infusion, patients receive nivolumab IV over 30 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Ipilimumab
  • Nivolumab
  • Placebo Administration
Group B (neoadjuvant nivolumab and ipilimumab)ExperimentalNEOADJUVANT: Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes 14 days before undergoing standard of care surgical resection. ADJUVANT COMBINATION INFUSION: After recovery from surgery (no more than 35 days afterwards), patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. ADJUVANT MAINTENANCE: After completion of combination infusion, patients receive nivolumab IV over 30 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Ipilimumab
  • Nivolumab
Group C (neoadjuvant placebo and ipilimumab)ExperimentalNEOADJUVANT: Patients receive placebo IV over 30 minutes and ipilimumab IV over 30 minutes 14 days before undergoing standard of care surgical resection. ADJUVANT COMBINATION INFUSION: After recovery from surgery (no more than 35 days afterwards), patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. ADJUVANT MAINTENANCE: After completion of combination infusion, patients receive nivolumab IV over 30 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Ipilimumab
  • Nivolumab
  • Placebo Administration

Eligibility Criteria

        Inclusion Criteria:

          -  Participants with recurrent or progressive HGG (World Health Organization (WHO) grade
             III or grade IV) who are candidates for surgical tumor debulking will be enrolled in
             this trial

          -  All assessments are to occur within 14 days of registration except where otherwise
             noted. The participant and their legal parent/guardian must be thoroughly informed
             about all aspects of the study, including the study visit schedule and required
             evaluations and all regulatory requirements for informed consent. The written informed
             consent must be obtained from the participant and legal parent/guardian prior to
             enrollment

          -  Have a history of previously treated histologically confirmed World Health
             Organization grade III or IV HGG. Previous first line therapy with radiation and/or
             chemotherapy

          -  Have evidence of recurrence or progression of disease by MRI scan

          -  Participants must be adequate medical candidates for surgical resection. The intent of
             surgical resection is to allow both cytoreduction and tumor debulking as part of
             standard of care, and also collect a minimum of 100 mg of tumor tissue for the study
             tissue endpoints

          -  A primary goal of surgery must be cytoreduction, and not solely on diagnostic biopsy

          -  Karnofsky >= 50 for participants > 16 years of age and Lansky >= 50 for participants
             =< 16 years of age. Participants who are unable to walk because of paralysis, but who
             are up in a wheelchair, will be considered ambulatory for the purpose of assessing the
             performance score

          -  Prior Therapy: Participants must have fully recovered from the acute toxic effects of
             all prior anti-cancer therapy and must meet the following minimum duration from prior
             anti-cancer directed therapy prior to enrollment. If after the required timeframe, the
             defined eligibility criteria are met, e.g. blood count criteria, the patient is
             considered to have recovered adequately

               -  Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive.
                  At least 21 days after the last dose of cytotoxic or myelosuppressive
                  chemotherapy (42 days if prior nitrosourea)

               -  An interval of at least 12 weeks from the completion of radiation therapy to
                  registration unless there is unequivocal histologic confirmation of tumor
                  progression

               -  Hematopoietic growth factors: At least 14 days after the last dose of a
                  long-acting growth factor (e.g. pegfilgrastim) or 7 days for short acting growth
                  factor. For agents that have known adverse events occurring beyond 7 days after
                  administration, this period must be extended beyond the time during which adverse
                  events are known to occur. The duration of this interval must be discussed with
                  the study chair

               -  Anti-cancer agents not known to be myelosuppressive (e.g. not associated with
                  reduced platelet or absolute neutrophil count [ANC] counts): At least 7 days
                  after the last dose of agent

               -  Interleukins, interferons and cytokines (other than hematopoietic growth
                  factors): >= 21 days after the completion of interleukins, interferon or
                  cytokines (other than hematopoietic growth factors)

               -  Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody,
                  and toxicity related to prior antibody therapy must be recovered to grade =< 1

               -  Participants must not have received prior exposure to PD-1, PD-L1 or CTLA4
                  inhibitors

               -  Stem cell infusion (with or without total-body irradiation (TBI)):

                    -  Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem
                       cell infusion including donor lymphocyte infusions (DLI) or boost infusion:
                       >= 100 days after infusion, no evidence of graft versus host disease (GVHD)
                       and no requirement for immunosuppression

                    -  Autologous stem cell infusion including boost infusion: >= 42 days

          -  Participants must be willing to forego cytotoxic anti-tumor therapies except
             study-defined therapy while being treated on study

          -  Peripheral absolute neutrophil count (ANC) >= 1000/mm^3

          -  Platelet count >= 100,000/mm^3

          -  Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
             mL/min/1.73 m^2 OR a serum creatinine based on age/gender as follows:

               -  Age: Maximum Serum Creatinine (mg/dL)

               -  6 months to < 3 years: 0.6 (male and female)

