6-TG, Capecitabine and Celecoxib Plus TMZ or CCNU for Anaplastic Glioma Patients
6-TG, Capecitabine and Celecoxib Plus TMZ or CCNU for Anaplastic Glioma Patients
The goal of this clinical research study is to learn if the combination of 6-Thioguanine,
 Xeloda (capecitabine), and Celebrex (celecoxib) with Temodar (temozolomide) or Lomustine
 (CCNU) is effective in the treatment of recurrent or progressive anaplastic glioma or
 glioblastoma multiforme in patients who have failed previous treatments. The safety of these
 combination treatment will also be studied.

 Objectives:

 1.1 To determine the efficacy, as measured by 12 month progression-free survival, of
 TEMOZOLOMIDE or CCNU with 6-THIOGUANINE followed by CAPECITABINE and CELECOXIB in the
 treatment of patients with recurrent and/or progressive anaplastic gliomas or glioblastoma
 multiforme.

 1.2 To determine the long-term toxicity of TEMOZOLOMIDE or CCNU with 6-THIOGUANINE followed
 by CAPECITABINE and CELECOXIB in recurrent anaplastic glioma or glioblastoma multiforme
 patients treated in this manner.

 1.3 To determine the clinical relevance of genetic subtyping tumors as a predictor of
 response to this chemotherapy and long term survival
Capecitabine is a drug that damages the DNA (deoxyribonucleic acid) of tumor cells and blocks
 the function of DNA and RNA (ribonucleic acid) of tumor cells. These actions help to kill the
 tumor cells.

 Celecoxib is a drug that may help to prevent the development of some types of cancer by
 blocking a type of enzyme (COX-2) that is found in tumor cells.

 Temozolomide and CCNU are the current standard treatment for malignant brain tumors. Both
 drugs work by damaging the DNA (deoxyribonucleic acid) of tumor cells to kill these tumor
 cells.

 6-Thioguanine is a drug that helps to increase the effects of Temozolomide and CCNU on tumor
 cells.

 Depending on the previous treatment you have received, you will be treated according to Arms
 1, 2, or 3.

 If you have not received temozolomide before, you will be treated on Arm 1. If you have
 received temozolomide before but only during radiation therapy and not as chemotherapy
 afterwards and the treatment was over 6 months ago, you will be treated with temozolomide
 according to Arm 1.

 If you have not received lomustine or carmustine, you will be treated on Arm 2. If you have
 received Gliadel wafers at surgery greater than 6 months ago and have not been treated with
 lomustine or carmustine, you will be treated with CCNU according to Arm 2.

 Arm 3 will include glioblastoma multiforme patients who may be treated with either
 temozolomide or lomustine according to the above guidelines and regimens described in Arms 1
 and 2.

 Arm 1:

 Treatment will begin with 6-thioguanine taken by mouth 4 times a day (every 6 hours) for 3
 days in a row (Days 1-3). This will be followed by temozolomide taken by mouth at bedtime for
 5 days in a row (Days 4-8). After a rest period of 6 days, capecitabine and celecoxib will be
 taken by mouth twice a day (12 hours apart) for 14 days (Days 14-27). Each cycle of treatment
 on arm 1 will be 28 days.

 Arm 2:

 Treatment will begin with 6-thioguanine taken by mouth 4 times a day (every 6 hours) for 3
 days in a row (Days 1-3). This will be followed by lomustine taken by mouth at bedtime for 1
 day (Day 4). After a rest period of 1 week, capecitabine and celecoxib will be taken by mouth
 twice a day (12 hours apart) for 14 days (Days 11-24). Each cycle of treatment on arm 2 will
 take 42 days.

 Blood tests (less than 2 teaspoons) will be repeated every 2 weeks and before each new cycle
 of treatment (a total of about 2 tablespoons). The neurological exam, anticonvulsant level
 blood tests and the stool test for blood, will be repeated before every cycle on Arms 2 and 3
 (CCNU) and before every 2 cycles on Arms 1 and 3 (temozolomide). Kidney function will be
 evaluated from the blood tests before every other course. Patients taking anticoagulants
 (coumadin, warfarin) will have procedures to test the clotting ability of the blood before
 each cycle or more frequently if the doctor feels it is necessary.

