Clinical Trials /

Surgical Nivolumab And Ipilimumab For Recurrent GBM

NCT04606316

Description:

This research trial is studying the safety and effectiveness of nivolumab in combination with ipilimumab and surgery when used in the treatment of recurrent glioblastoma. The names of the study drugs involved in this study are: - Nivolumab - Ipilimumab - Placebo (IV solution with no medicine)

Related Conditions:
  • Glioblastoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Surgical Nivolumab And Ipilimumab For Recurrent GBM
  • Official Title: A Phase Ib Clinical Trial to Evaluate Early Immunologic Pharmacodynamic Parameters Following Neoadjuvant Anti-PD-1 (Nivolumab), or the Combination of Anti-PD-1 Plus Anti-CTLA-4 (Nivolumab Plus Ipilimumab) in Patients With Surgically Accessible Glioblastoma

Clinical Trial IDs

  • ORG STUDY ID: 20-494
  • NCT ID: NCT04606316

Conditions

  • Glioblastoma
  • GBM
  • Glioblastoma Multiforme
  • Grade IV Astrocytoma

Interventions

DrugSynonymsArms
Nivolumab-PlaceboPlacebo-Nivolumab and Placebo-Ipilimumab Before Surgery, Nivolumab and Ipilimumab After Surgery
NivolumabOpdivoNivolumab and Ipilimumab Before and After Surgery
Ipilimumab-PlaceboNivolumab and Placebo-Ipilimumab Before Surgery, Nivolumab After Surgery
IpilimumabYervoyNivolumab and Ipilimumab Before and After Surgery

Purpose

This research trial is studying the safety and effectiveness of nivolumab in combination with ipilimumab and surgery when used in the treatment of recurrent glioblastoma. The names of the study drugs involved in this study are: - Nivolumab - Ipilimumab - Placebo (IV solution with no medicine)

Detailed Description

      The research study procedures include screening for eligibility and study treatment including
      evaluations and follow up visits. It is expected that about 60 people will take part in this
      research study.

      There are 3 study groups participating in this study and each group receives different study
      drugs. After screening, participants will be randomized into one of three study groups.

      Participants will receive one of the following study treatments prior to undergoing surgery
      for tumor removal:

        -  Group A receives nivolumab plus ipilimumab

        -  Group B receives nivolumab plus placebo-ipilimumab

        -  Group C receives two placebo infusions, placebo-nivolumab plus placebo-ipilimumab

      Neither the participant nor the research doctor will know which study drugs the participant
      will receive prior to surgery.

      After recovering from surgery, participants will receive doses of study medication based on
      the study group:

        -  Group A receives nivolumab plus ipilimumab every 3 weeks for 3 doses followed by
           nivolumab every 4 weeks

        -  Group B receives nivolumab every four weeks

        -  Group C receives nivolumab plus ipilimumab every 3 weeks for 4 doses followed by
           nivolumab every 4 weeks

      This research study is a Phase Ib clinical trial, which tests the safety and effectiveness of
      an investigational drug to learn whether the drug works in treating a specific disease.
      "Investigational" means the drug is being studied.

      The U.S. Food and Drug Administration (FDA) has not approved the use of nivolumab or
      ipilimumab for your specific disease, but it has been approved for other uses.

      Both nivolumab and ipilimumab are antibodies (types of human protein) that work to stop tumor
      cells from growing and multiplying by immunotherapy.

      Immunotherapy is trying to have the body's own immune system work against tumor cells.
      Nivolumab and ipilimumab have been used in other research studies, and information from those
      other research studies suggest these drugs may help to stop glioblastoma cells from growing.
    

Trial Arms

NameTypeDescriptionInterventions
Nivolumab and Ipilimumab Before and After SurgeryExperimentalOne dose of nivolumab plus ipilimumab will be administered 14(±5) days before surgery. After surgery, participants receive nivolumab in combination with ipilimumab every 3 weeks for 9 weeks and then nivolumab alone every 4 weeks.
  • Nivolumab
  • Ipilimumab
Nivolumab and Placebo-Ipilimumab Before Surgery, Nivolumab After SurgeryExperimentalOne dose of nivolumab plus placebo-ipilimumab will be administered 14(±5) days before surgery. After surgery, participants receive nivolumab alone every 4 weeks.
  • Nivolumab
  • Ipilimumab-Placebo
Placebo-Nivolumab and Placebo-Ipilimumab Before Surgery, Nivolumab and Ipilimumab After SurgeryExperimentalOne dose of placebo-nivolumab plus placebo-ipilimumab will be administered 14(±5) days before surgery. After surgery, participants receive nivolumab in combination with ipilimumab every 3 weeks for 12 weeks and then nivolumab alone every 4 weeks.
  • Nivolumab-Placebo
  • Nivolumab
  • Ipilimumab-Placebo
  • Ipilimumab

Eligibility Criteria

        Inclusion Criteria:

          -  Have histologically confirmed World Health Organization Grade IV IDH wildtype
             glioblastoma or variants including gliosarcoma or IDH wildtype glioma with molecularly
             features of glioblastoma.

