Clinical Trials /

Nivolumab Plus Standard Dose Bevacizumab Versus Nivolumab Plus Low Dose Bevacizumab in GBM

NCT03452579

Description:

The purpose of this study is to test the effectiveness (how well the drug works), safety and tolerability of an investigational drug called nivolumab (also known as BMS-936558) in glioblastoma (a malignant tumor, or GBM), when added to bevacizumab. Nivolumab is an antibody (a kind of human protein) that is being tested to see if it will allow the body's immune system to work against glioblastoma tumors. Opdivo (Nivolumab) is currently FDA approved in the United States for melanoma (a type of skin cancer), non-small cell lung cancer, renal cell cancer (a type of kidney cancer), Hodgkin's lymphoma but is not approved in glioblastoma. Nivolumab may help your immune system detect and attack cancer cells. Bevacizumab is a drug which works on the blood vessel that supply the tumor and potentially can starve the tumor by cutting off the blood supply to these tumors. Bevacizumab is commercially available and FDA approved for patients with recurrent glioblastoma. This study has two study groups. Arm 1 will receive the study drug Nivolumab 240mg and bevacizumab 10 mg (standard dose) every 2 weeks and Arm 2 will receive the study drug Nivolumab 240 mg and bevacizumab 3 mg (reduced dose) every 2 weeks. A process will be used to assign patients, by chance, to one of the study groups. Neither patients nor doctors can choose which group patients are in. This is done by chance because no one knows if one study group is better or worse than the other. 90 total patients are expected to participate in this study (45 patients in each arm). Your total participation in this study from the time you have signed the informed consent to your last visit, including follow-up visits, may be more than three years (depending on what effect the treatment has on your cancer, and how well you tolerate the treatment).

Related Conditions:
  • Glioblastoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab Plus Standard Dose Bevacizumab Versus Nivolumab Plus Low Dose Bevacizumab in GBM
  • Official Title: CA209-382 A Randomized Phase 2 Open Label Study of Nivolumab Plus Standard Dose Bevacizumab Versus Nivolumab Plus Low Dose Bevacizumab in Recurrent Glioblastoma (GBM)

Clinical Trial IDs

  • ORG STUDY ID: CASE1317
  • NCT ID: NCT03452579

Conditions

  • Glioblastoma

Interventions

DrugSynonymsArms
NivolumabOpdivoNivolumab + Standard Dose Bevacizumab
Standard Dose BevacizumabAvastinNivolumab + Standard Dose Bevacizumab
Reduced Dose BevacizumabAvastinNivolumab + Reduced Dose Bevacizumab

Purpose

The purpose of this study is to test the effectiveness (how well the drug works), safety and tolerability of an investigational drug called nivolumab (also known as BMS-936558) in glioblastoma (a malignant tumor, or GBM), when added to bevacizumab. Nivolumab is an antibody (a kind of human protein) that is being tested to see if it will allow the body's immune system to work against glioblastoma tumors. Opdivo (Nivolumab) is currently FDA approved in the United States for melanoma (a type of skin cancer), non-small cell lung cancer, renal cell cancer (a type of kidney cancer), Hodgkin's lymphoma but is not approved in glioblastoma. Nivolumab may help your immune system detect and attack cancer cells. Bevacizumab is a drug which works on the blood vessel that supply the tumor and potentially can starve the tumor by cutting off the blood supply to these tumors. Bevacizumab is commercially available and FDA approved for patients with recurrent glioblastoma. This study has two study groups. Arm 1 will receive the study drug Nivolumab 240mg and bevacizumab 10 mg (standard dose) every 2 weeks and Arm 2 will receive the study drug Nivolumab 240 mg and bevacizumab 3 mg (reduced dose) every 2 weeks. A process will be used to assign patients, by chance, to one of the study groups. Neither patients nor doctors can choose which group patients are in. This is done by chance because no one knows if one study group is better or worse than the other. 90 total patients are expected to participate in this study (45 patients in each arm). Your total participation in this study from the time you have signed the informed consent to your last visit, including follow-up visits, may be more than three years (depending on what effect the treatment has on your cancer, and how well you tolerate the treatment).

