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

• Sponsor: M.D. Anderson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00050986
• Collaborator: Johnson & Johnson (Industry)
• Enrollment: 55
• Location: 1
• Arm: 1
• Duration (Months): 70
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

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 or Disease	Intervention/Treatment	Phase
Glioblastoma Multiforme	Drug: Temozolomide; Drug: R115777	Phase 1/Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 55 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (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
• Study Start Date: Dec 1, 2002
• Actual Primary Completion Date: Oct 1, 2008
• Actual Study Completion Date: Oct 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
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 Names: 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 Names: Zarnestra

Outcome Measures

Primary Outcome Measures

1. Maximal Tolerating Dose (MTD for Phase I) [End of first cycle (4 weeks) evaluation]

   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

1. Progression-free Survival (Phase II) [6 months]

   Efficacy measured by 6 month progression-free survival assessment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• UT MD Anderson Cancer Center website

Publications

None provided.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT00050986
• Other Study ID Numbers: ID02-126
• First Posted: Jan 3, 2003
• Last Update Posted: Sep 22, 2020
• Last Verified: Sep 1, 2020

• Keywords provided by M.D. Anderson Cancer Center: Brain Neoplasms; CNS Diseases; Glioblastoma Multiforme; Temozolomide; Temodar; R115777; Zarnestra
• Additional relevant MeSH terms: Glioblastoma; Temozolomide; Tipifarnib

Study Results

Participant Flow

Recruitment Details	Total of 55 participants recruited in between 12/30/2002 and 11/30/2005, all at M. D. Anderson Cancer Center.
Pre-assignment Detail	5 patients were not evaluated for response because of the following: 1 early, non-treatment related death; 3 withdrew consent; 1 discontinued for intercurrent illness (pneumonia).

Arm/Group Title	Temozolomide and R115777
Arm/Group Description
Period Title: Overall Study
STARTED	55
COMPLETED	53
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Temozolomide and R115777
Arm/Group Description
Overall Participants	55
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	52 94.5%
>=65 years	3 5.5%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	52
Sex: Female, Male (Count of Participants)
Female	13 23.6%
Male	42 76.4%
Region of Enrollment (participants) [Number]
United States	55 100%

Outcome Measures

1. Primary Outcome

Title	Maximal Tolerating Dose (MTD for Phase I)
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
Time Frame	End of first cycle (4 weeks) evaluation

Outcome Measure Data

Analysis Population Description

As treated.

Arm/Group Title	Temozolomide and R115777
Arm/Group Description
Measure Participants	15
Dose Level 1	3 5.5%
Dose Level 2	3 5.5%
Dose Level 3	6 10.9%
Dose Level 4	3 5.5%

2. Secondary Outcome

Title	Progression-free Survival (Phase II)
Description	Efficacy measured by 6 month progression-free survival assessment.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	2 years, 11 months
Adverse Event Reporting Description	Including all serious adverse events regardless of attribution. Including all grade 3 or higher adverse events regardless of attribution.
Arm/Group Title	Temozolomide and R115777
Arm/Group Description
All Cause Mortality
	Temozolomide and R115777
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Temozolomide and R115777
	Affected / at Risk (%)	# Events
Total	24/53 (45.3%)
Blood and lymphatic system disorders
Neutrophils	3/53 (5.7%)	3
Hemoglobin	1/53 (1.9%)	1
thrombocytopenia	2/53 (3.8%)	2
CNS Hemorrhage	1/53 (1.9%)	1
Infections and infestations
Herpes Zoster	2/53 (3.8%)	2
Infection	5/53 (9.4%)	5
Metabolism and nutrition disorders
hypokalemia	2/53 (3.8%)	2
hypophasphatemia	1/53 (1.9%)	1
Amyliase, Lipase, Pancreatitis	1/53 (1.9%)	1
Nervous system disorders
Seizure	3/53 (5.7%)	3
Death	2/53 (3.8%)	2
confusion	1/53 (1.9%)	1
Depressed level of consiousness	1/53 (1.9%)	1
Pyramidal Tract Dysfunction	1/53 (1.9%)	1
Respiratory, thoracic and mediastinal disorders
Pneumonitis	2/53 (3.8%)	2
Vascular disorders
Thrombosis/embolism	4/53 (7.5%)	4
Other (Not Including Serious) Adverse Events
	Temozolomide and R115777
	Affected / at Risk (%)	# Events
Total	47/53 (88.7%)
Blood and lymphatic system disorders
Hemoglobin	5/53 (9.4%)	6
Neutrophils	21/53 (39.6%)	76
Lymphocytopenia	40/53 (75.5%)	210
Thrombocytopenia	16/53 (30.2%)	30
Thrombosis	3/53 (5.7%)	3
Cardiac disorders
Hypotension	1/53 (1.9%)	1
Ear and labyrinth disorders
Hearing	1/53 (1.9%)	1
Gastrointestinal disorders
Abdominal pain	1/53 (1.9%)	1
Anorexia	1/53 (1.9%)	1
Constipation	2/53 (3.8%)	4
Dehydration	2/53 (3.8%)	2
Dry mouth	1/53 (1.9%)	1
Nausea	1/53 (1.9%)	1
General disorders
Fatigue	7/53 (13.2%)	12
Pain	6/53 (11.3%)	8
Weight gain	1/53 (1.9%)	1
Weight loss	1/53 (1.9%)	1
Metabolism and nutrition disorders
ALT	2/53 (3.8%)	2
Hyperglycemia	6/53 (11.3%)	11
Hyperuricemia	1/53 (1.9%)	1
Hypoalbuminemia	1/53 (1.9%)	1
Hypocalcemia	1/53 (1.9%)	1
Hypokalemia	2/53 (3.8%)	4
Hyponatremia	2/53 (3.8%)	2
Hypophosphatemia	4/53 (7.5%)	5
Musculoskeletal and connective tissue disorders
Muscle weakness	4/53 (7.5%)	4
Nervous system disorders
Ataxia	1/53 (1.9%)	1
Mental Status	3/53 (5.7%)	3
Motor	6/53 (11.3%)	6
Personality/behavioral	2/53 (3.8%)	2
Seizures	4/53 (7.5%)	4
Speech impairment	1/53 (1.9%)	1
Syncope	1/53 (1.9%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/53 (1.9%)	1
Hypoxia	1/53 (1.9%)	1
Pneumonits	4/53 (7.5%)	4
Skin and subcutaneous tissue disorders
decubitus Ulcer	2/53 (3.8%)	2
Pruritus	1/53 (1.9%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.