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GlioblastomaPhase 2NCT03452579

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

A Phase 2 study testing Nivolumab, Standard Dose Bevacizumab and Low Dose Bevacizumab in people with Glioblastoma, run by David Peereboom at 2 sites in United States.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Glioblastoma
What is being tested?
Nivolumab, Standard Dose Bevacizumab and Low Dose Bevacizumab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
90 participants
Where
2 sitesUnited States
Study dates
21 May 2018to 30 Jun 2025
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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:
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  • 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)

Who cannot join

  • 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
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  • 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

Trial locations and contacts

2 sites in 1 country.

United States2 sites

  • Dana-Farber Cancer Institute

    Boston, Massachusetts, 02215

  • Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

    Cleveland, Ohio, 44195

Other trials in United States

About this study

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)

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.

Read more

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).

Read the 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

Conditions
Glioblastoma
Being tested
Nivolumab, Standard Dose Bevacizumab, Low Dose Bevacizumab
Keywords
Nivolumab, Bevacizumab
Medical subject headings
Glioblastoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • NivolumabDrug

    Also called Opdivo

    240mg

  • Standard Dose BevacizumabDrug

    Also called Avastin

    10mg/kg

  • Low Dose BevacizumabDrug

    Also called Avastin

    3mg/kg

Study groups in NCT03452579
Study groupRoleWhat they receive
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
Receives: Drug: Nivolumab; Drug: 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
Receives: Drug: Nivolumab; Drug: Low Dose Bevacizumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  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

    Measured: Up to 12 months after beginning therapy

Secondary outcomes (6)

  1. 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

    Measured: Up to six months after beginning treatment

  2. 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

    Measured: Up to six months after beginning treatment

  3. 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

    Measured: Up to 18 months after beginning treatment

  4. 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.

    Measured: Up to 3 years after beginning treatment

  5. 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

    Measured: Up to 3 years after beginning treatment

  6. 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

    Measured: Up to 3 years after beginning treatment

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted2 Mar 2018
  2. Study start21 May 2018
  3. Primary completion30 Dec 2020
  4. Study completion30 Jun 2025 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
90 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03452579
Sponsor's protocol ID
CASE1317
Status last verified
Feb 2025
First submitted
29 Jan 2018
Last updated
28 Feb 2025
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • 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.

    PubMed 39777725

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Nivolumab, Standard Dose Bevacizumab and Low Dose Bevacizumab in people with Glioblastoma, run by David Peereboom at 2 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 59 inclusion and 27 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 28 Feb 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 13 Jan 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Overall Survival at 12 Months (OS-12) (time frame: Up to 12 months after beginning therapy). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03452579, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Feb 2025.

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