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Glioblastoma

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Glioma

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Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

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Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

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Central Nervous System Neoplasms

Nervous System Neoplasms

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All Drugs and Chemicals

Antineoplastic Agents

Antibodies

Antibodies, Monoclonal

Bevacizumab

Lomustine

Immunoglobulins

Antineoplastic Agents, Immunological

Immunoglobulins, Intravenous

Angiogenesis Inhibitors

Growth Inhibitors

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Bevacizumab 10 mg/kg by vein (IV) over 90 minutes on Days 1, 15, and 29 of 6 week cycle.

Bevacizumab 5 mg/kg IV over 90 minutes on Day 1 and 22 (every 3 weeks) of 6 week cycle. Lomustine starting dose of 75 mg/m2 administered orally at sleep time on Day 3 of every 6 week cycle.

10 mg/kg by vein (IV) over 90 minutes on Days 1, 15, and 29 of 6 week cycle.

Standard Dose Bevacizumab

5 mg/kg IV over 90 minutes on Day 1 and 22 (every 3 weeks) of 6 week cycle.

Low Dose Bevacizumab

Starting dose of 75 mg/m2 administered orally at sleep time on Day 3 of every 6 week cycle.

John DeGroot, MD

The goal of this clinical research study is to learn if the combination of bevacizumab and lomustine can help to control glioblastoma. The safety of this combination will also be studied.

The Study Drugs:

Bevacizumab is designed to prevent or slow down the growth of cancer cells by blocking the growth of blood vessels.

Lomustine is designed to damage the DNA (genetic material of cells) of tumor cells, which may cause the tumor cells to die.

Study Groups:

If you are found to be eligible to take part in this study, you will be randomly assigned (as in the flip of a coin) to 1 of 2 groups. You will have an equal chance of being in either group.

* If you are in Group 1, you will receive a higher dose of bevacizumab.
* If you are in Group 2, you will receive lomustine and a lower dose of bevacizumab

Study Drug Administration:

Each treatment cycle is 42 days.

If you are in Group 1:

On Days 1, 15, and 29 of every cycle, you will receive bevacizumab by vein over 90 minutes.

If you are in Group 2:

* On Days 1 and 22 of every cycle, you will receive bevacizumab by vein over 90 minutes.
* On Day 3 of every cycle, you will take lomustine by mouth 1 time a day. You should take lomustine at bedtime 1 hour before or 2 hours after your last meal of the day with 1 cup (about 8 ounces) of water.

Study Visits:

If you are in Group 1 or 2, every 6 weeks:

* You will be asked about any drugs you may be taking and if you have had any side effects.
* You will have a physical exam, including measurement of your vital signs and weight.
* You will have a neurological exam.
* Your performance status will be recorded.
* You will have an MRI scan.
* If you are on anti-seizure drugs, blood (about 1 teaspoon) will be drawn to measure the amount of anti-seizure drugs in your blood.

If you are in Group 1:

* During Weeks 1-6, blood (about 3 teaspoons) drawn for routine tests 1 time a week.
* After Week 6, blood (about 3 teaspoons) will be drawn for routine tests every 2 weeks.
* On Weeks 2, 4, and 6, and then every 6 weeks after that, urine will be collected to check your kidney function.

If you are in Group 2:

* During Weeks 1-6, blood (about 3 teaspoons) drawn for routine tests 1 time a week.
* After Week 6, blood (about 3 teaspoons) will be drawn for routine tests every 3 weeks.
* On Weeks 3 and 6, and then every 6 weeks after that, urine will be collected to check your kidney function.

Length of Study:

You may stay on study treatment of lomustine and/or bevacizumab for up to 1 1/2 years. After that, you may continue taking bevacizumab for as long as the study doctor thinks it is in your best interest. You will be taken off study early if the disease gets worse or you experience intolerable side effects.

End of Study Treatment Visit:

After you are off study treatment, you will have an end of study treatment visit. At this visit, you may have some or all of the following tests and procedures performed:

* You will be asked about any drugs you may be taking and if you have had any side effects.
* You will have physical exam, including measurement of your vital signs and weight.
* Blood (about 3 teaspoons) will be drawn for routine tests.
* You will have a neurological exam.
* Your performance status will be recorded.

Long-Term Follow-up:

After the end of study treatment visit, the study staff will call you every 3 months to check how you are doing. Each phone call will take about 5 minutes.

