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).
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
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
90
Dana-Farber Cancer Institute
Boston, Massachusetts, United States
Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center
Cleveland, Ohio, United States
Overall Survival at 12 Months (OS-12)
OS-12 is the percentage 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
Time frame: Up to 12 months after beginning therapy
Progression-Free Survival (PFS) at Six Months
The percentage of participants in the analysis population who remain progression-free for at least six months following initiation of study therapy. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions Participants without efficacy evaluation data or without survival data will be censored at Day 1
Time frame: Up to six months after beginning treatment
Overall Survival (OS)
OS, as defined as number of participants alive from beginning of treatment up to 6 six months Participants without efficacy evaluation data or without survival data will be censored at Day 1
Time frame: Up to six months after beginning treatment
Overall Survival (OS)
OS, as defined as the percentage of participants alive from beginning of treatment up to 18 months. Participants without efficacy evaluation data or without survival data will be censored at Day 1
Time frame: Up to 18 months after beginning treatment
Overall Response Rate (ORR)
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.
Time frame: Up to 3 years after beginning treatment
Progression-Free Survival
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
Time frame: Up to 3 years after beginning treatment
Duration of Response
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
Time frame: Up to 3 years after beginning treatment
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