The goal of this clinical research study is to find the highest tolerable dose of sorafenib
that can be given in combination with temozolomide. The safety of this combination will also
The Study Drugs:
Sorafenib is designed to stop the cell growth and to block the formation of new blood
vessels (the tubes that carry blood around the body), which are involved in the growth and
development of tumors.
Temozolomide is designed to kill cancer cells by damaging DNA (the genetic material of
cells). The damaged DNA may cause tumor cell death.
If you are found to be eligible to take part in this study, you will be assigned to 1 of 4
groups based on when you joined this study. You will remain in the same group for the entire
study. In this study, the dose of the study drugs is different from group to group, and the
doses are also different during and after radiation. During radiation, the study drugs and
doses are as follows:
- If you are in Group 1, you will take temozolomide.
- If you are in Groups 2 or 3, you will take temozolomide and the lower dose of
- If you are in Group 4, you will take temozolomide and the higher dose of sorafenib.
- During radiation, all the groups will take the same dose of temozolomide.
- If you are in Groups 1 or 2, you will take the higher dose of temozolomide on a shorter
cycle and the higher dose of sorafenib.
- If you are in Group 3, you will take the lower dose of temozolomide on a longer cycle
and the lower dose of sorafenib.
- If you are in Group 4, you will take the lower dose of temozolomide on a longer cycle
and the higher dose of sorafenib.
The amount of study drugs you receive may change if you experience side effects. If at any
time you experience any intolerable side effects, tell the study doctor right away.
Study Drug Administration:
As a part of standard of care, you will receive radiation therapy Monday-Friday for a total
of 30 radiation treatments (about 6 weeks).
Every day while you are receiving radiation, you will take the temozolomide by mouth once a
day (up to a maximum of 7 weeks). On Monday-Friday, you will take temozolomide 1 hour before
radiation therapy. On Saturday and Sunday, you will take temozolomide in the morning.
You should swallow temozolomide whole, one right after the other, without chewing them. If
you vomit while taking temozolomide, you cannot take more capsules before the next scheduled
dose. They should be taken on an empty stomach (at least 1 hour before and 2 hours after
eating) with 1 cup (about 8 oz.) of water.
Every day while you are receiving radiation, you will take sorafenib by mouth 2 times a day
(in the morning and evening) (up to a maximum of 7 weeks). You should take sorafenib without
food (1 hour before or 2 hours after eating), with at least 1 cup (8 oz.) of water. If you
are in Group 1, you will not take sorafenib.
You will not take the study drug(s) for about 4 weeks after the radiation therapy ends.
After 4 weeks:
- If you are in Group 1 or 2, on Days 1-5 of every 28-day study cycle, you will take
temozolomide by mouth once a day.
- If you are in Group 3 or 4, on Days 1-21 of every cycle, you will take temozolomide by
mouth once a day.
Every day of each cycle, all groups will take sorafenib by mouth 2 times (in the morning and
Once a week while you are receiving radiation therapy, you will be asked about any drugs you
may be taking and if you have experienced any side effects. Your blood pressure will be
measured. Blood (about 3-4 teaspoons) will be drawn for routine tests.
About 3-4 weeks after the end of radiation therapy, you will have a MRI scan to check the
status of the disease.
On Day 1 of every cycle, the following tests and procedures will be performed:
- You will have a physical exam, including measurement of your vital signs.
- You will have a neurological exam.
- You will have a performance status evaluation.
- You will be asked about any drugs you may be taking and if you have experienced any
- Blood (about 3-4 teaspoons) will be drawn for routine tests.
On Days 7, 14, and 21 of Cycle 1 and on Days 7 and 14 (or 21) of Cycles 2 and beyond, blood
(about 3-4 teaspoons) will be drawn for routine tests.
On Day 1 of every other cycle (Cycles 3, 5, 7, and so on), you will have a MRI scan to check
the status of the disease.
Every week of Cycle 1, your blood pressure will be measured.
Length of Study:
You will be on study for about 15 months total. You will be taken off study early if the
disease gets worse or you experience intolerable side effects.
After you go off study, you will have an end-of-study visit. At this visit, the following
tests and procedures will be performed:
- You will have a physical exam, including measurement of your weight and vital signs.
- You will be have a performance status evaluation.
- You will be asked about any drugs you may be taking and if you have experienced any
- You will have a neurological exam.
- You will have a MRI scan to check the status of the disease.
- Blood (about 3 teaspoons) will be drawn for routine tests.
This is an investigational study. Temozolomide is FDA approved and commercially available
for the treatment of brain tumors. Sorafenib is FDA approved and commercially available for
the treatment of kidney cancer, but it is experimental for use in brain tumors. In addition,
the combination of temozolomide and Sorafenib is experimental for use in brain tumors. At
this time, the combination is only being used in research.
Up to 51 participants will take part in this study. All will be enrolled at M. D. Anderson.
1. Histopathologically proven diagnosis of glioblastoma. Since gliosarcoma is a variant
of glioblastoma, gliosarcoma is also an eligible diagnosis.
2. Patients must have at least 1 block of tumor tissue available for submission to the
central pathologist for analysis of gene expression status by QRT-PCR; there must be
at least 1 cm^2 of tumor from the block when cut on a slide: fresh frozen tumor
tissue acquisition is also encouraged, but not required. Unstained slide submission
without a block submission is not acceptable for study entry.
3. Diagnosis must be established by open biopsy or tumor resection. Patients who have
only had a stereotactic biopsy are not eligible..
4. The tumor must have a supratentorial component.
5. Patients must have recovered from the effects of surgery, postoperative infection,
and other complications before study registration.
