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

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ClinicalTrials.gov Identifier: NCT00068250
Recruitment Status : Completed
First Posted : September 11, 2003
Results First Posted : February 7, 2018
Last Update Posted : February 7, 2018
Sponsor:
Collaborators:
National Cancer Institute (NCI)
NRG Oncology
Information provided by (Responsible Party):
Radiation Therapy Oncology Group

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.


Condition or disease Intervention/treatment Phase
Brain and Central Nervous System Tumors Lymphoma Drug: rituximab Drug: methotrexate Drug: temozolomide 100 mg/m^2 Drug: temozolomide 150 mg/m^2 Drug: temozolomide 200 mg/m^2 Radiation: radiation therapy Drug: post-radiation therapy temozolomide Phase 1 Phase 2

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.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 60 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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 Start Date : July 2003
Actual Primary Completion Date : December 2016
Actual Study Completion Date : December 2016


Arm Intervention/treatment
Experimental: Phase I: Temozolomide 100 mg
Rituximab, methotrexate, temozolomide 100 mg/m^2, followed by radiation therapy, then post-radiation therapy temozolomide 200 mg/m^2.
Drug: rituximab
375 mg/m2, intravenously three days prior to the first cycle of methotrexate

Drug: 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.

Drug: temozolomide 100 mg/m^2
Temozolomide 100 mg/m^2 by mouth per day 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.
Other Name: radiotherapy

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.

Experimental: Phase I: Temozolomide 150 mg
Rituximab, methotrexate, temozolomide 150 mg/m^2, followed by radiation therapy, then post-radiation therapy temozolomide 200 mg/m^2.
Drug: rituximab
375 mg/m2, intravenously three days prior to the first cycle of methotrexate

Drug: 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.

Drug: temozolomide 150 mg/m^2
Temozolomide 150 mg/m^2 by mouth per day 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.
Other Name: radiotherapy

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.

Experimental: Phase I: Temozolomide 200 mg
Rituximab, methotrexate, temozolomide 200 mg/m^2, followed by radiation therapy, then post-radiation therapy temozolomide 200 mg/m^2.
Drug: rituximab
375 mg/m2, intravenously three days prior to the first cycle of methotrexate

Drug: 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.

Drug: 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.
Other Name: radiotherapy

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.

Experimental: Phase II: Temozolomide 100 mg
Rituximab, methotrexate, temozolomide 100 mg/m^2, followed by radiation therapy, then post-radiation therapy temozolomide 200 mg/m^2.
Drug: rituximab
375 mg/m2, intravenously three days prior to the first cycle of methotrexate

Drug: 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.

Drug: temozolomide 100 mg/m^2
Temozolomide 100 mg/m^2 by mouth per day 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.
Other Name: radiotherapy

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.




Primary Outcome Measures :
  1. Number of Phase I Participants Experiencing Toxicity [ Time Frame: From start of treatment to 10 weeks if radiation therapy received, to 15 weeks if not. ]
    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.

  2. Phase II: Overall Survival Rate at 2 Years (Including Phase I Patients at Same Dose) [ 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. ]
    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 :
  1. Phase II: Pre-irradiation Chemotherapy Tumor Response Rate (Including Phase I Patients at Same Dose) [ Time Frame: From start of treatment to 10 weeks if RT received, to 15 weeks if not. ]
    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. )

  2. Phase II: Progression-free Survival (Including Phase I Patients at Same Dose) [ 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. ]
    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. )



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00068250


Locations
United States, Florida
Integrated Community Oncology Network
Jacksonville Beach, Florida, United States, 32250
Baptist Cancer Institute - Jacksonville
Jacksonville, Florida, United States, 32207
Integrated Community Oncology Network at Southside Cancer Center
Jacksonville, Florida, United States, 32207
Baptist Medical Center South
Jacksonville, Florida, United States, 32258
Integrated Community Oncology Network - Orange Park
Orange Park, Florida, United States, 32073
Florida Cancer Center - Palatka
Palatka, Florida, United States, 32177
Flagler Cancer Center
Saint Augustine, Florida, United States, 32086
United States, Michigan
Borgess Medical Center
Kalamazoo, Michigan, United States, 49001
West Michigan Cancer Center
Kalamazoo, Michigan, United States, 49007-3731
Bronson Methodist Hospital
Kalamazoo, Michigan, United States, 49007
United States, Missouri
CCOP - Kansas City
Kansas City, Missouri, United States, 64131
Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
Saint Louis, Missouri, United States, 63110
United States, Nevada
CCOP - Nevada Cancer Research Foundation
Las Vegas, Nevada, United States, 89106
United States, New Jersey
John F. Kennedy Medical Center
Edison, New Jersey, United States, 08818
United States, Ohio
Cleveland Clinic Taussig Cancer Center
Cleveland, Ohio, United States, 44195
United States, Oregon
Providence Milwaukie Hospital
Milwaukie, Oregon, United States, 97222
Providence Cancer Center at Providence Portland Medical Center
Portland, Oregon, United States, 97213-2967
CCOP - Columbia River Oncology Program
Portland, Oregon, United States, 97225
Providence St. Vincent Medical Center
Portland, Oregon, United States, 97225
United States, Pennsylvania
Kimmel Cancer Center at Thomas Jefferson University - Philadelphia
Philadelphia, Pennsylvania, United States, 19107-5541
United States, South Carolina
Hollings Cancer Center at Medical University of South Carolina
Charleston, South Carolina, United States, 29425
United States, Utah
Jon and Karen Huntsman Cancer Center at Intermountain Medical Center
Murray, Utah, United States, 84157
Utah Valley Regional Medical Center - Provo
Provo, Utah, United States, 84604
United States, Washington
Southwest Washington Medical Center Cancer Center
Vancouver, Washington, United States, 98668
United States, Wisconsin
Community Memorial Hospital Cancer Care Center
Menomonee Falls, Wisconsin, United States, 53051
Medical College of Wisconsin Cancer Center
Milwaukee, Wisconsin, United States, 53226
Sponsors and Collaborators
Radiation Therapy Oncology Group
National Cancer Institute (NCI)
NRG Oncology
Investigators
Study Chair: Jon Glass, MD Sidney Kimmel Cancer Center at Thomas Jefferson University

Publications of Results:
Responsible Party: Radiation Therapy Oncology Group
ClinicalTrials.gov Identifier: NCT00068250     History of Changes
Other Study ID Numbers: RTOG-0227
CDR0000301563
First Posted: September 11, 2003    Key Record Dates
Results First Posted: February 7, 2018
Last Update Posted: February 7, 2018
Last Verified: February 2018

Keywords provided by Radiation Therapy Oncology Group:
primary central nervous system non-Hodgkin lymphoma
primary central nervous system Hodgkin lymphoma

Additional relevant MeSH terms:
Lymphoma
Nervous System Neoplasms
Central Nervous System Neoplasms
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Neoplasms by Site
Nervous System Diseases
Temozolomide
Rituximab
Methotrexate
Dacarbazine
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Nucleic Acid Synthesis Inhibitors