- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00582075
Phase II Study of Gamma Knife Radiosurgery and Temozolomide for Brain Metastases (RAD0102)
Phase II Study of Gamma Knife Radiosurgery and Temozolomide (Temodar) for Newly Diagnosed Brain Metastases
Study Overview
Detailed Description
This is a phase II study. The primary endpoint is the proportion of patients with newly developed metastases who develop new brain metastases within the first year of undergoing stereotactic radiation combined with the administration of temozolamide within the first year post treatment. Retrospective and prospective studies suggest that 50- 60% of long-term survivors develop new brain metastases. Since it is important to observe all patients recruited for a minimum of a year to measure the primary outcome, traditional phase 2 designs such as Simon's two stage optimal design or the mini-max design are not practical in this case. Survival and QOL are secondary end points. QOL will be measured using the Functional Assessment of Cancer Therapy (FACT -BR). It will be administered at baseline, at week four and every three months for 24 months.
This protocol includes radiosurgery with standard radiation doses (15-24 Gy based upon RTOG 9005). Patient may be registered after radiosurgery as long as Temodar is started within two weeks of radiosurgery.
Beginning within two weeks after radiosurgery: TMZ 200mg/m2 days 1-5 repeat q28 days. Patients who have received prior chemotherapy will receive 150 mg/m2 days 1-5.
Temozolomide is continued until there is disease progression defined by systemic progression or new metastases. If lesion treated with radiosurgery progresses in the absence of new CNS tumors or systemic progression, then TMZ will continue. Temozolomide is discontinued for systemic progression requiring other systemic chemotherapy.
Palliative radiation may be administered to non-CNS sites during protocol treatment, but additional systemic chemotherapy will not be administered until patients progress systemically or until new metastases develop.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
-
-
Alabama
-
Birmingham, Alabama, United States, 35233
- University of Alabama at Birmingham
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- All subjects must have history of histologically confirmed malignancy. Brain biopsy is not required unless diagnosis is judged to be in doubt by the treating physician.
- Newly diagnosed brain metastases (four or fewer by thin slice post-contrast MRI).
- ECOG performance status of less than or equal to 2 for patients with no prior chemotherapy, and less than or equal to 1 for patients with prior chemotherapy.
- Age greater than 18
- Life expectancy greater than 12 weeks
- Subjects given written informed consent
Adequate hematologic, renal and liver function as demonstrated by laboratory values performed within 14 days, inclusive, prior to administration of study drug:
- Absolute neutrophil count (ANC) >= 1500/mm3
- Platelet count >= 100,000/mm3
- Hemoglobin >= 9 g/dL
- BUN and serum creatinine <= 1.5 times upper limit of laboratory normal
- Total and direct bilirubin <= 2 times upper limit of laboratory normal or in the presence of documented liver metastases, total and direct bilirubin <=5 times upper limit of normal
- SGOT and SGPT <= 2 times upper limit of laboratory normal or in the presence of documented liver metastases, SGOT and SGPT <=5 times upper limit of normal
- Alkaline phosphatase <= 2 times upper limit of laboratory normal or in the presence of documented liver metastases, alkaline phosphatase of <= 5 times upper limit of normal
Exclusion Criteria:
- Patients with small cell lung cancer and lymphoma are ineligible.
- More than four metastases by thin slice MRI. Note that if a diagnostic study prior to radiosurgery demonstrates only four tumors but the gamma knife treatment-planning scan reveals greater than four tumors, the patients will still be eligible for the protocol if all tumors can be treated with radiosurgery.
- Chemotherapy within four weeks prior to study drug administration
- Patients, who in the opinion of the treating medical oncologist, require immediate cytotoxic chemotherapy other than the study drug. Allowed medications include antihormonal agents (i.e., Tamoxifen), herceptin and bisphosphonates.
- Radiation therapy to greater than or equal to 50% of the bone marrow. Completion of radiation therapy less than 4 weeks prior to study drug administration for radiotherapy to >= 15% of bone marrow and less than 2 weeks prior for radiotherapy to < 15% of bone marrow.
- Insufficient recovery from all active toxicities of prior therapies
- Subjects who are poor medical risks because of non-malignant systemic disease
- Frequent vomiting or medical condition that could interfere with oral medication intake (e.g., partial bowel obstruction).
