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Phase I/II Evaluation of Temozolomide and ZARNESTRA (R115777) for Recurrent and Progressive Glioblastoma Multiforme

This study has been completed.
Sponsor:
Collaborator:
Johnson & Johnson
Information provided by (Responsible Party):
M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier:
NCT00050986
First received: December 31, 2002
Last updated: July 27, 2012
Last verified: July 2012
  Purpose

The goal of this clinical research study is to find the highest safe dose of the new drug ZARNESTRA (R115777) and temozolomide that can be given to patients with brain tumors (glioblastoma multiforme, GBM). The second goal is to learn if these drugs given in combination can shrink or slow the growth of brain tumors. The safety of this treatment will also be studied.


Condition Intervention Phase
Glioblastoma Multiforme
Drug: Temozolomide
Drug: R115777
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I/II Evaluation Temozolomide and Farnesyl Transferase Inhibitor ZARNESTRA (R115777) for the Treatment of Recurrent and Progressive Glioblastoma Multiforme

Resource links provided by NLM:


Further study details as provided by M.D. Anderson Cancer Center:

Primary Outcome Measures:
  • Maximal Tolerating Dose (MTD for Phase I) [ Time Frame: End of first cycle (4 weeks) evaluation ] [ Designated as safety issue: Yes ]

    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



Secondary Outcome Measures:
  • Progression-free Survival (Phase II) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    Efficacy measured by 6 month progression-free survival assessment.


Enrollment: 55
Study Start Date: December 2002
Study Completion Date: October 2008
Primary Completion Date: October 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Temozolomide and R115777 Drug: Temozolomide
Starting Dose Level: 100 mg/m^2 taken by mouth once daily for 7 days, followed by 7 days rest and another 7-day dosing period and 7-day rest period.
Other Name: Temodar
Drug: R115777
Starting Dose Level: 400 mg taken by mouth for 7 consecutive days every other week on alternating weeks (days 8-14 and 22-28) every 4 weeks.
Other Name: Zarnestra

Detailed Description:

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 tumors.

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 basis.

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.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 </= 2.5 times normal, bilirubin </= 2 mg%), and adequate renal function (BUN and creatinine <1.5 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00050986

Locations
United States, Texas
MD Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
Johnson & Johnson
Investigators
Principal Investigator: Mark R. Gilbert MDAnderson Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT00050986     History of Changes
Other Study ID Numbers: ID02-126
Study First Received: December 31, 2002
Results First Received: September 25, 2009
Last Updated: July 27, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by M.D. Anderson Cancer Center:
Brain Neoplasms
CNS Diseases
Glioblastoma Multiforme
Temozolomide
Temodar
R115777
Zarnestra

Additional relevant MeSH terms:
Glioblastoma
Astrocytoma
Glioma
Neoplasms
Neoplasms by Histologic Type
Neoplasms, Germ Cell and Embryonal
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Dacarbazine
Temozolomide
Tipifarnib
Alkylating Agents
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on November 27, 2014