Detailed Description

      Primary Endpoint(s) To evaluate the efficacy of nivolumab when administered with standard and
      reduced bevacizumab dosing among recurrent glioblastoma patients as measured by the rate of
      overall survival at twelve months.

      Secondary Endpoint(s) To evaluate the safety and tolerability of nivolumab in combination
      with bevacizumab administered according to standard and reduced dosage schedules for
      recurrent glioblastoma patients.

      To compare progression free survival (PFS) at 6 months of nivolumab when administered with
      standard and reduced bevacizumab dosing for recurrent glioblastoma patients.

      To compare the overall survival rate of nivolumab when administered with standard and reduced
      bevacizumab dosing for recurrent glioblastoma patients.

      To compare progression free survival (PFS) of when administered with standard and reduced
      bevacizumab dosing for recurrent glioblastoma patients.

      To compare the objective response rate (ORR) of nivolumab and bevacizumab administered
      according to standard and reduced dosage schedules for recurrent glioblastoma patients

      Exploratory Endpoints (s) To evaluate whether baseline values or subsequent changes in
      circulating immunologic parameters (including but not limited to the number of T-cells,
      B-cells and natural killer (NK) cells; the number of T cell subsets; soluble circulating
      cytokines) are associated with outcome.

      To assess neurologic functioning in the treatment arms using the Neurologic Assessment in
      Neuro-Oncology (NANO).

      To assess the perfusion and diffusion base imaging to correlate with changes and response to
      nivolumab when administered with standard and reduced bevacizumab dosing.

      To assess response using the immunotherapy response assessment in neuro-oncology criteria
      relative to survival.

      Study design and duration This is a randomized, open-label, phase 2 safety study of nivolumab
      and bevacizumab administered according to standard and reduced dosage schedules in adult (≥
      18 years) subjects with a first recurrence or second recurrence of glioblastoma (GBM).
      Subjects must have received previous treatment with radiotherapy and may have up to 2
      recurrences. Patients will undergo 1:1 randomization to receive treatment with either
      nivolumab (240 mg flat dosing IV every 2 weeks) and bevacizumab administered according to
      standard (10 mg/kg IV every 2 weeks; Arm A) and reduced (3 mg/kg IV every 2 weeks; Arm B)
      dosage schedules for recurrent glioblastoma patients. The study will allow patients that
      require decadron up to 4 mg/ day to participate in the study.
    

Trial Arms

NameTypeDescriptionInterventions
Nivolumab + Standard Dose BevacizumabActive Comparatornivolumab 240 mg and standard dose bevacizumab 10 mg/kg every 2 weeks until disease progression or unacceptable toxicity
  • Nivolumab
  • Standard Dose Bevacizumab
Nivolumab + Reduced Dose BevacizumabExperimentalnivolumab 240 mg and reduced dose bevacizumab 3mg/kg every 2 weeks until disease progression or unacceptable toxicity
  • Nivolumab
  • Reduced Dose Bevacizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Written informed consent and HIPAA authorization (applies to covered entities in the
             USA only) obtained from the subject/legal representative prior to performing any
             protocol-related procedures, including screening evaluations

          -  Subjects must be willing and able to comply with scheduled visits, treatment schedule,
             laboratory testing, and other requirements of the study, including disease assessment
             by MRI.

          -  Histologically confirmed diagnosis of supratentorial glioblastoma

          -  Previous first line treatment with at least radiotherapy

          -  Documented first or second recurrence of GBM by diagnostic biopsy or contrast enhanced
             magnetic resonance imaging (MRI) performed within 21 days of randomization per RANO
             criteria.

          -  If first recurrence of GBM is documented by MRI, an interval of at least 12 weeks
             after the end of prior radiation therapy is required unless there is either:

          -  histopathologic confirmation of recurrent tumor, or

          -  new enhancement on MRI outside of the radiotherapy treatment field

          -  An interval of > 28 days and full recovery (i.e., no ongoing safety issues) from
             surgical resection prior to randomization.

          -  An interval of > 4 weeks after the last administration of any other treatment for GBM.