          -  Previous first line therapy with at least radiotherapy.

          -  Patients must be undergoing surgery that is clinically indicated as determined by
             their care providers.

          -  Be at first or second relapse. Note: Relapse is defined as progression following
             initial therapy (i.e., radiation ± chemotherapy).

          -  Participants must have shown unequivocal evidence for tumor progression by MRI per
             RANO criteria.

          -  Participants must have confirmation of availability of sufficient tissue from prior
             surgery revealing glioblastoma or variants for submission following registration. The
             following amount of tissue is required:

               -  1 formalin-fixed paraffin-embedded (FFPE) tumor tissue block (preferred) OR

               -  10 FFPE unstained slides (5 μm thick)

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

          -  Participants must have recovered to grade 0 or 1 or pre-treatment baseline from
             clinically significant toxic effects of prior therapy (including but not limited to
             exceptions of alopecia, laboratory values listed per inclusion criteria, and
             lymphopenia (which is common after therapy with temozolomide).

          -  An interval of at least 4 weeks (to registration) between prior surgical resection or
             one week for stereotactic biopsy.

          -  From registration, the following time periods must have elapsed: 5 half-lives from any
             investigational agent, 4 weeks from cytotoxic therapy (except 23 days for temozolomide
             and 6 weeks from nitrosoureas), 4 weeks from antibodies, or 4 weeks (or 5 half-lives,
             whichever is shorter) from other anti-tumor therapies (including vaccines). No washout
             period required from tumor treating fields (TTF).

          -  Be willing and able to provide written informed consent/assent for the trial.

          -  Be ≥ 18 years of age on day of signing informed consent.

          -  Have a Karnofsky performance status (KPS) ≥ 70.

          -  MRI within 14 days prior of registration.

          -  All screening labs should be performed within 14 days of registration and demonstrate
             adequate organ function as defined below:

               -  Absolute neutrophil count (ANC) ≥1,500 /mcL

               -  Platelets ≥100,000 / mcL

               -  Hemoglobin ≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency (within 7
                  days of assessment)

               -  Serum creatinine OR measured or calculated a creatinine clearance (GFR can be
                  used in place of creatinine or CrCl) ≤1.5 X institutional upper limit of normal
                  (ULN) OR ≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN
                  (Creatinine clearance should be calculated per institutional standard.)

               -  Serum total bilirubin ≤ 1.5 X institutional ULN OR direct bilirubin ≤
                  institutional ULN for subjects with total bilirubin levels > 1.5 institutional
                  ULN

               -  AST (SGOT) and ALT (SGPT) ≤ 2.5 X institutional ULN OR ≤ 5 X institutional ULN
                  for subjects with Gilberts syndrome

               -  Albumin ≥ 2.5 mg/dL

               -  International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X
                  institutional ULN unless subject is receiving anticoagulant therapy as long as PT
                  or PTT is within therapeutic range of intended use of anticoagulants

               -  Activated Partial Thromboplastin Time (aPTT) ≤1.5 X institutional ULN unless
                  subject is receiving anticoagulant therapy as long as PT or PTT is within
                  therapeutic range of intended use of anticoagulants

          -  Female subject of childbearing potential should have a negative urine or serum
             pregnancy within 72 hours prior to registration. If the urine test is positive or
             cannot be confirmed as negative, a serum pregnancy test will be required. Women are
             considered post-menopausal and not of child bearing potential if they have had 12
             months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g.,
             age appropriate, history of vasomotor symptoms) or six months of spontaneous
             amenorrhea with serum FSH levels > 40 mIU/mL and estradiol < 20 pg/mL or have had
             surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago.
             In the case of oophorectomy alone, only when the reproductive status of the woman has
             been confirmed by follow up hormone level assessment if she considered not of child
             bearing potential.

          -  Women of child-bearing potential (WOCBP), defined as all women physiologically capable
             of becoming pregnant, must use highly effective contraception during study treatment
             and for 5 months after study discontinuation. Highly effective contraception is
             defined as either:

               -  True Abstinence: When this is in line with the preferred and usual lifestyle of
                  the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal,
                  postovulation methods) and withdrawal are not acceptable methods of
                  contraception.