 Arm 3:

 Glioblastoma Multiforme patients will be treated on Arm 3 which will include the drug regimen
 from either Arm 1 or Arm 2.

 Treatment on all arms will continue for 1 year as long as the tumor does not grow and any
 side effects are tolerable. Treatment may continue beyond one year if your doctor feels it is
 needed. During the study, you may not receive any other investigational drug or have any
 other treatment for the cancer, including surgery.

 This is an investigational study. All drugs used in this study are FDA approved and are
 commercially available. A total of 140 patients will take part in this study. All patients
 will be enrolled at M. D. Anderson.
Inclusion Criteria:

 1. 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.

 2. Patients with histologically proven supratentorial anaplastic oligodendrogliomas,
 anaplastic mixed oligoastrocytomas anaplastic astrocytomas or glioblastoma multiforme.

 3. Patients must have unequivocal evidence for tumor recurrence or progression by MRI
 scan performed within 14 days prior to enrollment or documented recurrence by tumor
 resection. Patients must have received radiation therapy previously.

 4. Patients having undergone recent resection of recurrent or progressive tumor will be
 eligible as long as all the following conditions are met: a) Patients have recovered
 from the effects of surgery; b) Extent of residual disease (if present) has been
 documented by MRI performed no later than 72 hours after surgery or, if not possible,
 at least 4 weeks post-operative. Radiographic evidence of residual disease is not
 mandated for enrollment.

 5. The baseline on-study MRI is performed within 14 days of enrollment and on a steroid
 dosage that has been stable. If the steroid dose is increased between the date of
 imaging and the initiation of chemotherapy, a new baseline MRI is required on stable
 steroids for 7 days.

 6. Patients must be equal to or greater than 12 years old.

 7. Patients must have a Karnofsky performance status of equal to or greater than 60
 (Karnofsky Performance Scale; Appendix D).

 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 equal or greater than 1,500/mm3
 and platelet count of equal or greater than 100,000/mm3), adequate liver function
 (SGPT and alkaline phosphatase <2 times normal, bilirubin <1.5 mg%), and adequate
 renal function (BUN and creatinine <1.5 times institutional normal) prior to starting
 therapy.

 Exclusion Criteria:

 1. Patients with a history of any other cancer (except non-melanoma skin cancer or
 carcinoma in-situ of the cervix), unless in complete remission and off of all therapy
 for that disease for a minimum of 3 years (1 year for localized prostate carcinoma
 treated by prostatectomy or irradiation) are ineligible.

 2. Patients of childbearing potential must not be pregnant or become pregnant.

 3. Patients must not have: a) active infection; b) disease that will obscure toxicity or
 dangerously alter drug metabolism; c) serious intercurrent medical illness; d) acute
 or chronic pulmonary disease, pulmonary embolus, hypertension, diabetes, metabolic
 syndrome, stroke, heart disease,myocardial infarction, angina, coronary angioplasty,
 congestive heart failure, or coronary bypass surgery; e) allergies to sulfa drugs; f)
 severe psychiatric illness; g) uncontrolled hypertension (i.e. ->135/>85 mm Hg) on
 three repeated measurements during the 6 weeks prior to enrollment on the study

 4. Patients must not have (continued): h) family history of premature coronary disease
 (i.e. - onset < 55 years of age); i) uncontrolled hypercholesteremia [low-density
 lipoprotein cholesterol (LDL-C >130]. Hypercholesteremia must be controlled for at
 least 3 months prior to enrollment on study; j) history of systemic lupus
 erythematous, family history of protein S or C deficiencies, prior heparin-induced
 thrombocytopenia, Factor V Leiden deficiencies or high homocysteine levels; k) any
 indications for ASA deficiency

 5. Patients must not have had prior treatment with Capecitabine, 5-FU or a combination of
 Temozolomide with CCNU (Lomustine) or BCNU (Carmustine). Patients who received only
 Temozolomide during radiation therapy and did not receive adjuvant chemotherapy with
 Temozolomide and/or those who received Gliadel (BCNU) wafers at surgery without
 adjuvant chemotherapy with BCNU or CCNU are eligible if 6 months has passed since the
 treatment(s).