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


Phase 2
18 Years
N/A
Open (Enrolling)
Both
Brain Cancer, Glioblastoma

Thank you

Trial Information

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


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 for up to 2 years. 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.


Inclusion Criteria:



1. Signed Informed Consent Form

2. Age >/= 18 years

3. Histologically confirmed glioblastoma in first, second or third relapse. A pathology
report constitutes adequate documentation of histology for study inclusion. Subjects
with an initial diagnosis of a lower grade glioma are eligible if a subsequent biopsy
is determined to be glioblastoma. The amount of prior systemic therapy for this
population is, nevertheless, restricted to three regimens, with one including
temozolomide.

4. Radiographic demonstration of disease progression following prior therapy

5. Bi-dimensionally measurable disease with a minimum measurement of 1 cm (10 mm) in one
diameter on MRI performed within 14 days prior to registration (Day 1). Baseline MRIs
for subjects who underwent salvage surgery after first or second relapse must be
obtained >/= 4 weeks after the procedure. If receiving corticosteroids, subjects must
be on a stable or decreasing dose of corticosteroids for >/= 5 days prior to baseline
MRI.

6. Patients having undergone recent resection of recurrent or progressive tumor will be
eligible as long as all of the following conditions apply: 1) They have recovered
from the effects of surgery. 2) Evaluable or measurable disease following resection
of recurrent tumor is not mandated for eligibility into the study. 3) To best assess
the extent of residual measurable disease post-operatively, a MRI should be done no
later than 96 hours in the immediate post-operative period or 4-6 weeks
post-operatively. .

7. An interval of >/= 4 weeks since surgical resection is required prior to starting
protocol therapy.

8. Prior standard radiation for glioblastoma

9. Prior chemotherapy: All first-relapse subjects must have received temozolomide. All
second- and third-relapse subjects must have received temozolomide. Patients may not
have received prior nitrosureas.

10. Recovery from the effects of prior therapy, including the following: Four weeks from
cytotoxic agents (3 weeks from procarbazine, 2 weeks from vincristine); Four weeks
from any investigational agent; One week from non-cytotoxic agents(eg accutane,
thalidomide); Eight weeks from radiotherapy to minimize the potential for MRI changes
related to radiation necrosis that might be misdiagnosed as progression of disease,
or 4 weeks if a new lesion, relative to the pre-radiation MRI, develops that is
outside the primary radiation field; Patients may have had gliadel wafers during
their original surgery but they must be >/= 9 months post their original surgery
date.

11. Prior therapy with gamma knife or other focal high-dose radiation is allowed, but the
subject must have subsequent histologic documentation of recurrence or PET or MR
Spectroscopic documentation of tumor, unless the recurrence is a new lesion outside
the irradiated field

12. Patients must have adequate bone marrow function (WBC >/= 3,000/µl, ANC >/=
1,500/mm^3, platelet count of >/= 100,000/mm^3, and hemoglobin >/= 10 gm/dl),
adequate liver function (SGPT < 3 times normal and alkaline phosphatase < 2 times
normal, bilirubin <1.5 mg/dl), adequate renal function (creatinine creatinine clearance >/= 60 cc/min/1.73 m^2) and a urine protein:creatinine ratio of
registration. Eligibility level for hemoglobin may be reached by transfusion.

13. Patients must have a Karnofsky performance status (KPS) equal or greater than 60

14. Use of an effective means of contraception in males and in females of childbearing
potential. Women of childbearing potential must have a negative β-HCG pregnancy test
documented within 14 days prior to registration. Should a woman become pregnant or
suspect she is pregnant while participating in this study, she should inform her
treating physician immediately.

15. Ability to comply with study and follow-up procedures

16. Patients receiving treatment with other antiepileptic medications will not be
excluded. Patients should preferably be treated with non-enzyme inducing
anti-epileptic medications to avoid any potential interactions with lomustine.
However, the use of non-enzyme inducing anti-epileptic medications is not mandatory.
If enzyme-inducing antiepileptic drugs are used, monitoring of drug levels should be
considered, as considered clinically appropriate by the treating physician.

17. Patients on the following medications will be included:
Anticoagulants/Anti-platelets: Patients on stable dose anticoagulants (e.g. warfarin,
low molecular-weight heparin) and in-range INR (2-3) are eligible. Patients are
allowed to take aspirin, clopidogrel, ticlopidine, Aggrenox, ibuprofen and other
NSAIDS.