- Previous or concurrent malignancies at other sites, or treatment for malignancy at the site within 5 years of study start with the exception of surgically cured carcinoma in-situ of the cervix and basal or squamous cell carcinoma of the skin.
- Known HIV positively or AIDS-related illness.
- Pregnant or nursing women.
- Women of childbearing potential who are not using an effective method of contraception. Women of childbearing potential must have a negative serum pregnancy test 24 hours prior to administration of study drug and be practicing medically approved contraceptive precautions.
- Men who are not advised to use an effective method of contraception.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Radiosurgery 15-24 Gy + Adjuvant Temozolomide
|
TMZ 200mg/m2 days 1-5 repeat q28 days.
Patients who have received prior chemotherapy will receive 150 mg/m2 days 1-5
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Percentage of Participants With Distant Brain Failure (DBF) at One Year
Time Frame: 1 years
|
Patients developing distant brain failure (DBF) at one year.
An approximation method was used to arrive at the reported percentage.
|
1 years
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Overall Survival
Time Frame: 2 years
|
2 years
|
Collaborators and Investigators
Collaborators
Publications and helpful links
General Publications
- Patchell RA, Tibbs PA, Regine WF, Dempsey RJ, Mohiuddin M, Kryscio RJ, Markesbery WR, Foon KA, Young B. Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA. 1998 Nov 4;280(17):1485-9. doi: 10.1001/jama.280.17.1485.
- DeAngelis LM, Delattre JY, Posner JB. Radiation-induced dementia in patients cured of brain metastases. Neurology. 1989 Jun;39(6):789-96. doi: 10.1212/wnl.39.6.789.
- Newlands ES, Blackledge GR, Slack JA, Rustin GJ, Smith DB, Stuart NS, Quarterman CP, Hoffman R, Stevens MF, Brampton MH, et al. Phase I trial of temozolomide (CCRG 81045: M&B 39831: NSC 362856). Br J Cancer. 1992 Feb;65(2):287-91. doi: 10.1038/bjc.1992.57.
- Pirzkall A, Debus J, Lohr F, Fuss M, Rhein B, Engenhart-Cabillic R, Wannenmacher M. Radiosurgery alone or in combination with whole-brain radiotherapy for brain metastases. J Clin Oncol. 1998 Nov;16(11):3563-9. doi: 10.1200/JCO.1998.16.11.3563.
- Sneed PK, Lamborn KR, Forstner JM, McDermott MW, Chang S, Park E, Gutin PH, Phillips TL, Wara WM, Larson DA. Radiosurgery for brain metastases: is whole brain radiotherapy necessary? Int J Radiat Oncol Biol Phys. 1999 Feb 1;43(3):549-58. doi: 10.1016/s0360-3016(98)00447-7.
- Stevens MF, Hickman JA, Stone R, Gibson NW, Baig GU, Lunt E, Newton CG. Antitumor imidazotetrazines. 1. Synthesis and chemistry of 8-carbamoyl-3-(2-chloroethyl)imidazo[5,1-d]-1,2,3,5-tetrazin-4(3 H)-one , a novel broad-spectrum antitumor agent. J Med Chem. 1984 Feb;27(2):196-201. doi: 10.1021/jm00368a016.
- Tsang LL, Quarterman CP, Gescher A, Slack JA. Comparison of the cytotoxicity in vitro of temozolomide and dacarbazine, prodrugs of 3-methyl-(triazen-1-yl)imidazole-4-carboxamide. Cancer Chemother Pharmacol. 1991;27(5):342-6. doi: 10.1007/BF00688855.
- Bull VL, Tisdale MJ. Antitumour imidazotetrazines--XVI. Macromolecular alkylation by 3-substituted imidazotetrazinones. Biochem Pharmacol. 1987 Oct 1;36(19):3215-20. doi: 10.1016/0006-2952(87)90636-8.
- Tisdale MJ. Antitumour imidazotetrazines--XVIII. Modification of the level of 5-methylcytosine in DNA by 3-substituted imidazotetrazinones. Biochem Pharmacol. 1989 Apr 1;38(7):1097-101. doi: 10.1016/0006-2952(89)90254-2.
