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Nivolumab With Radiation Therapy and Bevacizumab for Recurrent MGMT Methylated Glioblastoma

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ClinicalTrials.gov Identifier: NCT03743662
Recruitment Status : Recruiting
First Posted : November 16, 2018
Last Update Posted : May 8, 2020
Sponsor:
Information provided by (Responsible Party):
Memorial Sloan Kettering Cancer Center

Tracking Information
First Submitted Date  ICMJE November 13, 2018
First Posted Date  ICMJE November 16, 2018
Last Update Posted Date May 8, 2020
Actual Study Start Date  ICMJE November 12, 2018
Estimated Primary Completion Date November 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 25, 2019)
Overall survival [ Time Frame: 2 years ]
in participants with recurrent glioblastoma (first recurrence)treated with re-irradiation with concurrent nivolumab (as well as bevacizumab if the investigator feels that the patient benefits from the addition) followed by adjuvant nivolumab in two parallel cohorts.
Original Primary Outcome Measures  ICMJE
 (submitted: November 15, 2018)
Overall survival in participants with recurrent glioblastoma (first recurrence)treated with re-irradiation with concurrent bevacizumab and nivolumab followed by adjuvant nivolumab in two parallel cohorts. [ Time Frame: 2 years ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 15, 2018)
  • 6 month progression-free survival [ Time Frame: 6 months ]
  • Median progression-free survival [ Time Frame: 2 years ]
  • Objective response rate [ Time Frame: 2 years ]
    ORR using the iRANO criteria
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 Nivolumab With Radiation Therapy and Bevacizumab for Recurrent MGMT Methylated Glioblastoma
Official Title  ICMJE A Phase II Trial of the PD-1 Antibody Nivolumab in Combination With Hypofractionated Re-irradiation and Bevacizumab for Recurrent MGMT Methylated Glioblastoma
Brief Summary This study is being done to see if adding nivolumab to radiation therapy and bevacizumab can increase the effectiveness of the treatment for recurrent glioblastoma.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Glioblastoma
Intervention  ICMJE
  • Radiation: Re-irradiation (RT)
    Re-RT will start on day 28 +/- 5 days for 5 fractions of 600cGy every other day over a 2-week period.
  • Drug: Bevacizumab
    Bevacizumab if deemed beneficial by the investigator, will be started at the initiation of re-RT and continued for three doses in the medical arm. Patients in the surgical arm will omit the first bevacizumab dose to assure adequate wound healing after surgery and receive two doses. Bevacizumab will be dosed at 10mg/kg and given intravenously on day 28 (medical arm only), day 42 and day 56. Following day 56, further bevacizumab doses can be given every two weeks at the discretion of the treating physician.
  • Drug: Nivolumab

    Nivolumab will be started at enrollment and each patient will receive two doses of nivolumab prior to radiation.

    Nivolumab will be dosed at 3mg/kg given intravenously before re-RT (day 1 +/- 5 and 14 +/- 5) and when given with bevacizumab if deemed beneficial by the investigator, (day 28 +/- 5 (medical arm only), day 42 +/- 5, and day 56 +/-5). Nivolumab will be dosed based on body weight while combined with re-radiation and bevacizumab for safety considerations to reduce adverse events. Single agent nivolumab will be given at 240mg flat dose every 2 weeks thereafter until disease progression, withdrawal, adverse event, or death.

  • Procedure: Re-resection
    Re-resection will be performed in the surgical arm at day 14 (+/- 5 days).
Study Arms  ICMJE
  • Experimental: Recurrent Glioblastoma, No Surgery
    One cohort is for patients with recurrent GBM who are not undergoing surgical debulking as part of their treatment plan
    Interventions:
    • Radiation: Re-irradiation (RT)
    • Drug: Bevacizumab
    • Drug: Nivolumab
  • Experimental: Recurrent Glioblastoma, Surgery
    The second cohort is for patients with recurrent GBM who are undergoing surgery as part of their treatment.
    Interventions:
    • Radiation: Re-irradiation (RT)
    • Drug: Bevacizumab
    • Drug: Nivolumab
    • Procedure: Re-resection
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: November 15, 2018)
94
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 2021
Estimated Primary Completion Date November 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Histologic confirmed glioblastoma (WHO grade IV), IDH wildtype confirmed by DNA sequencing
  • MGMT hypermethylation in archival tumor biopsy, determined by any CLIAapproved, DNA-based assay
  • Prior maximal feasible surgical resection of biopsy
  • Prior treatment with radiation and temozolomide chemotherapy
  • Pathologic and/or Radiographic evidence of recurrent disease
  • Circumscribed enhancing tumor ≤ 5.0 cm in largest diameter (T1 post contrast)
  • 1 prior course of radiation therapy
  • Age ≥ 18 years
  • Karnofsky performance status ≥ 70%
  • Adequate bone marrow function

    • Hemoglobin ≥ 10g/dL
    • Absolute neutrophil count ≥ 1,500/mm 3
    • Absolute lymphocyte count ≥ 200/mm 3
    • Platelet count ≥ 100,000/mm3
  • Adequate liver function

    • Bilirubin <1.5 times upper limit normal (ULN)
    • AST and ALT ≤ 3 times ULN
    • Alkaline phosphatase ≤ 2 times ULN
  • Adequate renal function

    • BUN and Creatinine <1.5 times ULN

Exclusion Criteria:

  • Infratentorial location of the recurrence
  • IDH mutated glioblastoma
  • More than one prior tumor recurrence after standard first-line therapy
  • Prior radiation to the brain within ≤ 4 months
  • Circumscribed enhancing tumor >5.0 cm in largest diameter (T1 post contrast)
  • Pulmonary embolus or deep vein thrombosis within preceding 2 months
  • Grade 2 or greater congestive heart failure
  • Unstable angina, myocardial infarction within past 12 months
  • Peptic ulcer, abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within past 6 months
  • Nonhealing wound, ulcer or bone fracture
  • Prior spontaneous CNS hemorrhage (as determined from clinical history, CT, or MRI)
  • Uncontrollable hypertension
  • Requiring escalating or chronic supraphysiologic doses of corticosteroids (> 4 mg dexamethasone daily) for control of disease at the time of registration
  • Previous or current treatment with an anti-CTLA-4, anti-PD-1, anti-PD-L1, or anti-PDL2 agent.
  • Previous or current treatment with bevacizumab
  • Hypersensitivity to nivolumab or bevacizumab or any of its excipients
  • Diagnosis of immunodeficiency, including Human Immunodeficiency Virus (HIV) or acquired immunodeficiency syndrome (AIDS)
  • Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
  • Known history of active TB (Bacillus Tuberculosis)
  • Known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
  • 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.
  • Known history of, or any evidence of active, non-infectious pneumonitis.
  • Active infection requiring systemic therapy.
  • Pregnancy or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
  • Unable to undergo MRI of the brain (i.e. pacemaker or any other contraindication for MRIs).
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: Christian Grommes, MD 212-610-0344 grommesc@mskcc.org
Contact: Kathryn Beal, MD 212-639-5159 bealk@mskcc.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03743662
Other Study ID Numbers  ICMJE 18-400
Has Data Monitoring Committee Not Provided
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: Undecided
Responsible Party Memorial Sloan Kettering Cancer Center
Study Sponsor  ICMJE Memorial Sloan Kettering Cancer Center
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Christian Grommes, MD Memorial Sloan Kettering Cancer Center
PRS Account Memorial Sloan Kettering Cancer Center
Verification Date May 2020

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