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

NCT00068250 | Completed Phase 1 Results DMC

• 2 other identifiers: RTOG-0227CDR0000301563
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 26

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.

Conditions

Brain and Central Nervous System Tumors; Lymphoma

Keywords

primary central nervous system non-Hodgkin lymphoma; primary central nervous system Hodgkin lymphoma

Outcome Measures

Primary Outcomes (2)

• 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.

• 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 Outcomes (2)

• Phase II: Pre-irradiation Chemotherapy Tumor Response Rate (Including Phase I Patients at Same Dose)

  From start of treatment to 10 weeks if RT received, to 15 weeks if not.

• Phase II: Progression-free Survival (Including Phase I Patients at Same Dose)

  Analysis occured after all patients have been on study for 2 years. Maximum follow-up at time of analysis was 8.5 years.

Study Arms (4)

Phase I: Temozolomide 100 mg

EXPERIMENTAL

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

Drug: rituximab; Drug: methotrexate; Drug: temozolomide 100 mg/m^2; Radiation: radiation therapy; Drug: post-radiation therapy temozolomide

Phase I: Temozolomide 150 mg

EXPERIMENTAL

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

Drug: rituximab; Drug: methotrexate; Drug: temozolomide 150 mg/m^2; Radiation: radiation therapy; Drug: post-radiation therapy temozolomide

Phase I: Temozolomide 200 mg

EXPERIMENTAL

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

Drug: rituximab; Drug: methotrexate; Drug: temozolomide 200 mg/m^2; Radiation: radiation therapy; Drug: post-radiation therapy temozolomide

Phase II: Temozolomide 100 mg

EXPERIMENTAL

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

Drug: rituximab; Drug: methotrexate; Drug: temozolomide 100 mg/m^2; Radiation: radiation therapy; Drug: post-radiation therapy temozolomide

Interventions

rituximab DRUG

375 mg/m2, intravenously three days prior to the first cycle of methotrexate

Phase I: Temozolomide 100 mg; Phase I: Temozolomide 150 mg; Phase I: Temozolomide 200 mg; Phase II: Temozolomide 100 mg

methotrexate DRUG

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.

Phase I: Temozolomide 100 mg; Phase I: Temozolomide 150 mg; Phase I: Temozolomide 200 mg; Phase II: Temozolomide 100 mg

temozolomide 100 mg/m^2 DRUG

Temozolomide 100 mg/m\^2 by mouth per day for five days on weeks 4 and 8.

Phase I: Temozolomide 100 mg; Phase II: Temozolomide 100 mg

temozolomide 150 mg/m^2 DRUG

Temozolomide 150 mg/m\^2 by mouth per day for five days on weeks 4 and 8.

Phase I: Temozolomide 150 mg

temozolomide 200 mg/m^2 DRUG

Temozolomide 200 mg/m\^2 per day by mouth for five days on weeks 4 and 8.

Phase I: Temozolomide 200 mg

radiation therapy RADIATION

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.

Also known as: radiotherapy

Phase I: Temozolomide 100 mg; Phase I: Temozolomide 150 mg; Phase I: Temozolomide 200 mg; Phase II: Temozolomide 100 mg

post-radiation therapy temozolomide DRUG

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.

Phase I: Temozolomide 100 mg; Phase I: Temozolomide 150 mg; Phase I: Temozolomide 200 mg; Phase II: Temozolomide 100 mg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Radiation Therapy Oncology Group: lead
• National Cancer Institute (NCI): collaborator
• NRG Oncology: collaborator

Study Sites (26)

Baptist Cancer Institute - Jacksonville

Jacksonville, Florida, 32207, United States

Location

Integrated Community Oncology Network at Southside Cancer Center

Jacksonville, Florida, 32207, United States

Location

Baptist Medical Center South

Jacksonville, Florida, 32258, United States

Location

Integrated Community Oncology Network

Jacksonville Beach, Florida, 32250, United States

Location

Integrated Community Oncology Network - Orange Park

Orange Park, Florida, 32073, United States

Location

Florida Cancer Center - Palatka

Palatka, Florida, 32177, United States

Location

Flagler Cancer Center

Saint Augustine, Florida, 32086, United States

Location

Borgess Medical Center

Kalamazoo, Michigan, 49001, United States

Location

West Michigan Cancer Center

Kalamazoo, Michigan, 49007-3731, United States

Location

Bronson Methodist Hospital

Kalamazoo, Michigan, 49007, United States

Location

CCOP - Kansas City

Kansas City, Missouri, 64131, United States

Location

Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis

St Louis, Missouri, 63110, United States

Location

CCOP - Nevada Cancer Research Foundation

Las Vegas, Nevada, 89106, United States

Location

John F. Kennedy Medical Center

Edison, New Jersey, 08818, United States

Location

Cleveland Clinic Taussig Cancer Center

Cleveland, Ohio, 44195, United States

Location

Providence Milwaukie Hospital

Milwaukie, Oregon, 97222, United States

Location

Providence Cancer Center at Providence Portland Medical Center

Portland, Oregon, 97213-2967, United States

Location

CCOP - Columbia River Oncology Program

Portland, Oregon, 97225, United States

Location

Providence St. Vincent Medical Center

Portland, Oregon, 97225, United States

Location

Kimmel Cancer Center at Thomas Jefferson University - Philadelphia

Philadelphia, Pennsylvania, 19107-5541, United States

Location

Hollings Cancer Center at Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

Jon and Karen Huntsman Cancer Center at Intermountain Medical Center

Murray, Utah, 84157, United States

Location

Utah Valley Regional Medical Center - Provo

Provo, Utah, 84604, United States

Location

Southwest Washington Medical Center Cancer Center

Vancouver, Washington, 98668, United States

Location

Community Memorial Hospital Cancer Care Center

Menomonee Falls, Wisconsin, 53051, United States

Location

Medical College of Wisconsin Cancer Center

Milwaukee, Wisconsin, 53226, United States

Location

Related 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, 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.

  PMID: 27022122 RESULT

MeSH Terms

Conditions

Central Nervous System Neoplasms; Lymphoma

Interventions

Rituximab; Methotrexate; Temozolomide; Radiotherapy

Condition Hierarchy (Ancestors)

Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Nervous System Diseases; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Therapeutics

Limitations and Caveats

The 200 mg/m\^2 treatment arm in the phase I component of the study did not open. Outcome measures are categorized as the phase I or phase II study component, but phase I patients at corresponding dose level are included in the phase II analyses.

Results Point of Contact

• Title: Wendy Seiferheld, M.S.
• Organization: NRG Oncology

seiferheldw@nrgoncology.org

Study Officials

• Jon Glass, MD

  Sidney Kimmel Cancer Center at Thomas Jefferson University

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 10, 2003
• First Posted: September 11, 2003
• Study Start: July 1, 2003
• Primary Completion: December 1, 2016
• Study Completion: December 1, 2016
• Last Updated: February 7, 2018
• Results First Posted: February 7, 2018

Record last verified: 2018-02

Locations

US (26)