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

NCT03452579 | Active Not Recruiting Phase 2 Results DMC FDA Drug

• 1 other identifier: CASE1317
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 2

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 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).

Conditions

Glioblastoma

Keywords

Nivolumab; Bevacizumab

Outcome Measures

Primary Outcomes (1)

• 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

  Up to 12 months after beginning therapy

Secondary Outcomes (6)

• Progression-Free Survival (PFS) at Six Months

  Up to six months after beginning treatment

• Overall Survival (OS)

  Up to six months after beginning treatment

• Overall Survival (OS)

  Up to 18 months after beginning treatment

• Overall Response Rate (ORR)

  Up to 3 years after beginning treatment

• Progression-Free Survival

  Up to 3 years after beginning treatment

Study Arms (2)

Nivolumab + Standard Dose Bevacizumab

ACTIVE COMPARATOR

nivolumab 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

Drug: Nivolumab; Drug: Standard Dose Bevacizumab

Nivolumab + Low Dose Bevacizumab

EXPERIMENTAL

nivolumab 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

Drug: Nivolumab; Drug: Low Dose Bevacizumab

Interventions

Nivolumab DRUG

240mg

Also known as: Opdivo

Nivolumab + Low Dose Bevacizumab; Nivolumab + Standard Dose Bevacizumab

Standard Dose Bevacizumab DRUG

10mg/kg

Also known as: Avastin

Nivolumab + Standard Dose Bevacizumab

Low Dose Bevacizumab DRUG

3mg/kg

Also known as: Avastin

Nivolumab + Low Dose Bevacizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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;

Sponsors & Collaborators

• David Peereboom: lead

Study Sites (2)

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

Cleveland, Ohio, 44195, United States

Location

Related Publications (1)

• de Melo SM, Elias Nunes da Silva ME, Torloni MR, Riera R, De Cicco K, Latorraca CO, Pinto ACPN. Anti-PD-1 and anti-PD-L1 antibodies for glioma. Cochrane Database Syst Rev. 2025 Jan 8;1(1):CD012532. doi: 10.1002/14651858.CD012532.pub2.

  PMID: 39777725 DERIVED

MeSH Terms

Conditions

Glioblastoma

Interventions

Nivolumab; Bevacizumab

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: David Peereboom, MD
• Organization: Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer Center

TaussigResearch@ccf.org

1-866-223-8100

Study Officials

• David Peereboom, MD

  Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: January 29, 2018
• First Posted: March 2, 2018
• Study Start: May 21, 2018
• Primary Completion: December 30, 2020
• Study Completion: June 30, 2025
• Last Updated: February 28, 2025
• Results First Posted: January 13, 2025

Record last verified: 2025-02

Locations

US (2)