               -  Sterilization: Surgical bilateral oophorectomy (with or without hysterectomy) or
                  tubal ligation at least six weeks ago. In case of oophorectomy alone, only when
                  the reproductive status of the woman has been confirmed by follow up hormone
                  level assessment (as described above).

               -  Male Partner Sterilization (with the appropriate post-vasectomy documentation of
                  the absence of sperm in the ejaculate). For female subjects on the study, the
                  vasectomised male partner should be the sole partner for that participant.

               -  Use of a combination of any two of the following:

                    -  Placement of an intrauterine device (IUD) or intrauterine system (IUS)

                    -  Barrier methods of contraception: Condom or Occlusive cap (diaphragm or
                       cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal
                       suppository

                    -  Appropriate hormonal contraceptives (including any registered and marketed
                       contraceptive agent that contains an estrogen and/or a progestational agent
                       - including oral, subcutaneous, intrauterine, or intramuscular agents).

          -  Male subjects should agree to use adequate method of contraception starting with the
             first dose of study therapy through 7 months after the last dose of therapy.

        Exclusion Criteria:

          -  IDH mutation by immunohistochemistry.

          -  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, aside from systemic
             corticosteroids (such as methotrexate, chloroquine, azathioprine, etc.) within six
             months of registration.

          -  Has received anti-angiogenic or anti-vascular endothelia growth factor (VEGF) targeted
             agents (e.g. bevacizumab, cediranib, aflibercept, vandetanib, XL-184, sunitinib, etc.)

          -  Requires treatment with high dose systemic corticosteroids defined as dexamethasone >
             2 mg/day or bioequivalent for at least 3 consecutive days within 2 weeks of
             registration.

          -  Has received prior interstitial brachytherapy, implanted chemotherapy, stereotactic
             radiosurgery or therapeutics delivered by local injection or convection enhanced
             delivery.

          -  Has history of known coagulopathy that increases risk of bleeding or a history of
             clinically significant hemorrhage within 12 months of registration.

          -  Has a known history of active TB (Bacillus Tuberculosis).

          -  Has gastrointestinal bleeding or any other hemorrhage/bleeding event CTCAE Grade > 3
             within 6 months of registration.

          -  Has a known additional malignancy that is progressing or requires active treatment.
             Those patients whose natural history or treatment does not have the potential to
             interfere with the safety or efficacy assessment of the investigational regimen will
             be eligible including, but not limited to, basal cell carcinoma of the skin, squamous
             cell carcinoma of the skin, localized prostate cancer not requiring treatment, 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 history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the trial, interfere with the subject's
             participation for the full duration of the trial, or is not in the best interest of
             the subject to participate, in the opinion of the treating investigator. Examples
             include but are not limited to symptomatic congestive heart failure, unstable angina
             pectoris, cardiac arrhythmia or psychiatric illness/social situations that would limit
             compliance with study requirements.

          -  Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

          -  Is pregnant, breastfeeding, or expecting to conceive within the projected duration of
             the trial, starting with the screening visit through 5 months after the last dose of
             trial treatment. It is unknown whether nivolumab and/or ipilimumab is excreted in
             human milk or may have adverse effects on a fetus in utero. Since many drugs are
             excreted in human milk, and because of the potential for serious adverse reactions in
             the nursing infant or fetus, these subjects are not eligible for enrollment.

          -  Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or
             anti-Cytotoxic T-lymphocyte-Associated Antigen-4 (CTLA-4) antibody (including
             ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation
             or checkpoint pathways).

          -  Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

          -  Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
             [qualitative] is detected).

          -  Has received a live vaccine within 30 days prior to registration.

          -  Has a known hypersensitivity to any of the study therapy products.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Tumor Infiltrating T Lymphocyte (TIL) Density
Time Frame:24 Months
Safety Issue:
Description:TIL density will be assessed and compared between the three arms using the Two-sample t-Test.

Secondary Outcome Measures

Measure:Cell Cycle-Related Genetic Signature within the Tumor Microenvironment
Time Frame:24 months
Safety Issue:
Description:Multiplex IHC staining will be performed on tumor tissue to evaluate the influence of the neoadjuvant administration on the cell cycle-related genetic signature within the tumor microenvironment of recurrent glioblastoma.
Measure:Percentage of Progression Free Survival (PFS-6)
Time Frame:24 months
Safety Issue:
Description:PFS-6 will be assessed using pooled data in comparison to appropriate historical controls. Percent PFS-6 will be estimated and compared using the Exact Binomial Test.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Patrick Y. Wen, MD

Trial Keywords

  • Glioblastoma
  • GBM
  • Glioblastoma Multiforme
  • Grade IV Astrocytoma

Last Updated

October 24, 2020