          -  Karnofsky performance status of 70 or higher

          -  Life expectancy > 12 weeks

          -  Women of childbearing potential (WOCBP, as defined in Section 5.4) must have a
             negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent
             units of HCG) within 1 days prior to the start of study drug

          -  Women must not be breastfeeding

          -  WOCBP must use appropriate method(s) of contraception from the time of enrollment for
             the duration of treatment with study drug (s) plus 5 half-lives of study drug (s) plus
             30 days (duration of ovulatory cycle) for a total of 23 weeks post treatment
             completion for subjects enrolled to treatment arm A (nivolumab). Subjects enrolled to
             treatment arm B (nivolumab + bevacizumab) must use appropriate method(s) of
             contraception for 6 months post treatment completion.

          -  Men who are sexually active with WOCBP must use any contraceptive method with a
             failure rate of less than 1% per year. Men receiving nivolumab and who are sexually
             active with WOCBP will be instructed to adhere to contraception for the duration of
             treatment with study drug (s) plus 5 half-lives of study drug (s) plus 90 days
             (duration of sperm turnover) for a total of 31 weeks post-treatment completion.

          -  Women who are not of childbearing potential (i.e., who are postmenopausal or
             surgically sterile as well as azoospermic men) do not require contraception.

          -  Azoospermic males and WOCBP who are continuously not heterosexually active are exempt
             from contraceptive requirements. However WOCBP subjects must still undergo pregnancy
             testing as described in these sections.

          -  Recovery from the toxic effects of prior therapy, with a minimum time of:

               -  ≥ 28 days elapsed from the administration of any investigational agent

               -  ≥ 28 days elapsed from the administration of any prior cytotoxic agents, except

               -  ≥ 14 days from vincristine, ≥ 21 days from procarbazine, and ≥ 42 days from

               -  nitrosureas

               -  ≥ 14 days elapsed from administration of any non-cytotoxic agent (e.g.,
                  interferon, tamoxifen, thalidomide, cis-retinoic acid)

        Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on
        the importance of pregnancy prevention and the implications of an unexpected pregnancy.
        Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on
        the use of highly effective methods of contraception. Highly effective methods of
        contraception have a failure rate of < 1% per year when used consistently and correctly.

        - Screening/Baseline laboratory values must meet the following criteria:

          -  White Blood Cells ≥ 2000/uL

          -  Neutrophils ≥ 1500/uL

          -  Platelets ≥ 100x103/uL

          -  Hemoglobin ≥ 9.0 g/dL

          -  Serum creatinine < 1.5 x upper limit of normal (ULN) or creatinine clearance (CrCl) >
             40 mL/min (using the Cockcroft-Gault formula) Female CrCl = (140 - age in years) x
             weight in kg x 0.85 /72 x serum creatinine in mg/dL Male CrCl = (140 - age in years) x
             weight in kg x 1.00/72 x serum creatinine in mg/dL

          -  aspartate transaminase (AST) ≤ 3x ULN

          -  alanine transaminase (ALT) ≤ 3x ULN

          -  Bilirubin ≤ 1.5x ULN (except subjects with Gilbert Syndrome, who can have total
             bilirubin < 3.0 mg/dL)

        Exclusion Criteria:

          -  More than two recurrences of GBM

          -  Presence of extracranial metastatic, significant leptomeningeal disease or tumors
             primarily localized to the brainstem or spinal cord.

          -  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 subject to receive protocol therapy, or
             interfere with the interpretation of study results.

          -  Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo,
             type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only
             requiring hormone replacement, psoriasis not requiring chronic and systemic
             immunosuppressive treatment, or conditions not expected to recur in the absence of an
             external trigger are permitted to enroll. Subjects have any other condition requiring
             systemic treatment with corticosteroids or other immunosuppressive agents within 14
             days. Inhaled or topical steroids and adrenal replacement doses >10mg daily prednisone
             equivalent are permitted in absence of active autoimmune disease.

          -  Previous radiation therapy with anything other than standard radiation therapy (i.e.,
             focally directed radiation) administered as first line therapy.