6. All patients must sign an informed consent indicating that they are aware of the
investigational nature of this study.
7. A diagnostic contrast-enhanced MRI or CT scan (if MRI is contraindicated) of the
brain must be performed postoperatively in the period between surgery and initiation
of radiation therapy.
8. Therapy must begin </=5 weeks after the most recent brain tumor surgery.
9. History/physical examination within 14 days prior to study registration.
10. Neurologic examination within 14 days prior to study registration.
11. Documentation of steroid doses within 14 days prior to study registration and stable
or decreasing steroid dose within 5 days prior to registration.
12. Karnofsky performance status of >/= 60.
13. Age >/= 18 years.
14. Patients with well-controlled hypertension are eligible (systolic blood pressure of
</= 140 mgHg or diastolic pressure </= 90 mgHg).
15. Complete blood count (CBC)/differential obtained within 14 days prior to study
registration, with adequate bone marrow function as defined below: Absolute
neutrophil count (ANC) >/= 1500 cells/mm^3; Platelets >/= 100,000
cells/mm^3;Hemoglobin >/= 10 g/dl.
16. Adequate renal function, as defined below: Serum creatinine </= 1.7 mg/dl within 14
days prior to study registration
17. Adequate hepatic function, as defined below: Bilirubin </= 2.0 mg/dl within 14 days
prior to study registration; ALT </= 2 x upper limit of normal range (ULN) within 14
days prior to study registration; AST </= 2 x ULN range within 14 days prior to study
18. Fasting cholesterol < 300 mg/dL (9.0 mmol/L) and fasting triglycerides < 2.5 times
19. International normalized ratio (INR) < 1.5 or a PT/PTT within normal limits for
patients not on anti-coagulation treatment
20. Patients receiving anti-coagulation treatment with an agent such as warfarin or low
molecular weight heparin may be allowed to participate with the following criteria:
For patients on prophylactic anticoagulation therapy (low-dose warfarin): INR level <
1.5; Patients on prophylactic dose or full dose low molecular weight heparins are
eligible provided that the patient has no active bleeding or pathological condition
that carries a high risk of bleeding;
21. (20. continued) Patients on full-dose anticoagulants (e.g., warfarin) are eligible
provided that both of the following criteria are met: (a) Patient has an in-range INR
(usually between 2-3) on a stable dose or oral anticoagulant or on a stable dose of
low molecular weight heparin. (b) Patient has no active bleeding or pathological
condition that carries a high risk of bleeding.
22. If the patient's mental status precludes his/her giving informed consent, written
informed consent may be given by the responsible family member.
23. For females of child-bearing potential, negative serum pregnancy test within 72 hours
prior to starting temozolomide
24. Women of childbearing potential and men must agree to use adequate contraception
(barrier method of birth control) prior to study entry and for the duration of study
participation. Men should use adequate birth control for at least six months after
the last administration of sorafenib or temozolomide.
1. Prior invasive malignancy (except for non-melanomatous skin cancer) unless disease
free for >/= 3 years.
2. Recurrent or multifocal malignant gliomas
3. Metastases detected below the tentorium or beyond the cranial vault.
4. Prior chemotherapy or radiosensitizers for cancers of the head and neck region; note
that prior chemotherapy for a different cancer is allowable.
5. Prior use of Gliadel wafers or any other intratumoral or intracavitary treatment are
6. Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in
overlap of radiation fields.
7. Severe, active co-morbidity, defined as follows: Cardiac disease - Congestive heart
failure > class II New York Heart Association (NYHA). Patients must not have unstable
angina (anginal symptoms at rest) or new onset angina (began within the last 3
months) or myocardial infarction within the past 6 months; Cardiac ventricular
arrhythmias requiring anti-arrhythmic therapy; Acute bacterial or fungal infection
requiring intravenous antibiotics at the time of registration; Chronic Hepatitis B or
8. (7. continued) Chronic Obstructive Pulmonary Disease exacerbation or other
respiratory illness requiring hospitalization or precluding study therapy at the time
of registration; Hepatic insufficiency resulting in clinical jaundice and/or
9. (7. continued) Known history or symptoms and laboratory results consistent with
Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition (note,
however, that HIV testing is not required for entry into this protocol. The need to
exclude patients with AIDS from this protocol is necessary because the treatments
involved in this protocol may be significantly immunosuppressive); Major medical
illnesses or psychiatric impairments that in the investigator's opinion will prevent
administration or completion of protocol therapy;
10. (7. continued) Active connective tissue disorders, such as lupus or scleroderma, that
in the opinion of the treating physician may put the patient at high risk for
radiation toxicity; Arterial thrombotic or embolic events such as a cerebrovascular
accident including transient ischemic attacks within the past 6 months; Pulmonary
hemorrhage/bleeding event > Common Toxicity Criteria for Adverse Effects (CTCAE)
Grade 2 within 4 weeks of first dose of study drug;
11. (7. continued) Any other hemorrhage/bleeding event > CTCAE Grade 3 within 4 weeks of
first dose of study drug; Serious non-healing wound, ulcer, or bone fracture;
Evidence or history of bleeding diathesis or coagulopathy
12. Uncontrolled hypertension defined as systolic blood pressure > 140 mmHg or diastolic
pressure > 90 mmHg, despite optimal medical management.
13. Major surgery, open biopsy or significant traumatic injury within 4 weeks of first
14. Use of St. John's Wort or rifampin (rifampicin).
15. Pregnancy or women of childbearing potential and men who are sexually active and not
willing/able to use medically acceptable forms of contraception; this exclusion is
necessary because the treatment involved in this study may be significantly
16. No tissue provided for histopathologic review and QRT-PCR analysis.