- Tsang LL, Farmer PB, Gescher A, Slack JA. Characterisation of urinary metabolites of temozolomide in humans and mice and evaluation of their cytotoxicity. Cancer Chemother Pharmacol. 1990;26(6):429-36. doi: 10.1007/BF02994094.
- Clark AS, Stevens MF, Sansom CE, Schwalbe CH. Anti-tumour imidazotetrazines. Part XXI. Mitozolomide and temozolomide: probes for the major groove of DNA. Anticancer Drug Des. 1990 Feb;5(1):63-8.
- Stevens MF, Hickman JA, Langdon SP, Chubb D, Vickers L, Stone R, Baig G, Goddard C, Gibson NW, Slack JA, et al. Antitumor activity and pharmacokinetics in mice of 8-carbamoyl-3-methyl-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045; M & B 39831), a novel drug with potential as an alternative to dacarbazine. Cancer Res. 1987 Nov 15;47(22):5846-52.
- Gibson NW, Hickman JA, Erickson LC. DNA cross-linking and cytotoxicity in normal and transformed human cells treated in vitro with 8-carbamoyl-3-(2-chloroethyl)imidazo[5,1-d] -1,2,3,5-tetrazin-4(3H)-one. Cancer Res. 1984 May;44(5):1772-5.
- Hartley JA, Gibson NW, Kohn KW, Mattes WB. DNA sequence selectivity of guanine-N7 alkylation by three antitumor chloroethylating agents. Cancer Res. 1986 Apr;46(4 Pt 2):1943-7.
- SN92384: SCH 52365: Pharmacokinetics of SCH 52365 in Rats Following a Single Oral Gavage or Intravenous Dose. Schering-Plough Research Institute
- SN92385: SCH 52365: Pharmacokinetics of SCH 52365 in Beagle Dogs Following a Single Oral Gavage or a Single Intravenous Cross-Over Study. Schering Plough Research Institute
- SN92131: Single-Cycle Oral Toxicity Study of SCH 52365 in Rats. Schering Plough Research Institute.
- SN93092: Single-Cycle Oral Toxicity Study with Lower Doses of SCH 52365 in Rats. Schering-Plough Research Institute
- SN92133: Three-Cycle Oral Toxicity Study of SCH 52365 in Rats. Schering Plough Research Institute.
- SN92132: Single-Cycle Oral Toxicity Study of SCH 52365 in Dogs. Schering-Plough Research Institute
- SN93093: Single-Cycle Oral Toxicity Study with Lower Doses of SCH 52365 in Dogs. Schering-Plough Research Institute
- SN92134: Three-Cycle Oral Toxicity Study of SCH 52365 in Dogs. Schering-Plough Research Institute
- SN92380: SCH 52365: Mass Balance and Excretion of 14C-SCH 52365 Following a Single Intravenous or Oral Dose in Male Rats. Schering-Plough Research Institute
- SN92383: SCH 52365: Absorption, Distribution and Metabolism of 14C SCH 52365 Following a Single Oral Dose in Male Rats. Schering-Plough Research Institute
- SN92381: SCH 52365: Absorption, Metabolism, Excretion, and Pharmacokinetics of 14C-SCH 52365 Following a Single Oral or Intravenous Dose in the Male Rat. Schering-Plough Research Institute
- SN92382: SCH 52365: Absorption, Metabolism, Excretion, and Pharmacokinetics of 14C-SCH 52365 Following a Single Oral And Intravenous Dose in the Male Dog. Schering-Plough Research Institute
- Patel M, McCully C, Godwin K, Balis F: Plasma and cerebrospinal fluid pharmacokinetics of temozolomide. Proc. ASCO. 1995; 14:1485
- O'Reilly SM, Newlands ES, Stevens MFG, Brampton MH, Slack JA et al: Temozolomide (CCRG 81045; M&B 39831; NSC 362856): a new oral cytotoxic agent with activity against melanoma, mycosis fungoides and high-grade glioma. Proc. AACR. 1992; 33: A1267
- O'Reilly SM, Newlands ES, Glaser MG, Brampton M, Rice-Edwards JM, Illingworth RD, Richards PG, Kennard C, Colquhoun IR, Lewis P, et al. Temozolomide: a new oral cytotoxic chemotherapeutic agent with promising activity against primary brain tumours. Eur J Cancer. 1993;29A(7):940-2. doi: 10.1016/s0959-8049(05)80198-4. Erratum In: Eur J Cancer 1993;29A(10):1500.
