Nivolumab With Radiation Therapy and Bevacizumab for Recurrent MGMT Methylated Glioblastoma

NCT ID: NCT03743662

Last Updated: 2026-01-07

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 39 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-11-12
• Study Completion Date: 2026-11-30

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.

Conditions

Glioblastoma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Recurrent Glioblastoma, No Surgery

One cohort is for patients with recurrent GBM who are not undergoing surgical debulking as part of their treatment plan

Group Type: EXPERIMENTAL

Re-irradiation (RT)

Intervention Type: RADIATION

Re-RT will start on day 28 +/- 5 days for 5 fractions of 600cGy every other day over a 2-week period.

Bevacizumab

Intervention Type: DRUG

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.

Nivolumab

Intervention Type: DRUG

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.

Recurrent Glioblastoma, Surgery

The second cohort is for patients with recurrent GBM who are undergoing surgery as part of their treatment.

Group Type: EXPERIMENTAL

Re-irradiation (RT)

Intervention Type: RADIATION

Re-RT will start on day 28 +/- 5 days for 5 fractions of 600cGy every other day over a 2-week period.

Bevacizumab

Intervention Type: DRUG

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.

Nivolumab

Intervention Type: DRUG

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.

Re-resection

Intervention Type: PROCEDURE

Re-resection will be performed in the surgical arm at day 14 (+/- 5 days).

Interventions

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.

Intervention Type: RADIATION

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.

Intervention Type: 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.

Intervention Type: DRUG

Re-resection

Re-resection will be performed in the surgical arm at day 14 (+/- 5 days).

Intervention Type: PROCEDURE

Eligibility Criteria

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% or ECOG 0 or 1
• 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).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Memorial Sloan Kettering Cancer Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Christian Grommes, MD

Role: PRINCIPAL_INVESTIGATOR

Memorial Sloan Kettering Cancer Center

Locations

Hartford Healthcare (Data Collection)

Hartford, Connecticut, United States

Indiana University (Data Collection Only)

Indianapolis, Indiana, United States

Memorial Sloan Kettering Basking Ridge

Basking Ridge, New Jersey, United States

Memorial Sloan Kettering Monmouth

Middletown, New Jersey, United States

Memorial Sloan Kettering Bergen

Montvale, New Jersey, United States

Memorial Sloan Kettering Commack

Commack, New York, United States

Memorial Sloan Kettering Westchester

Harrison, New York, United States

Memorial Sloan Kettering Cancer Center

New York, New York, United States

Memorial Sloan Kettering Nassau

Uniondale, New York, United States

Lehigh Valley Health Network (Data Collection Only)

Allentown, Pennsylvania, United States

University of Vermont Medical Center (Data Collection Only)

Burlington, Vermont, United States

Countries

United States

Related Links

http://www.mskcc.org

Memorial Sloan Kettering Cancer Center

Other Identifiers

18-400

Identifier Type: -

Identifier Source: org_study_id