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Surgical Nivolumab And Ipilimumab For Recurrent GBM

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04606316
Recruitment Status : Recruiting
First Posted : October 28, 2020
Last Update Posted : February 9, 2021
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Patrick Y. Wen, MD, Dana-Farber Cancer Institute

Tracking Information
First Submitted Date  ICMJE October 24, 2020
First Posted Date  ICMJE October 28, 2020
Last Update Posted Date February 9, 2021
Actual Study Start Date  ICMJE February 1, 2021
Estimated Primary Completion Date December 31, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 24, 2020)
  • Tumor Infiltrating T Lymphocyte (TIL) Density [ Time Frame: 24 Months ]
    TIL density will be assessed and compared between the three arms using the Two-sample t-Test.
  • Safety of Study Drug Therapy [ Time Frame: 24 Months ]
    Adverse events will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Safety will be assessed by quantifying the toxicities and grades experienced by participants who have received at least one dose of study treatment.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 24, 2020)
  • Cell Cycle-Related Genetic Signature within the Tumor Microenvironment [ Time Frame: 24 months ]
    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.
  • Percentage of Progression Free Survival (PFS-6) [ Time Frame: 24 months ]
    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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Surgical Nivolumab And Ipilimumab For Recurrent GBM
Official Title  ICMJE 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
Brief Summary

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Masking Description:
The neoadjuvant treatment administered prior to surgery will be blinded. The participants, Sponsor, site investigators, and site staff will not know the treatment administered. An assigned Site Investigational Pharmacist will not be blinded. Designated staff of the DF/HCC Office of Data Quality will be unblinded to facilitate randomization and safety monitoring. Treatment after surgery is not blinded.
Primary Purpose: Treatment
Condition  ICMJE
  • Glioblastoma
  • GBM
  • Glioblastoma Multiforme
  • Grade IV Astrocytoma
Intervention  ICMJE
  • Drug: Nivolumab-Placebo
    Intravenous (IV) solution that has no therapeutic effect, used as a control in testing investigational drug. One dose is received prior to surgery.
  • Drug: Nivolumab
    Given as intravenous (IV) infusion into a vein.
    Other Name: Opdivo
  • Drug: Ipilimumab-Placebo
    Intravenous (IV) solution that has no therapeutic effect, used as a control in testing investigational drug. One dose is received prior to surgery.
  • Drug: Ipilimumab
    Given as intravenous (IV) infusion into a vein.
    Other Name: Yervoy
  • Procedure: Surgery
    Treatment of disease or injury by cutting, abrading, suturing, or otherwise physically changing body tissues and organs.
    Other Name: Resection
Study Arms  ICMJE
  • Experimental: Nivolumab and Ipilimumab Before and After Surgery

    One 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.

    Interventions:
    • Drug: Nivolumab
    • Drug: Ipilimumab
    • Procedure: Surgery
  • Experimental: Nivolumab and Placebo-Ipilimumab Before Surgery, Nivolumab After Surgery

    One dose of nivolumab plus placebo-ipilimumab will be administered 14(±5) days before surgery.

    After surgery, participants receive nivolumab alone every 4 weeks.

    Interventions:
    • Drug: Nivolumab
    • Drug: Ipilimumab-Placebo
    • Procedure: Surgery
  • Experimental: Placebo-Nivolumab and Placebo-Ipilimumab Before Surgery, Nivolumab and Ipilimumab After Surgery

    One 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.

    Interventions:
    • Drug: Nivolumab-Placebo
    • Drug: Nivolumab
    • Drug: Ipilimumab-Placebo
    • Drug: Ipilimumab
    • Procedure: Surgery
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 24, 2020)
60
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2023
Estimated Primary Completion Date December 31, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Patrick Wen, MD (617) 632-2166 PWEN@PARTNERS.ORG
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04606316
Other Study ID Numbers  ICMJE 20-494
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to Sponsor Investigator or designee. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Time Frame: Data can be shared no earlier than 1 year following the date of publication
Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu
Responsible Party Patrick Y. Wen, MD, Dana-Farber Cancer Institute
Study Sponsor  ICMJE Patrick Y. Wen, MD
Collaborators  ICMJE Bristol-Myers Squibb
Investigators  ICMJE
Principal Investigator: Patrick Y Wen, MD Dana-Farber Cancer Institute
PRS Account Dana-Farber Cancer Institute
Verification Date February 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP