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

Primary Purpose

Brain and Central Nervous System Tumors, Lymphoma

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
rituximab
methotrexate
temozolomide 100 mg/m^2
temozolomide 150 mg/m^2
temozolomide 200 mg/m^2
radiation therapy
post-radiation therapy temozolomide
Sponsored by
Radiation Therapy Oncology Group
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Brain and Central Nervous System Tumors focused on measuring primary central nervous system non-Hodgkin lymphoma, primary central nervous system Hodgkin lymphoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria: 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. Life expectancy ≥ 8 weeks; Zubrod performance status of 0-2; 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; Patients must sign a study-specific informed consent prior to study entry. Age ≥ 18 Exclusion criteria: Evidence of systemic lymphoma; Prior malignancy (excluding in situ carcinoma of the cervix or non-melanomatous skin cancer)unless disease free for at least five years; Prior radiotherapy to the brain or head/neck; Prior chemotherapy; History of idiopathic sensitivity to any of the drugs to be used; Active infectious process; Seropositive for HIV, AIDS, or post-organ transplant; Pregnant women are ineligible as treatment involves unforeseeable risks to the participant and to the embryo or fetus. Active hepatitis B.

Sites / Locations

  • Integrated Community Oncology Network
  • Baptist Cancer Institute - Jacksonville
  • Integrated Community Oncology Network at Southside Cancer Center
  • Baptist Medical Center South
  • Integrated Community Oncology Network - Orange Park
  • Florida Cancer Center - Palatka
  • Flagler Cancer Center
  • Borgess Medical Center
  • West Michigan Cancer Center
  • Bronson Methodist Hospital
  • CCOP - Kansas City
  • Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
  • CCOP - Nevada Cancer Research Foundation
  • John F. Kennedy Medical Center
  • Cleveland Clinic Taussig Cancer Center
  • Providence Milwaukie Hospital
  • Providence Cancer Center at Providence Portland Medical Center
  • CCOP - Columbia River Oncology Program
  • Providence St. Vincent Medical Center
  • Kimmel Cancer Center at Thomas Jefferson University - Philadelphia
  • Hollings Cancer Center at Medical University of South Carolina
  • Jon and Karen Huntsman Cancer Center at Intermountain Medical Center
  • Utah Valley Regional Medical Center - Provo
  • Southwest Washington Medical Center Cancer Center
  • Community Memorial Hospital Cancer Care Center
  • Medical College of Wisconsin Cancer Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Phase I: Temozolomide 100 mg

Phase I: Temozolomide 150 mg

Phase I: Temozolomide 200 mg

Phase II: Temozolomide 100 mg

Arm Description

Rituximab, methotrexate, temozolomide 100 mg/m^2, followed by radiation therapy, then post-radiation therapy temozolomide 200 mg/m^2.

Rituximab, methotrexate, temozolomide 150 mg/m^2, followed by radiation therapy, then post-radiation therapy temozolomide 200 mg/m^2.

Rituximab, methotrexate, temozolomide 200 mg/m^2, followed by radiation therapy, then post-radiation therapy temozolomide 200 mg/m^2.

Rituximab, methotrexate, temozolomide 100 mg/m^2, followed by radiation therapy, then post-radiation therapy temozolomide 200 mg/m^2.

Outcomes

Primary Outcome Measures

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.
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. )

Secondary Outcome Measures

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. )
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. )

Full Information

First Posted
September 10, 2003
Last Updated
February 1, 2018
Sponsor
Radiation Therapy Oncology Group
Collaborators
National Cancer Institute (NCI), NRG Oncology
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1. Study Identification

Unique Protocol Identification Number
NCT00068250
Brief Title
Combination Chemotherapy, Monoclonal Antibody, and Radiation Therapy in Treating Patients With Primary Central Nervous System Lymphoma
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
Study Type
Interventional

2. Study Status

Record Verification Date
February 2018
Overall Recruitment Status
Completed
Study Start Date
July 2003 (undefined)
Primary Completion Date
December 2016 (Actual)
Study Completion Date
December 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Radiation Therapy Oncology Group
Collaborators
National Cancer Institute (NCI), NRG Oncology