- Data on file at the Cancer Research Campaign Data Center. Phase II trial of temozolomide in high-grade glioma. Schering-Plough Research Institute. Study No. H93-090-50).
- Data on file at the Cancer Research Campaign Data Center. Phase II trial of temozolomide in advanced malignant melanoma. Schering-Plough Research Institute. Study No. H93 088-50
- Bleehen NM, Newlands ES, Lee SM, Thatcher N, Selby P, Calvert AH, Rustin GJ, Brampton M, Stevens MF. Cancer Research Campaign phase II trial of temozolomide in metastatic melanoma. J Clin Oncol. 1995 Apr;13(4):910-3. doi: 10.1200/JCO.1995.13.4.910.
- Data on file at the Cancer Research Campaign Data Center. Phase II trial of temozolomide in low-grade non-Hodgkin's lymphoma. Schering-Plough Research Institute. Study No. H93-089-50).
- Woll PJ, Crowther D, Johnson PW, Soukop M, Harper PG, Harris M, Brampton MH, Newlands ES. Phase II trial of temozolomide in low-grade non-Hodgkin's lymphoma. Br J Cancer. 1995 Jul;72(1):183-4. doi: 10.1038/bjc.1995.299.
- Data on file at Schering-Plough Research Institute (I93-114-01).
- Brada M, Moore S, Judson I, Batra VJ, Quartey P, Dugan M: A Phase I study of SCH 52365 (temozolomide) in adult patients with advanced cancer. Proc. ASCO. 1995; 14:1521
- Data on file at Schering-Plough Research Institute (C94-022-01).
- Hammond LA, Eckardt JR, Baker SD, Eckhardt SG, Dugan M, Forral K, Reidenberg P, Statkevich P, Weiss GR, Rinaldi DA, Von Hoff DD, Rowinsky EK. Phase I and pharmacokinetic study of temozolomide on a daily-for-5-days schedule in patients with advanced solid malignancies. J Clin Oncol. 1999 Aug;17(8):2604-13. doi: 10.1200/JCO.1999.17.8.2604.
- Yung A, Levin VA, Albright R, Olson J, Fredericks R, Fink K, Prados M, Brada M, Spence A, Brunner J, Yue N, Dugan MH, Zaknoen S. Temodal Brain Tumor Group: Randomized trial of temodal (TEM) vs. procarbazine (PCB) in glioblastoma multi-forme (GBM) at first relapse [abstract]. Proceedings of the American Society of Clinical Oncology. 1999; 18:139a.
- Christodoulou C, Bafaloukos D, Kosmidis P, Samantas E, Bamias A, Papakostas P, Karabelis A, Bacoyiannis C, Skarlos DV; Hellenic Cooperative Oncology Group. Phase II study of temozolomide in heavily pretreated cancer patients with brain metastases. Ann Oncol. 2001 Feb;12(2):249-54. doi: 10.1023/a:1008354323167.
- Paraskevaidis E, Antonadou D, Sarris G, Kolliarakis N, Economou I, Karageirgus P, Throuvalas N. A Phase II randomized trial of synchronous radiotherapy with temozolomide in brain metastases. Metaxas Cancer Hospital, Pireus, Greece
- Abrey JD, Olson DY, Boutros M, Mack A, Rodavitch JJ, Raizer MG. A Phase II Study of Temozolomide for Recurrent Brain Metastases. Malkin; Memorial Sloan-Kettering Cancer Center, New York, NY. Abstract 643
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Brain Diseases
- Central Nervous System Diseases
- Nervous System Diseases
- Neoplasms
- Neoplasms by Site
- Neoplastic Processes
- Central Nervous System Neoplasms
- Nervous System Neoplasms
- Neoplasm Metastasis
- Brain Neoplasms
- Molecular Mechanisms of Pharmacological Action
- Antineoplastic Agents
- Antineoplastic Agents, Alkylating
- Alkylating Agents
- Temozolomide
Other Study ID Numbers
- F020522015
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