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Phase I/II Evaluation Temozolomide and Farnesyl Transferase Inhibitor ZARNESTRA (R115777) for the Treatment of Recurrent and Progressive Glioblastoma Multiforme

Phase 1/Phase 2
Not Enrolling
Glioblastoma Multiforme

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Trial Information

Phase I/II Evaluation Temozolomide and Farnesyl Transferase Inhibitor ZARNESTRA (R115777) for the Treatment of Recurrent and Progressive Glioblastoma Multiforme

Temozolomide works by killing cancer cells. R115777 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

Before treatment starts, patients will have a complete exam, including measurement of height
and weight. Blood tests (less than 2 tablespoons of blood) will be performed. A MRI scan
will be done. Women who are able have children must have a negative blood pregnancy test.

Temozolomide and R115777 will both be taken by mouth. Participants in this study will take
temozolomide once a day for 7 days every other week (Days 1-7 and 15-21). This will be
repeated every 28 days (1 course). Patients must not eat for 1 hour before and after
taking the drug; drinking water is allowed. All treatment may be given on an outpatient

During the alternate weeks (Days 8-14 and 22-28), participants will take R115777 tablets by
mouth in the morning and evening with food. At the beginning of the study, groups of 3
participants each will take increasing doses of both R115777 and temozolomide until the
highest safe dose of each drug, when given in combination, is found. Participants entering
the study after the highest safe dose is found will receive that dosage.

If tumors do not grow and serious side effects do not occur, participants may keep on taking
temozolomide and R115777 for up to 2 year. If your physician thinks it is advisable,
treatment may continue with R115777 alone after that time. In this case, routine blood
tests for counts, liver and kidney function (less than 2 tablespoons) will be repeated every
4 weeks and MRI scans, physical, and neurological exams will be done every 8 weeks.
Participants may not receive any other treatment for cancer (including surgery) while taking
part in this study.

Participants will come to the clinic to have a complete physical and neurological exam and
blood tests (less than 2 tablespoons of blood) before each course. Blood tests will be
repeated once a week for the first 2 courses of treatment and then on Days 14 and 28 of each
later course. A MRI scan will be done before the odd-numbered (3, 5, 7, etc.) courses of
treatment or at any time clinically indicated.

At the end of the study, participants will have another complete physical exam. Blood tests
(less than 2 tablespoons of blood) will be performed. A MRI scan will be done.

This is an investigational study. Temozolomide is approved by the FDA for the treatment of
some brain tumors and is commercially available. R115777 is approved for research use only
in the treatment of brain tumors. The use of these two drugs together is experimental.

Inclusion Criteria:

1. Patients with histologically proven supratentorial glioblastoma multiforme (GBM).

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 primary investigator to document tumor volume
changes to provide a gross assessment of growth rate.

3. Patients may have had: a) no prior chemotherapy, b) 1 prior adjuvant chemotherapy, c)
1 prior adjuvant chemotherapy followed by 1 regimen for recurrent disease, or d) 1 or
2 prior chemotherapy regimens for recurrent or progressive tumor.

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 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 with recent resection of recurrent or progressive tumor will be eligible if all
of the following conditions apply: Pt has recovered from the effects of surgery;
Residual disease after resection of recurrent tumor is not mandated for eligibility.
To assess the extent of residual disease post-operatively, a CT/MRI should be done no
later than 96 hours post-operatively or at least 4 weeks post-operatively, and within
14 days before registration. If steroid dose increased between the day of imaging and
registration, a new baseline scan is required after stable steroids for 5 days.

7. Patients must have a Karnofsky performance status of >/= 60

8. 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.

9. Patients must have adequate bone marrow function (ANC>/= 1,500/mm(3) and platelet
count of >/= 100,000/mm(3)), adequate liver function (SGPT and SGOT normal, bilirubin times institutional normal) prior to starting therapy.

10. ZARNESTRA may interfere with coumadin dosing and patients who are taking this
combination will require more frequent monitoring of their PT, PTT and INR.

11. Patient has no risk factors for HIV or is serologically negative.

Exclusion Criteria:

1. Patients must not be taking primidone, carbamazepine, phenobarbital or phenytoin
anticonvulsants. Patients changing from these anticonvulsants to others that are
allowed must be off the drugs listed above for at least 1 week.

2. Patients must not be taking cimetidine, erythromycin azole antifungals, paclitaxel,
tacrolimus or cyclosporine.

3. Patients must not have uncontrolled high blood pressure, unstable angina, symptomatic
congestive heart failure, myocardial infarction within the previous six months, or
serious uncontrolled cardiac arrhythmia.

4. Because of the concerns of potentially harmful interactions of ZARNESTRA and other
medications taken by patients who are HIV positive or have AIDS related diseases,
patients who are HIV positive will not be eligible for entry into this study. Only
patients with suspected HIV will be tested and if positive, will be ineligible.

5. 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.

6. Patients must not have: a) active infection b) disease that will obscure toxicity or
dangerously alter drug metabolism c) serious intercurrent medical illness. d) prior
recurrence with either Temozolomide or a farnesyl transferase inhibitor.

7. Patients must not be pregnant and must practice adequate contraception

Type of Study:


Study Design:

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

Outcome Measure:

Maximal Tolerating Dose (MTD for Phase I)

Outcome Description:

Phase I Dose limiting toxicity evaluation at end of first cycle based on blood tests every two weeks and participants' subjective and objective symptoms. Start Dose Level 100 mg/m² Temozolomide once daily + 400 mg ZARNESTRA twice daily; Dose Level 1 100 mg/m² Temozolomide once daily + 500 mg ZARNESTRA twice daily; Dose Level 2 150 mg/m² Temozolomide once daily + 500 mg ZARNESTRA twice daily; Dose Level 3 150 mg/m² Temozolomide once daily + 600 mg ZARNESTRA twice daily; Dose Level 4 150 mg/m² Temozolomide once daily + 800 mg ZARNESTRA twice daily

Outcome Time Frame:

End of first cycle (4 weeks) evaluation

Safety Issue:


Principal Investigator

Mark R. Gilbert

Investigator Role:

Principal Investigator

Investigator Affiliation:

MDAnderson Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

December 2002

Completion Date:

October 2008

Related Keywords:

  • Glioblastoma Multiforme
  • Brain Neoplasms
  • CNS Diseases
  • Glioblastoma Multiforme
  • Temozolomide
  • Temodar
  • R115777
  • Zarnestra
  • Glioblastoma



MD Anderson Cancer Center Houston, Texas  77030-4096