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

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ClinicalTrials.gov Identifier: NCT03452579
Recruitment Status : Recruiting
First Posted : March 2, 2018
Last Update Posted : May 14, 2018
Sponsor:
Information provided by (Responsible Party):
Case Comprehensive Cancer Center

Brief Summary:

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).


Condition or disease Intervention/treatment Phase
Glioblastoma Drug: Nivolumab Drug: Standard Dose Bevacizumab Drug: Reduced Dose Bevacizumab Phase 2

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.


Study Type : Interventional
Estimated Enrollment : 90 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : May 10, 2018
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : December 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Nivolumab + Standard Dose Bevacizumab
nivolumab 240 mg and standard dose bevacizumab 10 mg/kg every 2 weeks until disease progression or unacceptable toxicity
Drug: Nivolumab
240mg
Other Name: Opdivo

Drug: Standard Dose Bevacizumab
10mg/kg
Other Name: Avastin

Experimental: Nivolumab + Reduced Dose Bevacizumab
nivolumab 240 mg and reduced dose bevacizumab 3mg/kg every 2 weeks until disease progression or unacceptable toxicity
Drug: Nivolumab
240mg
Other Name: Opdivo

Drug: Reduced Dose Bevacizumab
3mg/kg
Other Name: Avastin




Primary Outcome Measures :
  1. Overall Survival at 12 Months [ Time Frame: Up to 12 months after beginning therapy ]
    The proportion of subjects in the analysis population who remain alive for at least twelve months following initiation of study therapy.


Secondary Outcome Measures :
  1. Overall Survival [ Time Frame: Up to 3 years after beginning treatment ]
    Time from beginning of treatment to death

  2. Overall Response Rate [ Time Frame: Up to 3 years after beginning treatment ]
    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.

  3. Duration of Response [ Time Frame: Up to 3 years after beginning treatment ]
    Time from first RANO response to disease progression in subjects who achieve a PR or better

  4. Progression-Free Survival [ Time Frame: Up to 3 years after beginning treatment ]
    Defined as the time from allocation to the first documented disease progression according to RANO or death due to any cause, whichever occurs first

  5. Progression-Free Survival at Six Months [ Time Frame: Up to six months after beginning treatment ]
    The proportion of subjects in the analysis population who remain progression-free for at least six months following initiation of study therapy



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03452579


Contacts
Contact: Manmeet Ahluwalia, MD 866-223-8100 ahluwam@ccf.org

Locations
United States, Massachusetts
Dana-Farber Cancer Institute Not yet recruiting
Boston, Massachusetts, United States, 02215
Contact: David A Reardon, MD    617-632-4750    David_Reardon@DFCI.harvard.edu   
Principal Investigator: David A Reardon, MD         
United States, Ohio
Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center Recruiting
Cleveland, Ohio, United States, 44195
Contact: Manmeet Ahluwalia, MD    216-444-6145    ahluwam@ccf.org   
Principal Investigator: Manmeet Ahluwalia, MD         
Sponsors and Collaborators
Case Comprehensive Cancer Center
Investigators
Principal Investigator: Manmeet Ahluwalia, MD Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

Responsible Party: Case Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT03452579     History of Changes
Other Study ID Numbers: CASE1317
First Posted: March 2, 2018    Key Record Dates
Last Update Posted: May 14, 2018
Last Verified: May 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Case Comprehensive Cancer Center:
Nivolumab
Bevacizumab

Additional relevant MeSH terms:
Glioma
Glioblastoma
Astrocytoma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Bevacizumab
Nivolumab
Antibodies, Monoclonal
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents
Immunologic Factors