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

• Sponsor: Radiation Therapy Oncology Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT00068250
• Collaborator: National Cancer Institute (NCI) (NIH), NRG Oncology (Other)
• Enrollment: 60
• Locations: 26
• Arms: 4
• Duration (Months): 161.1
• Patients Per Site: 2.3
• Patients Per Site Per Month: 0

Study Details

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.

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 Design

• Study Type: Interventional
• 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: Jul 1, 2003
• Actual Primary Completion Date: Dec 1, 2016
• Actual Study Completion Date: Dec 1, 2016

Arms and Interventions

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 Names: 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 Names: 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 Names: 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 Names: 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.

Outcome Measures

Primary Outcome Measures

1. Number of Phase I Participants Experiencing Toxicity [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) [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) [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) [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. )

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Integrated Community Oncology Network	Jacksonville Beach	Florida	United States	32250
2	Baptist Cancer Institute - Jacksonville	Jacksonville	Florida	United States	32207
3	Integrated Community Oncology Network at Southside Cancer Center	Jacksonville	Florida	United States	32207
4	Baptist Medical Center South	Jacksonville	Florida	United States	32258
5	Integrated Community Oncology Network - Orange Park	Orange Park	Florida	United States	32073
6	Florida Cancer Center - Palatka	Palatka	Florida	United States	32177
7	Flagler Cancer Center	Saint Augustine	Florida	United States	32086
8	Borgess Medical Center	Kalamazoo	Michigan	United States	49001
9	West Michigan Cancer Center	Kalamazoo	Michigan	United States	49007-3731
10	Bronson Methodist Hospital	Kalamazoo	Michigan	United States	49007
11	CCOP - Kansas City	Kansas City	Missouri	United States	64131
12	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	Saint Louis	Missouri	United States	63110
13	CCOP - Nevada Cancer Research Foundation	Las Vegas	Nevada	United States	89106
14	John F. Kennedy Medical Center	Edison	New Jersey	United States	08818
15	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio	United States	44195
16	Providence Milwaukie Hospital	Milwaukie	Oregon	United States	97222
17	Providence Cancer Center at Providence Portland Medical Center	Portland	Oregon	United States	97213-2967
18	CCOP - Columbia River Oncology Program	Portland	Oregon	United States	97225
19	Providence St. Vincent Medical Center	Portland	Oregon	United States	97225
20	Kimmel Cancer Center at Thomas Jefferson University - Philadelphia	Philadelphia	Pennsylvania	United States	19107-5541
21	Hollings Cancer Center at Medical University of South Carolina	Charleston	South Carolina	United States	29425
22	Jon and Karen Huntsman Cancer Center at Intermountain Medical Center	Murray	Utah	United States	84157
23	Utah Valley Regional Medical Center - Provo	Provo	Utah	United States	84604
24	Southwest Washington Medical Center Cancer Center	Vancouver	Washington	United States	98668
25	Community Memorial Hospital Cancer Care Center	Menomonee Falls	Wisconsin	United States	53051
26	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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Radiation Therapy Oncology Group
• ClinicalTrials.gov Identifier: NCT00068250
• Other Study ID Numbers: RTOG-0227; CDR0000301563
• First Posted: Sep 11, 2003
• Last Update Posted: Feb 7, 2018
• Last Verified: Feb 1, 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; Rituximab; Methotrexate; Temozolomide

