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 individuals 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 (low dose) every 2 weeks. A process will be used to assign participants, by chance, to one of the study groups. Neither participants nor doctors can choose which group participants are in. This is done by chance because no one knows if one study group is better or worse than the other. 90 total participants are expected to participate in this study (45 participants 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 + Low Dose Bevacizumab
Standard Dose BevacizumabAvastinNivolumab + Standard Dose Bevacizumab
Low Dose BevacizumabAvastinNivolumab + Low 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 individuals 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 (low dose) every 2 weeks. A process will be used to assign participants, by chance, to one of the study groups. Neither participants nor doctors can choose which group participants are in. This is done by chance because no one knows if one study group is better or worse than the other. 90 total participants are expected to participate in this study (45 participants 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 low 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 low dosage schedules for recurrent glioblastoma
           patients.

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

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

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

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

      Study design and duration: This is a randomized, open-label, phase 2 safety study of
      nivolumab and bevacizumab administered according to standard and low dosage schedules in
      adult (≥ 18 years) participants with a first recurrence or second recurrence of glioblastoma
      (GBM). Participants must have received previous treatment with radiotherapy and one
      recurrence. The study will allow participants that require decadron up to 4mg/day to
      participate. Participants 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 low (3 mg/kg IV every 2 weeks; Arm B) dosage
      schedules for recurrent glioblastoma participants. The study will allow participants that
      require decadron up to 4 mg/ day to participate in the study.

      Note - In view of the Covid 19 crisis, all in person visits can be substituted for virtual
      visit. All nursing toxicity checks can be performed over the phone rather than in person
    

Trial Arms

NameTypeDescriptionInterventions
Nivolumab + Standard Dose BevacizumabActive Comparatornivolumab 240 mg IV and standard dose bevacizumab 10 mg/kg every 2 weeks until disease progression or unacceptable toxicity. Nivolumab is to be administered first. The second infusion will be bevacizumab, and will start no sooner than 10 minutes after completion of the nivolumab infusion
  • Nivolumab
  • Standard Dose Bevacizumab
Nivolumab + Low Dose BevacizumabExperimentalnivolumab 240 mg IV and low dose bevacizumab 3mg/kg every 2 weeks until disease progression or unacceptable toxicity Nivolumab is to be administered first. The second infusion will be bevacizumab, and will start no sooner than 10 minutes after completion of the nivolumab infusion
  • Nivolumab
  • Low Dose Bevacizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Written informed consent and HIPAA authorization 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 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.

          -  Karnofsky performance status (KPS) of 70 or higher (Appendix 1)

          -  Life expectancy > 12 weeks

          -  Up to ten unstained slides of 5 microns thickness or a block of tissue will be
             required to be sent if tissue is available. If the tissue is not available then
             Principal investigator permissions is required prior to enrollment

          -  Women of childbearing potential (WOCBP,) must have a negative serum or urine pregnancy
             test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 1 day 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
             6 months post treatment completion for a treatment arm A (nivolumab + standard dose
             bevacizumab)and treatment arm B (nivolumab + low dose bevacizumab).

          -  Men who are sexually active with WOCBP must use contraceptive method such as male
             condom with spermicide. 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.

          -  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.

          -  At a minimum, subjects must agree to the use of two methods of contraception, with one
             method being highly effective and the other method being either highly effective or
             less effective as listed below:

          -  HIGHLY EFFECTIVE METHODS OF CONTRACEPTION

               -  Hormonal methods of contraception including combined oral contraceptive pills,
                  vaginal ring, injectables, implants, and intrauterine devices (IUDs) such as
                  Mirena® by WOCBP subjects or male subject's WOCBP partner.

               -  Nonhormonal IUDs, such as ParaGard

               -  Tubal ligation

               -  Vasectomy.

               -  Complete Abstinence* ---*Complete abstinence is defined as complete avoidance of
                  heterosexual intercourse and is an acceptable form of contraception for all study
                  drugs. Subjects who choose complete abstinence are not required to use a second
                  method of contraception, but female subjects must continue to have pregnancy
                  tests. Acceptable alternate methods of highly effective contraception must be
                  discussed in the event that the subject chooses to forego complete abstinence.