This is an investigational study. Bevacizumab and lomustine are FDA approved drugs and commercially available for the treatment of brain tumors. The use of these drugs in this combination is investigational.

Up to 102 participants will take part in this study. All will be enrolled at MD Anderson.

Standard Dose Bevacizumab Versus Low Dose Bevacizumab Plus Lomustine (CCNU) for Recurrent Glioblastoma Multiforme (GBM)

Randomized Phase II Trial of Standard Dose Bevacizumab Versus Low Dose Bevacizumab Plus Lomustine (CCNU) In Adults With Recurrent Glioblastoma Multiforme

Participants with no disease progression as measured by magnetic resonance imaging (MRI) scans. Participants followed by MRI scans, as used for baseline tumor measurements, and removed from study if progression is documented after any cycle of treatment. PFS determined from date of registration in the trial and not date of randomization into chemotherapy arms (i.e. after surgery for resection of recurrent tumor).

Definition of Modified Radiographic Response Assessment Criteria for Glioblastoma (GBM) . Complete, Partial, Progressive Disease and Stable Disease. Radiographic response determined in comparison to the tumor measurements obtained at baseline (post-radiation scan will be baseline for newly diagnosed GBM and pre-treatment scans will be the baseline for recurrent GBM) for determination of response, and the smallest tumor measurement at either pre-treatment baseline or following initiation of therapy for determining progression.

Overall Survival(OS) is defined: Time of presentation to date of death or censored at last follow-up date

TTP is defined as the time from randomization to time of progressive disease

Adverse Events grade 3 and 4 hematologic toxicities reported in safety profile of bevacizumab (Avastin) in combination with Lomustine in patients with recurrent glioblastoma using Common Terminology Criteria for Adverse Events (CTCAE) version 3.

M.D. Anderson Cancer Center

Bevacizumab 5 mg/kg IV over 90 minutes on Day 1 and 22 (every 3 weeks) of 6 week cycle. Lomustine starting dose of 90 mg/m2 administered orally at sleep time on Day 3 of every 6 week cycle. Due to hematologic toxicities, the starting dose was reduced to 75 mg/m2.

Low Dose Bevacizumab + Lomustine

Total

Age, Continuous

<=50 years

>50 years

Age, Customized

Sex: Female, Male

Ethnicity (NIH/OMB)

United States

Region of Enrollment

KPS index scores range from 0 to 100. A higher score means the patient is better able to carry out daily activities.

Karnofsky Performance Status (KPS)

Recurrence of cancer prior to treatment on study.

# Previous recurrence

Dr. John F de Groot/Chair Ad Interim, Neuro-Oncology

Progression Free Survival (PFS)

Complete Response

Partial Response

Progressive Disease

Stable Disease

Radiographic Response (RR)

6-month Progression-free Survival (PFS-6)

Overall Survival (OS)

Data were not collected for the outcome for Time to Progression (TTP)

Time to Progression (TTP)

Summary of Treatment Related Toxicities

Overall Study

Nivolumab

Immune Checkpoint Inhibitors

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

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

David Peereboom, MD

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

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

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)

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

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

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

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.

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 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

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Standard Dose Bevacizumab Versus Low Dose Bevacizumab Plus Lomustine (CCNU) for Recurrent Glioblastoma Multiforme (GBM)	NCT01067469	Brain Cancer Glioblastoma	Standard Dose B... Low Dose Bevaci... Lomustine	18 Years -	M.D. Anderson Cancer Center
Standard Dose Bevacizumab Versus Low Dose Bevacizumab Plus Lomustine (CCNU) for Recurrent Glioblastoma Multiforme (GBM)	NCT01067469	Brain Cancer Glioblastoma	Standard Dose B... Low Dose Bevaci... Lomustine	18 Years -	M.D. Anderson Cancer Center
Standard Dose Bevacizumab Versus Low Dose Bevacizumab Plus Lomustine (CCNU) for Recurrent Glioblastoma Multiforme (GBM)	NCT01067469	Brain Cancer Glioblastoma	Standard Dose B... Low Dose Bevaci... Lomustine	18 Years -	M.D. Anderson Cancer Center
Nivolumab Plus Standard Dose Bevacizumab Versus Nivolumab Plus Low Dose Bevacizumab in GBM	NCT03452579	Glioblastoma	Nivolumab Standard Dose B... Low Dose Bevaci...	18 Years -	Case Comprehensive Cancer Center

Spots Global Cancer Trial Database for standard dose bevacizumab