The goal of this clinical research study is to find the highest safe dose of the new drug
Sarasar (lonafarnib) that can be given together with Temodar (temozolomide) in a continuous
daily dosing regimen to patients with brain tumors. The second goal is to learn if these
drugs given in combination can shrink or slow the growth of brain tumors.
Temozolomide is a chemotherapy drug that works by attacking cancer cells, causing them to
die. Lonafarnib is a new drug that may slow down the growth of cancer cells. Used in
combination, the two drugs may control the growth of brain tumors.
Before treatment starts, you will have a complete physical exam, including height and weight
measurements taken, as well as a neurological (brain) exam. Blood tests (less than 2
tablespoons of blood) will be performed. A MRI scan of the brain will be done. Women who are
able have children must have a negative blood pregnancy test.
If you are eligible to take part in the study, you will be given temozolomide and lonafarnib
as treatment. The size of study drug doses being given will increase after every 3
participants are enrolled on the study, until the highest safe dose of each drug, when given
in combination, is found.
If you are enrolled on the Phase Ib part of this study, you will be treated at the highest
tolerable dose that was found in the Phase I part of the study. You will receive this dose of
temozolomide on a 7-day on, 7-day off schedule. You will also receive Sarasar by mouth twice
a day using a 7-day on, 7-day off schedule.
Temozolomide and lonafarnib will be taken by mouth in this study. You will take temozolomide
once a day for 7 days every other week (Days 1-7 and 15-21). You must not eat for 1 hour
before and after taking the drug; drinking water is allowed. During the alternate weeks (Days
8-14 and 22-28), you will take the lonafarnib tablet by mouth in the morning and evening,
with water. You should not eat grapefruit or drink grapefruit juice while you are taking the
study medication as this will affect how study medication is broken down in your body. This
will be repeated every 28 days (1 study course). All treatment may be given on an outpatient
basis, and so you will not require a hospital stay.
You may keep on taking temozolomide and lonafarnib for up to 24 courses (about 2 years). You
will be taken off study if the disease gets worse or intolerable side effects occur. You may
not receive any other treatment for cancer (including surgery) while taking part in this
You will come to the clinic to have a complete physical exam before each course of treatment.
You will have a neurological exam within 14 days before every odd-numbered course (3, 5, 7,
etc), or at any time that the doctor feels it is needed. Blood counts (about 1 teaspoon) will
be done before every course of treatment and on Day 22 of each course. Blood chemistry tests
and anticonvulsant levels, if applicable, (less than 1 tablespoon) will be repeated before
each course of treatment. An MRI scan will be done before the odd-numbered (3, 5, 7, etc.)
courses of treatment, or at any time that the doctor feels it is needed. Patients taking the
blood thinner warfarin will have blood tests (less than 1 teaspoon) more often to check the
effects of the drug.
Your doctor may decide to take you off combination treatment before 2 years and give you only
the lonafarnib alone. If you continue to receive lonafarnib by itself without the addition of
temozolomide, after having received a minimum of 1 year of the combination therapy, you will
have routine blood (about 2-3 teaspoons) tests every 4 weeks and an MRI with clinic follow-up
for physical and neurological exams every 3 months while receiving continuation treatment.
When you have finished the study treatment, you will have another complete physical and
neurological exam. Blood tests (less than 2 tablespoons of blood) will be performed. Another
MRI scan will be done.
This is an investigational study. Temozolomide is approved by the FDA for the treatment of
some brain tumors. Lonafarnib is approved for research use only in the treatment of brain
tumors. The use of these two drugs together is experimental. About 35 patients will take part
in this study. All will be enrolled at MD Anderson.
1. Patients with histologically proven supratentorial glioblastoma multiforme (GBM) or
2. Patients must have shown unequivocal evidence for tumor recurrence or progression by
MRI scan after radiation therapy. The scan done prior to study entry documenting
progression will be reviewed by the treating physician to document tumor volume
changes to provide a gross assessment of growth rate.
3. Patients may have had as many as 2 prior chemotherapy regimens for recurrent or
progressive tumor. Patients must have had prior treatment with Temodar but may not
have had prior treatment with farnesyl transferase inhibitors (Sarasar or Zarnestra).
Patients in phase 1b expansion are required to have received a minimum of two cycles
of adjuvant TMZ.
4. All patients must sign an informed consent indicating that they are aware of the
investigational nature of this study in keeping with the policies of this hospital.
5. Patients must have shown unequivocal evidence for tumor progression by MRI or CT scan.
A scan should be performed within 14 days prior to registration and on a steroid dose
that has been stable or decreasing for at least 5 days. If the steroid dose is
increased between the date of imaging and registration a new baseline MR/CT is
required. The same type of scan, i.e., MRI or CT must be used throughout the period of
protocol treatment for tumor measurement.
6. Pts having had recent resection of recurrent or progressive tumor are eligible as long
as: a) Patients must be status post surgical resection at least 2 weeks prior to study
enrollment, have recovered from surgery, have adequate early wound healing and a
Karnofsky performance status of > or = 60.
7. Continued from Inclusion #6. b) Residual disease following resection of recurrent
tumor is not mandated for eligibility into the study. A CT/ MRI should be done within
96 hrs post-op or at least 4 wks post-op (within 14 days of registration). If the
steroid dose is increased between the scan date and registration, a new baseline
MRI/CT is required on a stable steroid dose for 5 days.
8. Patients must be >/= 18 years of age.
9. Patients must have a Karnofsky performance status of >/= 60.
10. Patients must have recovered from the toxic effects of prior therapy: 4 weeks from
prior cytotoxic therapy and/or at least two weeks from vincristine, 6 weeks from
nitrosoureas, 3 weeks from procarbazine administration, and 1 week for non-cytotoxic
agents, e.g., interferon, tamoxifen, thalidomide, cis-retinoic acid, etc.
(radiosensitizer does not count). Any questions related to the definition of
non-cytotoxic agents should be directed to the Study Chair.
11. Patients must have adequate bone marrow function (ANC >/= 1,500/mm3 and platelet count
of >/= 100,000/mm3), adequate liver function (SGPT and alkaline phosphatase <2.5 times
normal, bilirubin <1.5 mg%), and adequate renal function (BUN and creatinine <1.5
times institutional normal) prior to starting therapy.
1. Patients must not be taking primidone, carbamazepine, phenobarbital or phenytoin
anticonvulsants. Patients changing from these anticonvulsants to other allowable drugs
that are not enzyme inducing antiepileptic drugs (EIAEDs) must be off the drugs listed
above for at least 72 hours prior the initiation of treatment.
2. Patients with a history of any other cancer (except non-melanoma skin cancer or
carcinoma in-situ of the cervix), are ineligible unless in complete remission and off
of all therapy for that disease for a minimum of 3 years.
3. Patients must not have: a) uncontrolled active infection b) disease that will obscure
toxicity or dangerously alter drug metabolism c) serious intercurrent medical illness.
d) prior recurrence with a farnesyl transferase inhibitor e) oral contraceptives and
other hormonal methods (Depo-Provera) of birth control.