18. Patients must be willing to forego other cytotoxic and non-cytotoxic drug therapy
against the tumor while enrolled in the study.

19. This study was designed to include women and minorities, but was not designed to
measure differences of intervention effects. Males and females will be recruited with
no preference to gender. No exclusion to this study will be based on race. Minorities
will actively be recruited to participate.

Exclusion Criteria:

1. Prior treatment with anti-angiogenesis (eg bevacizumab, sorafenib, sunitinib) agent
or nitrosurea (eg. lomustine, carmustine, nimustine).

2. Prior treatment with polifeprosan 20 with carmustine wafer except for the patients
with gliadel wafers >/= 9 months post their original surgery date.

3. Patients must not have received any investigational agents within 28 days prior to
commencing study treatment.

4. Prior intracerebral agents

5. Need for urgent palliative intervention for primary disease (e.g., impending
herniation)

6. Evidence of recent hemorrhage on baseline MRI of the brain with the following
exceptions: (1) Presence of hemosiderin (2) Resolving hemorrhagic changes related to
surgery (3) Presence of punctate hemorrhage in the tumor

7. Blood pressure of > 140 mmHg systolic and > 90 mmHg diastolic

8. History of hypertensive encephalopathy

9. New York Heart Association (NYHA) Grade II or greater chronic heart failure(CHF)

10. History of myocardial infarction or unstable angina within 6 months prior to Day 1

11. History of stroke or transient ischemic attack within 6 months prior to study
enrollment

12. Significant vascular disease (e.g., aortic aneurysm, aortic dissection) or recent
peripheral arterial thrombosis within 6 months prior to Day 1

13. Evidence of bleeding diathesis or coagulopathy or INR >1.5 unless on a stable dose of
anticoagulation therapy. History of significant bleeding disorder unrelated to
cancer, including: (1) Diagnosed congenital bleeding disorders (e.g., von
Willebrand's disease) (2) Diagnosed acquired bleeding disorder within one year (e.g.,
acquired anti-factor VIII antibodies) (3) Ongoing or recent ( significant gastrointestinal bleeding

14. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 6 months prior to Day 1

15. History of intracerebral abscess within 6 months prior to Day 1

16. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to Day 1, anticipation of need for major surgical procedure during the course
of the study

17. Minor surgical procedures (excluding placement of a vascular access device),
stereotactic biopsy, fine needle aspirations, or core biopsies within 7 days prior to
Day 1

18. Serious non-healing wound, ulcer, or bone fracture

19. Pregnancy (positive pregnancy test) or lactation

20. Known hypersensitivity to any component of bevacizumab

21. History of any other malignancy (except non-melanoma skin cancer or carcinoma in situ
of the cervix), unless in complete remission and off of all therapy for that disease
for a minimum of 3 years are ineligible

22. Pregnant or nursing females

23. Unstable systemic disease, including active infection, uncontrolled hypertension, or
serious cardiac arrhythmia requiring medication

24. Subjects unable to undergo an MRI with contrast

25. Patients with a known allergy to bevacizumab, or a known allergy to nitrosoureas (eg.
lomustine, carmustine, nimustine) will be excluded

26. Patient must be able to tolerate the procedures required in this study including
periodic blood sampling, study related assessments, and management at the treating
institution for the duration of the study. Inability to comply with protocol or study
procedures (for example, an inability to swallow tablets) will be an exclusion
criteria.

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Number of Patients with PFS

Outcome Time Frame:

Monitored at 3 time points: 1) after a total of 28 events occur (to monitor futility), after 55 events occur and 3) after at least 82 events occur.

Safety Issue:

Yes

Principal Investigator

John DeGroot, MD

Investigator Role:

Study Chair

Investigator Affiliation:

UT MD Anderson Cancer Center

Authority:

United States: Institutional Review Board

Study ID:

2009-0597

NCT ID:

NCT01067469

Start Date:

February 2010

Completion Date:

Related Keywords:

  • Brain Cancer
  • Glioblastoma
  • CNS
  • Central Nervous System
  • malignant brain tumor
  • Recurrent Glioblastoma Multiforme
  • GBM
  • Bevacizumab
  • Lomustine
  • CCNU
  • Brain Neoplasms
  • Glioblastoma

Name

Location

UT MD Anderson Cancer CenterHouston, Texas  77030