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief 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.
Detailed 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Brain and Central Nervous System Tumors, Lymphoma
Keywords
primary central nervous system non-Hodgkin lymphoma, primary central nervous system Hodgkin lymphoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
60 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Phase I: Temozolomide 100 mg
Arm Type
Experimental
Arm Description
Rituximab, methotrexate, temozolomide 100 mg/m^2, followed by radiation therapy, then post-radiation therapy temozolomide 200 mg/m^2.
Arm Title
Phase I: Temozolomide 150 mg
Arm Type
Experimental
Arm Description
Rituximab, methotrexate, temozolomide 150 mg/m^2, followed by radiation therapy, then post-radiation therapy temozolomide 200 mg/m^2.
Arm Title
Phase I: Temozolomide 200 mg
Arm Type
Experimental
Arm Description
Rituximab, methotrexate, temozolomide 200 mg/m^2, followed by radiation therapy, then post-radiation therapy temozolomide 200 mg/m^2.
Arm Title
Phase II: Temozolomide 100 mg
Arm Type
Experimental
Arm Description
Rituximab, methotrexate, temozolomide 100 mg/m^2, followed by radiation therapy, then post-radiation therapy temozolomide 200 mg/m^2.
Intervention Type
Drug
Intervention Name(s)
rituximab
Intervention Description
375 mg/m2, intravenously three days prior to the first cycle of methotrexate
Intervention Type
Drug
Intervention Name(s)
methotrexate
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
temozolomide 100 mg/m^2
Intervention Description
Temozolomide 100 mg/m^2 by mouth per day for five days on weeks 4 and 8.
Intervention Type
Drug
Intervention Name(s)
temozolomide 150 mg/m^2
Intervention Description
Temozolomide 150 mg/m^2 by mouth per day for five days on weeks 4 and 8.
Intervention Type
Drug
Intervention Name(s)
temozolomide 200 mg/m^2
Intervention Description
Temozolomide 200 mg/m^2 per day by mouth for five days on weeks 4 and 8.
Intervention Type
Radiation
Intervention Name(s)
radiation therapy
Other Intervention Name(s)
radiotherapy
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
post-radiation therapy temozolomide
Intervention Description
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.
Primary Outcome Measure Information:
Title
Number of Phase I Participants Experiencing Toxicity
Description
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.
Time Frame
From start of treatment to 10 weeks if radiation therapy received, to 15 weeks if not.
Title
Phase II: Overall Survival Rate at 2 Years (Including Phase I Patients at Same Dose)
Description
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. )
Time Frame
Analysis occured after all patients have been on study for 2 years. Maximum follow-up at time of analysis was 8.5 years.
Secondary Outcome Measure Information:
Title
Phase II: Pre-irradiation Chemotherapy Tumor Response Rate (Including Phase I Patients at Same Dose)
Description
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. )
Time Frame
From start of treatment to 10 weeks if RT received, to 15 weeks if not.
Title
Phase II: Progression-free Survival (Including Phase I Patients at Same Dose)
Description
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. )
Time Frame
Analysis occured after all patients have been on study for 2 years. Maximum follow-up at time of analysis was 8.5 years.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion criteria: 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. Life expectancy ≥ 8 weeks; Zubrod performance status of 0-2; 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; Patients must sign a study-specific informed consent prior to study entry. Age ≥ 18 Exclusion criteria: Evidence of systemic lymphoma; Prior malignancy (excluding in situ carcinoma of the cervix or non-melanomatous skin cancer)unless disease free for at least five years; Prior radiotherapy to the brain or head/neck; Prior chemotherapy; History of idiopathic sensitivity to any of the drugs to be used; Active infectious process; Seropositive for HIV, AIDS, or post-organ transplant; Pregnant women are ineligible as treatment involves unforeseeable risks to the participant and to the embryo or fetus. Active hepatitis B.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jon Glass, MD
