Combination Chemotherapy, Monoclonal Antibody, and Radiation Therapy in Treating Patients With Primary Central Nervous System Lymphoma

Lymphoma Clinical Trial

Official title:

Phase I/II Study Of Pre-Irradiation Chemotherapy With Methotrexate, Rituximab, And Temozolomide And Post -Irradiation Temozolomide For Primary Central Nervous System Lymphoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00068250
• Other study ID #: RTOG-0227
• Secondary ID: CDR0000301563
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: September 10, 2003
• Last updated: February 1, 2018
• Start date: July 2003
• Est. completion date: December 2016

Study information

• Verified date: February 2018
• Source: Radiation Therapy Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

RATIONALE: Drugs used in chemotherapy such as methotrexate and temozolomide use different ways to stop cancer cells from dividing so they stop growing or die. Monoclonal antibodies such as rituximab can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. Radiation therapy uses high-energy x-rays to damage cancer cells. Combining methotrexate, temozolomide, and rituximab with radiation therapy may kill more cancer cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of temozolomide when given together with methotrexate and rituximab followed by radiation therapy and to see how well they work in treating patients with primary central nervous system lymphoma.

Description:

OBJECTIVES:

• To assess the maximum tolerated dose (MTD) of temozolomide (TMZ) in combination with methotrexate (MTX) and rituximab (RTX) when administered prior to twice daily fractionated whole brain radiation therapy (WBRT) in patients with primary central nervous system lymphoma.

• To compare the two-year survival rate in patients receiving pre-irradiation chemotherapy, twice daily fractionated whole brain radiation therapy and post-irradiation temozolomide to the reported two-year survival rate of Radiation Therapy Oncology Group (RTOG) trial 93-10. RTOG 9310 does not fall within ClinicalTrials.gov registration/reporting requirements.)

• To compare the pre-irradiation chemotherapy tumor response rates to the reported rate from RTOG 93-10.

• To report progression-free survival.

• To assess acute and long-term neurologic toxicity, and to collect quality of life data for this patient group.

Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 60
• Est. completion date: December 2016
• Est. primary completion date: December 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion criteria:

1. Primary central nervous system (CNS) lymphoma [B-cell, Cluster of Differentiation 20 (CD20) antigen positive] based on positive biopsy or cerebrospinal fluid (CSF) or vitreous cytology (in association with measurable intraparenchymal tumor). Cytology must demonstrate lymphoma or have an immunohistochemical diagnosis of malignant lymphocytes with a monoclonal lymphocytic population.

2. Life expectancy = 8 weeks;

3. Zubrod performance status of 0-2;

4. Absolute granulocyte count =1500/mm3; platelet count = 100,000/mm3; creatinine clearance = 50, calculated with the Cockcroft-Gault Equation: Cr Clearance = (140-age) x wt (kg)/(Cr[mg/dl]x 72); Bilirubin, serum glutamate oxaloacetate transaminase (SGOT), alkaline phosphatase (AST) = 2 x institutional upper limits of normal;

5. Patients must sign a study-specific informed consent prior to study entry.

6. Age = 18

Exclusion criteria:

1. Evidence of systemic lymphoma;

2. Prior malignancy (excluding in situ carcinoma of the cervix or non-melanomatous skin cancer)unless disease free for at least five years;

3. Prior radiotherapy to the brain or head/neck;

4. Prior chemotherapy;

5. History of idiopathic sensitivity to any of the drugs to be used;

6. Active infectious process;

7. Seropositive for HIV, AIDS, or post-organ transplant;

8. Pregnant women are ineligible as treatment involves unforeseeable risks to the participant and to the embryo or fetus.

9. Active hepatitis B.

Related Conditions & MeSH terms

• Brain and Central Nervous System Tumors
• Central Nervous System Neoplasms
• Lymphoma
• Nervous System Neoplasms

Intervention

Drug:
• rituximab
375 mg/m2, intravenously three days prior to the first cycle of methotrexate
• methotrexate
Five cycles of methotrexate (MTX) at 3.5 gm/m2 administered every two weeks on weeks 1, 3, 5, 7, and 9 via intravenous infusion over four hours once per cycle. Calcium leucovorin 25 mg orally or intravenously every six hours initiated exactly 24 hours following the start of the MTX infusion. Methotrexate levels to be monitored daily, and calcium leucovorin discontinued when the MTX level is less than 10 micromolar.
• temozolomide 100 mg/m^2
Temozolomide 100 mg/m^2 by mouth per day for five days on weeks 4 and 8.
• temozolomide 150 mg/m^2
Temozolomide 150 mg/m^2 by mouth per day for five days on weeks 4 and 8.
• temozolomide 200 mg/m^2
Temozolomide 200 mg/m^2 per day by mouth for five days on weeks 4 and 8.

Radiation:
• radiation therapy
Whole brain irradiation (WBRT) during weeks 11, 12, and 13, five days per week (excluding weekends). A daily dose of 2.4 Gy delivered in two fractions of 1.2 Gy each with a minimum inter-fraction interval of 6 hours, with a total dose to brain and meninges of 36 Gy.