          -  LESS EFFECTIVE METHODS OF CONTRACEPTION

               -  Diaphragm with spermicide

               -  Cervical cap with spermicide

               -  Vaginal sponge

               -  Male Condom without spermicide*

               -  Progestin only pills by WOCBP subjects or male subject's WOCBP partner

               -  Female Condom* ---*A male and female condom must not be used together

          -  Women of Child Bearing Potential (WOCBP)

             --A women of childbearing potential (WOCBP) is defined as any female who has
             experienced menarche and who has not undergone surgical sterilization (hysterectomy or
             bilateral oophorectomy) and is not postmenopausal. Menopause is defined as 12 months
             of amenorrhea in a woman over age 45 years in the absence of other biological or
             physiological causes. In addition, women under the age of 55 years must have a serum
             follicle stimulating hormone, (FSH) level > 40mIU/mL to confirm menopause.*

             ---*Women treated with hormone replacement therapy, (HRT) are likely to have
             artificially suppressed FSH levels and may require a washout period in order to obtain
             a physiologic FSH level. The duration of the washout period is a function of the type
             of HRT used. The duration of the washout period below are suggested guidelines and the
             investigators should use their judgment in checking serum FSH levels. If the serum FSH
             level is > 40 mIU/ml at any time during the washout period, the woman can be
             considered postmenopausal:

               -  1 week minimum for vaginal hormonal products (rings, creams, gels)

               -  4 week minimum for transdermal products

               -  8 week minimum for oral products

          -  Other parenteral products may require washout periods as long as 6 months Each of the
             criteria in the checklist that follows must be met in order for a patient to be
             considered eligible for this study. Use the checklist to confirm a patient's
             eligibility. The checklist must be completed for each patient and must be signed and
             dated by the treating physician.

          -  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)

          -  Screening/Baseline laboratory values must meet the following criteria (using CTCAE
             v5.0):

               -  WBC ≥ 2000/uL

               -  Neutrophils ≥ 1500/uL

               -  Platelets ≥ 100x103/uL

               -  Hemoglobin ≥ 9.0 g/dL

               -  Serum creatinine < 1.5 x 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

               -  AST ≤ 3x ULN

               -  ALT≤ 3x ULN

               -  Pregnancy test (serum)

               -  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 VEGF or anti-angiogenic treatment

          -  Previous treatment with a PD-1, PD-L1 or CTLA-4 targeted therapy

          -  Evidence of > Grade 1 CNS hemorrhage on the baseline MRI scan

          -  Inadequately controlled hypertension (defined as systolic blood pressure ≥160 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 within 3 months prior to start of
             study treatment;

          -  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 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 (OS-12)
Time Frame:Up to 12 months after beginning therapy
Safety Issue:
Description:OS-12 is the proportion of participants in the analysis population who remain alive for at least twelve months following initiation of study therapy. Participants without efficacy evaluation data or without survival data will be censored at Day 1

Secondary Outcome Measures

Measure:Progression-Free Survival at Six Months
Time Frame:Up to six months after beginning treatment
Safety Issue:
Description:The proportion of participants in the analysis population who remain progression-free for at least six months following initiation of study therapy Participants without efficacy evaluation data or without survival data will be censored at Day 1
Measure:Overall Survival (OS)
Time Frame:Up to 3 years after beginning treatment
Safety Issue:
Description:OS, as defined as time from beginning of treatment to death Participants without efficacy evaluation data or without survival data will be censored at Day 1
Measure:Overall Response Rate (ORR)
Time Frame:Up to 3 years after beginning treatment
Safety Issue:
Description:Proportion of participants in the analysis population who have complete response (CR) or partial response (PR) using Radiologic Assessment in Neuro-Oncology criteria (RANO) criteria. Participants without efficacy evalaluation data or survival data censored at day 1. Participants without measurable disease will not be included.
Measure:Progression-Free Survival
Time Frame:Up to 3 years after beginning treatment
Safety Issue:
Description:Median time from allocation to first documented disease progression per RANO or death due to any cause, whichever occurs first. Those without efficacy eval. data or survival data censored at day 1 RANO - progressive disease: (>) 25% increase in sum of products of perpendicular diameters of measurable lesions (over best response [smallest tumor size] or baseline if no decrease) on stable/increasing corticosteroid doses Any new measurable lesion that when added to change in initial tumor(s) exceeds 25% increase in x-sectional area. Clear clinical deterioration not attributable to causes apart from tumor. Def. is left to discretion of PI but recommended is: Decline in KPS from 100 or 90 to <= 70, decline in KPS of at least 20 from <= 80, or decline in KPS from any baseline to <= 50, for >= 7 days, be considered neurologic deterioration, unless attributable to co-morbid events or changes in corticosteroid dose. Failure to return for eval. due to death or deteriorating condition
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 participants who achieve a PR or better Participants without efficacy evaluation data or without survival data will be censored at Day 1

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Case Comprehensive Cancer Center

Trial Keywords

  • Nivolumab
  • Bevacizumab

Last Updated

May 25, 2021