Organizational Affiliation
Sidney Kimmel Cancer Center at Thomas Jefferson University
Official's Role
Study Chair
Facility Information:
Facility Name
Integrated Community Oncology Network
City
Jacksonville Beach
State/Province
Florida
ZIP/Postal Code
32250
Country
United States
Facility Name
Baptist Cancer Institute - Jacksonville
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32207
Country
United States
Facility Name
Integrated Community Oncology Network at Southside Cancer Center
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32207
Country
United States
Facility Name
Baptist Medical Center South
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32258
Country
United States
Facility Name
Integrated Community Oncology Network - Orange Park
City
Orange Park
State/Province
Florida
ZIP/Postal Code
32073
Country
United States
Facility Name
Florida Cancer Center - Palatka
City
Palatka
State/Province
Florida
ZIP/Postal Code
32177
Country
United States
Facility Name
Flagler Cancer Center
City
Saint Augustine
State/Province
Florida
ZIP/Postal Code
32086
Country
United States
Facility Name
Borgess Medical Center
City
Kalamazoo
State/Province
Michigan
ZIP/Postal Code
49001
Country
United States
Facility Name
West Michigan Cancer Center
City
Kalamazoo
State/Province
Michigan
ZIP/Postal Code
49007-3731
Country
United States
Facility Name
Bronson Methodist Hospital
City
Kalamazoo
State/Province
Michigan
ZIP/Postal Code
49007
Country
United States
Facility Name
CCOP - Kansas City
City
Kansas City
State/Province
Missouri
ZIP/Postal Code
64131
Country
United States
Facility Name
Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
CCOP - Nevada Cancer Research Foundation
City
Las Vegas
State/Province
Nevada
ZIP/Postal Code
89106
Country
United States
Facility Name
John F. Kennedy Medical Center
City
Edison
State/Province
New Jersey
ZIP/Postal Code
08818
Country
United States
Facility Name
Cleveland Clinic Taussig Cancer Center
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Facility Name
Providence Milwaukie Hospital
City
Milwaukie
State/Province
Oregon
ZIP/Postal Code
97222
Country
United States
Facility Name
Providence Cancer Center at Providence Portland Medical Center
City
Portland
State/Province
Oregon
ZIP/Postal Code
97213-2967
Country
United States
Facility Name
CCOP - Columbia River Oncology Program
City
Portland
State/Province
Oregon
ZIP/Postal Code
97225
Country
United States
Facility Name
Providence St. Vincent Medical Center
City
Portland
State/Province
Oregon
ZIP/Postal Code
97225
Country
United States
Facility Name
Kimmel Cancer Center at Thomas Jefferson University - Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19107-5541
Country
United States
Facility Name
Hollings Cancer Center at Medical University of South Carolina
City
Charleston
State/Province
South Carolina
ZIP/Postal Code
29425
Country
United States
Facility Name
Jon and Karen Huntsman Cancer Center at Intermountain Medical Center
City
Murray
State/Province
Utah
ZIP/Postal Code
84157
Country
United States
Facility Name
Utah Valley Regional Medical Center - Provo
City
Provo
State/Province
Utah
ZIP/Postal Code
84604
Country
United States
Facility Name
Southwest Washington Medical Center Cancer Center
City
Vancouver
State/Province
Washington
ZIP/Postal Code
98668
Country
United States
Facility Name
Community Memorial Hospital Cancer Care Center
City
Menomonee Falls
State/Province
Wisconsin
ZIP/Postal Code
53051
Country
United States
Facility Name
Medical College of Wisconsin Cancer Center
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53226
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
27022122
Citation
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, Followed By Whole-Brain Radiotherapy and Postirradiation Temozolomide for Primary CNS Lymphoma: NRG Oncology RTOG 0227. J Clin Oncol. 2016 May 10;34(14):1620-5. doi: 10.1200/JCO.2015.64.8634. Epub 2016 Mar 28.
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Combination Chemotherapy, Monoclonal Antibody, and Radiation Therapy in Treating Patients With Primary Central Nervous System Lymphoma

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