               -  3 to < 6 years: 0.8 (male and female)

               -  6 to < 10 years: 1 (male and female)

               -  10 to < 13 years: 1.2 (male and female)

               -  13 to < 16 years: 1.5 (male), 1.4 (female)

               -  >= 16 years: 1.7 (male), 1.4 (female)

          -  Bilirubin (sum of conjugated and unconjugated) =< 1.5 x upper limit of normal (ULN)
             for age (except participants with Gilbert syndrome who must have a total bilirubin
             level of < 3.0

          -  Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3.0 x ULN

          -  Serum albumin >= 2

          -  Pregnancy: The effects of nivolumab and ipilimumab on the developing human fetus are
             unknown. For this reason women of child-bearing potential and men must agree to use
             adequate contraception (hormonal or barrier method of birth control; abstinence) prior
             to study entry, for the duration of study participation and 4 months after completion
             of therapy. Should a woman become pregnant or suspect she is pregnant while she or her
             partner is participating in this study, she should inform her treating physician
             immediately

          -  MRI within 28 days prior to registration

        Exclusion Criteria:

          -  Current or planned participation in a study of an investigational agent or using an
             investigational device

          -  Has a diagnosis of immunodeficiency

          -  Has tumor primarily localized to the brainstem or spinal cord

          -  Has presence of diffuse leptomeningeal disease or extracranial disease

          -  Has received systemic immunosuppressive treatments (such as methotrexate, chloroquine,
             azathioprine, etc.), aside from anti-neoplastic chemotherapy or systemic
             corticosteroids within six months of registration

          -  Participants with a concurrent condition requiring systemic treatment with either
             corticosteroids (> 0.25 mg/kg daily prednisone equivalent) or other immunosuppressive
             medications within 14 days of start of study treatment. Inhaled or topical steroids,
             and adrenal replacement steroid doses > 0.25 mg/kg daily prednisone equivalent, are
             permitted in the absence of active autoimmune disease

          -  Unable to taper steroids due to ongoing mass effect; a maximum dexamethasone dose of
             0.1 mg/kg/day is allowed, but preferably have been discontinued (inhaled or topical
             use of steroids is allowed)

          -  Has a known history of active TB (Bacillus tuberculosis)

          -  Has a known additional malignancy that is progressing or requires active treatment
             within 3 years of registration. Exceptions include basal cell carcinoma of the skin,
             squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone
             potentially curative therapy

          -  Has active autoimmune disease that has required systemic treatment in the past 2 years
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment

          -  Has known history of, or any evidence of active non-infectious pneumonitis

          -  Has an active infection requiring systemic therapy

          -  Has a known hypersensitivity to any of the study therapy products

          -  Has a known history of positive test for human immunodeficiency virus (HIV) or known
             acquired immunodeficiency syndrome (AIDS)

               -  NOTE: Testing for HIV must be performed at sites where mandated locally

          -  Any prior positive test result for hepatitis B virus or hepatitis C virus indicating
             presence of virus, e.g., hepatitis B surface antigen (HBsAg, Australia antigen)
             positive, or hepatitis C antibody (anti-HCV) positive (except if HCV-ribonucleic acid
             (RNA) negative)

          -  Any serious or uncontrolled medical disorder that, in the opinion of the investigator
             may increase the risk associated with study participation or study drug
             administration, impair the ability of the participant to receive protocol therapy or
             interfere with interpretation of study results
      
Maximum Eligible Age:22 Years
Minimum Eligible Age:6 Months
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage change in cell cycle-related genetic signature
Time Frame:From screening to surgery visit (neoadjuvant treatment groups); at time of recurrent high grade glioma (HGG) tissue collection (for archived non-treated samples)
Safety Issue:
Description:Will assess the percentage change in cell cycle-related genetic signature post administration of neoadjuvant treatments in all 3 treatment groups compared to archived recurrent pediatric HGG group. The number of participants with high cell cycle gene signature (positive median gene set variation analysis (GSVA) score) will be tabulated. Variables involved in the primary analyses will be examined graphically and summarized by descriptive statistics.

Secondary Outcome Measures

Measure:Overall survival
Time Frame:Up to 12 months
Safety Issue:
Description:Survival will be assessed at 6 months and 12 months from the time of randomization until the time of death. Kaplan-Meier survival analyses will be performed. Medians together with 2-sided 95% confidence intervals will be computed using a log-log transformation.
Measure:Progression-free survival (PFS)
Time Frame:Up to 12 months
Safety Issue:
Description:PFS is defined as the the time of randomization until the time of progressive disease or death. Kaplan-Meier survival analyses will be performed. Medians together with 2-sided 95% confidence intervals will be computed using a log-log transformation.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Sabine Mueller, MD, PhD

Last Updated

March 24, 2020