Drug:
• post-radiation therapy temozolomide
Temozolomide (TMZ) 200 mg/m^2 by mouth per day for 5 days on weeks 14, 18, 22, 26, 30, 34, 38, 42, 46, and 50 for a total of 10 cycles.

Locations

Country	Name	City	State
United States	Hollings Cancer Center at Medical University of South Carolina	Charleston	South Carolina
United States	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio
United States	John F. Kennedy Medical Center	Edison	New Jersey
United States	Baptist Cancer Institute - Jacksonville	Jacksonville	Florida
United States	Baptist Medical Center South	Jacksonville	Florida
United States	Integrated Community Oncology Network at Southside Cancer Center	Jacksonville	Florida
United States	Integrated Community Oncology Network	Jacksonville Beach	Florida
United States	Borgess Medical Center	Kalamazoo	Michigan
United States	Bronson Methodist Hospital	Kalamazoo	Michigan
United States	West Michigan Cancer Center	Kalamazoo	Michigan
United States	CCOP - Kansas City	Kansas City	Missouri
United States	CCOP - Nevada Cancer Research Foundation	Las Vegas	Nevada
United States	Community Memorial Hospital Cancer Care Center	Menomonee Falls	Wisconsin
United States	Medical College of Wisconsin Cancer Center	Milwaukee	Wisconsin
United States	Providence Milwaukie Hospital	Milwaukie	Oregon
United States	Jon and Karen Huntsman Cancer Center at Intermountain Medical Center	Murray	Utah
United States	Integrated Community Oncology Network - Orange Park	Orange Park	Florida
United States	Florida Cancer Center - Palatka	Palatka	Florida
United States	Kimmel Cancer Center at Thomas Jefferson University - Philadelphia	Philadelphia	Pennsylvania
United States	CCOP - Columbia River Oncology Program	Portland	Oregon
United States	Providence Cancer Center at Providence Portland Medical Center	Portland	Oregon
United States	Providence St. Vincent Medical Center	Portland	Oregon
United States	Utah Valley Regional Medical Center - Provo	Provo	Utah
United States	Flagler Cancer Center	Saint Augustine	Florida
United States	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	Saint Louis	Missouri
United States	Southwest Washington Medical Center Cancer Center	Vancouver	Washington

Sponsors (3)

Lead Sponsor	Collaborator
Radiation Therapy Oncology Group	National Cancer Institute (NCI), NRG Oncology

Country where clinical trial is conducted

United States, 

References & Publications (1)

Glass J, Won M, Schultz CJ, Brat D, Bartlett NL, Suh JH, Werner-Wasik M, Fisher BJ, Liepman MK, Augspurger M, Bokstein F, Bovi JA, Solhjem MC, Mehta MP. Phase I and II Study of Induction Chemotherapy With Methotrexate, Rituximab, and Temozolomide, Followe — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Phase I Participants Experiencing Toxicity	A dose limiting toxicity (DLT) is defined as any grade 3 or 4 non-hematological toxicity (other than grade 3 nausea/vomiting) or any hematological toxicity resulting in the discontinuation of temozolomide. Toxicity evaluation for this dose escalation includes all toxicities occurring prior to the start of radiation therapy. If the patient did not receive radiation therapy, then toxicity evaluation included all toxicities occurring through week 15. Any grade 5 toxicity would result in immediate suspension of accrual.	From start of treatment to 10 weeks if radiation therapy received, to 15 weeks if not.
Primary	Phase II: Overall Survival Rate at 2 Years (Including Phase I Patients at Same Dose)	Survival time is defined as time from registration to date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. (Please note that this outcome measure is considered the primary endpoint for the Phase II component of the study, but that the patients from Phase I that were treated at the same dose level are included, as indicated in the treatment arm descriptions. )	Analysis occured after all patients have been on study for 2 years. Maximum follow-up at time of analysis was 8.5 years.
Secondary	Phase II: Pre-irradiation Chemotherapy Tumor Response Rate (Including Phase I Patients at Same Dose)	Tumor response was centrally reviewed. Complete response: Disappearance of all enhancing tumor, the patient must be off steroid therapy and neurologically stable or improved; partial response: = 50% decrease in enhancing tumor; progressive disease: = 25% increase in a lesion, progressive or newly emergent meningeal or ocular disease. (Please note that this outcome measure is considered a secondary endpoint for the Phase II component of the study, but that the patients from Phase I that were treated at the same dose level are included, as indicated in the treatment arm descriptions. )	From start of treatment to 10 weeks if RT received, to 15 weeks if not.
Secondary	Phase II: Progression-free Survival (Including Phase I Patients at Same Dose)	Progression is defined as greater than 25% increase in enhancing tumor or the appearance of new lesions in the brain, eye, or the appearance of a new positive cerebrospinal fluid (CSF) cytology. The patient may be neurologically stable or worse and on stable or increasing doses of corticosteroid. Progression-free survival time is defined as time from registration to the date of progression, death, or last known follow-up (censored). Progression-free survival rates are estimated using the Kaplan-Meier method. (Please note that this outcome measure is considered a secondary endpoint for the Phase II component of the study, but that the patients from Phase I that were treated at the same dose level are included, as indicated in the treatment arm descriptions. )	Analysis occured after all patients have been on study for 2 years. Maximum follow-up at time of analysis was 8.5 years.