          -  Previous treatment with carmustine wafer except when administered as first line
             treatment and at least 6 months prior to randomization

          -  Previous bevacizumab or other vascular endothelial growth factor (VEGF) or
             anti-angiogenic treatment

          -  Previous treatment with a programmed cell death protein 1 (PD-1), programmed death
             ligand 1 (PD-L1) or CTLA-4 targeted therapy

          -  Evidence of > Grade 1 central nervous system (CNS) hemorrhage on the baseline MRI scan

          -  Inadequately controlled hypertension (defined as systolic blood pressure ≥150 mmHg and
             /or diastolic blood pressure ≥100 mmHg) within 7 days of first study treatment

          -  Prior history of hypertensive crisis, hypertensive encephalopathy, reversible
             posterior leukoencephalopathy syndrome (RPLS);

          -  Prior history of gastrointestinal diverticulitis, perforation, or abscess;

          -  Clinically significant (i.e., active) cardiovascular disease, for example
             cerebrovascular accidents ≤ 6 months prior to study enrollment, myocardial infarction
             ≤ 6 months prior to study enrollment, unstable angina, New York Heart Association
             (NYHA) Grade II or greater congestive heart failure (CHF), or serious cardiac
             arrhythmia uncontrolled by medication or potentially interfering with protocol
             treatment;

          -  Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or
             recent arterial thrombosis) within 6 months prior to start of study treatment. Any
             previous venous thromboembolism > NCI CTCAE Grade 3;

          -  History of pulmonary hemorrhage/hemoptysis ≥ grade 2 (defined as ≥ 2.5 mL bright red
             blood per episode) within 1 month prior to randomization;

          -  History or evidence of inherited bleeding diathesis or significant coagulopathy at
             risk of bleeding (i.e., in the absence of therapeutic anticoagulation);

          -  Current or recent (within 10 days of study enrollment) use of anticoagulants that, in
             the opinion of the investigator, would place the subject at significant risk for
             bleeding. Prophylactic use of anticoagulants is allowed;

          -  Surgical procedure (including open biopsy, surgical resection, wound revision, or any
             other major surgery involving entry into a body cavity) or significant traumatic
             injury within 28 days prior to first study treatment, or anticipation of need for
             major surgical procedure during the course of the study;

          -  Minor surgical procedure (e.g., stereotactic biopsy within 7 days of first study
             treatment; placement of a vascular access device within 2 days of first study
             treatment);

          -  History of intracranial abscess within 6 months prior to randomization;

          -  History of active gastrointestinal bleeding within 6 months prior to randomization;

          -  Serious, non-healing wound, active ulcer, or untreated bone fracture;

          -  Subjects unable (due to existent medical condition, e.g., pacemaker or vascular
             endothelial growth factor (ICD) device) or unwilling to have a head contrast enhanced
             MRI

          -  Positive test for hepatitis B virus surface antigen (HBV sAg) or detectable hepatitis
             C virus ribonucleic acid (HCV RNA) indicating acute or chronic infection

          -  Known history of testing positive for human immunodeficiency virus (HIV) or known
             acquired immunodeficiency syndrome (AIDS)

          -  History of severe hypersensitivity reaction to any monoclonal antibody

          -  Patients that require decadron > 4 mg/ day or equivalent of steroids
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Survival at 12 Months
Time Frame:Up to 12 months after beginning therapy
Safety Issue:
Description:The proportion of subjects in the analysis population who remain alive for at least twelve months following initiation of study therapy.

Secondary Outcome Measures

Measure:Overall Survival
Time Frame:Up to 3 years after beginning treatment
Safety Issue:
Description:Time from beginning of treatment to death
Measure:Overall Response Rate
Time Frame:Up to 3 years after beginning treatment
Safety Issue:
Description:Proportion of subjects in the analysis population who have complete response (CR) or partial response (PR) using Radiologic Assessment in Neuro-Oncology criteria (RANO) criteria.
Measure:Duration of Response
Time Frame:Up to 3 years after beginning treatment
Safety Issue:
Description:Time from first RANO response to disease progression in subjects who achieve a PR or better
Measure:Progression-Free Survival
Time Frame:Up to 3 years after beginning treatment
Safety Issue:
Description:Defined as the time from allocation to the first documented disease progression according to RANO or death due to any cause, whichever occurs first
Measure:Progression-Free Survival at Six Months
Time Frame:Up to six months after beginning treatment
Safety Issue:
Description:The proportion of subjects in the analysis population who remain progression-free for at least six months following initiation of study therapy

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Case Comprehensive Cancer Center

Trial Keywords

  • Nivolumab
  • Bevacizumab

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