Study Results

Participant Flow

Arm/Group Title	Phase I: Temozolomide 100 mg	Phase I: Temozolomide 150 mg	Phase I: Temozolomide 200 mg	Phase II: Temozolomide 100 mg
Arm/Group 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.
Period Title: Phase I: Dose Level 1
STARTED	6	0	0	0
COMPLETED	6	0	0	0
NOT COMPLETED	0	0	0	0
Period Title: Phase I: Dose Level 1
STARTED	0	7	0	0
COMPLETED	0	6	0	0
NOT COMPLETED	0	1	0	0
Period Title: Phase I: Dose Level 1
STARTED	0	0	0	47
COMPLETED	0	0	0	47
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Phase I: Temozolomide 100 mg	Phase I: Temozolomide 150 mg	Phase II: Temozolomide 100 mg	Total
Arm/Group 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 100 mg/m^2, followed by radiation therapy, then post-radiation therapy temozolomide 200 mg/m^2.	Total of all reporting groups
Overall Participants	6	6	47	59
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	57	62	57	57
Sex: Female, Male (Count of Participants)
Female	4 66.7%	2 33.3%	24 51.1%	30 50.8%
Male	2 33.3%	4 66.7%	23 48.9%	29 49.2%

Outcome Measures

1. Primary Outcome

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.

Outcome Measure Data

Analysis Population Description

Eligible patients on Phase I arms who started study treatment

Arm/Group Title	Phase I: Temozolomide 100mg	Phase I: Temozolomide150 mg
Arm/Group Description	Phase I: Temozolomide 100mg	Phase I: Temozolomide 150 mg
Measure Participants	6	6
Count of Participants [Participants]	1 16.7%	3 50%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase I: Temozolomide 100mg, Phase I: Temozolomide150 mg
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Other Statistical Analysis		Dose escalation followed the standard 3+3 design, although up to six patients could be accrued per dose level before suspending accrual for toxicity evaluation. If none of the first three patients (0/3), or one of the first three and none of the second three (1/3 and 0/3), experience a DLT, then the current dose level would be considered acceptable, and the next dose opened. Otherwise, the current dose level would be considered too toxic. The highest dose achieved with an acceptable level of toxicity was to considered the Maximum Tolerable Dose (MTD). If at any time a grade 5 toxicity was observed, accrual will be suspended, and the Study Chair would review the event. Furthermore, if the cumulative incidence (obtained by time to event analysis), at any time, of combined acute/late DLTs estimated the toxicity rate to be greater than 30% at any dose level, then the Executive Committee will be notified, and the committee would determine whether to stop accrual.

2. Primary Outcome

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.

Outcome Measure Data

Analysis Population Description

Eligible patients on Temozolomide 100 mg arms who started study treatment

Arm/Group Title	Combined Temozolomide 100mg Arms
Arm/Group Description	Phase I: Temozolomide 100mg and Phase II: Temozolomide 100 mg
Measure Participants	53
Number (95% Confidence Interval) [percentage of participants]	80.8 1346.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase I: Temozolomide 100mg
	Comments	Null hypothesis: Two-year survival rate <= 64%; Alternative hypothesis: Two-year survival rate > 64%. The fixed survival rate for comparison comes from Radiation Therapy Oncology Group (RTOG) trial 9310. (RTOG 9310 does not fall within ClinicalTrials.gov registration/reporting requirements.)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments
	Method	One-sample z-test
	Comments

3. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

Eligible patients on Temozolomide 100 mg arms who started study treatment and have scans for central review

Arm/Group Title	Combined Temozolomide 100mg Arms
Arm/Group Description	Phase I: Temozolomide 100mg and Phase II: Temozolomide 100 mg
Measure Participants	35
Complete Response	18 300%
Partial Response	12 200%
Progressive Disease	2 33.3%
Not evaluable	3 50%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase I: Temozolomide 100mg
	Comments	RTOG 93-10 reported a pre-irradiation chemotherapy complete response rate of 59%. A chi-square test with a 0.20 one-sided significance level provides 81% power to detect the difference between a null hypothesis complete response rate of 59% and the alternative rate of 71% (a 20% increase) for the planned sample size of 52 patients.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.82
	Comments
	Method	Chi-squared
	Comments	One-sample test of proportions

4. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

Eligible patients on Temozolomide 100 mg arms who started study treatment

Arm/Group Title	Combined Temozolomide 100mg Arms
Arm/Group Description	Phase I: Temozolomide 100mg and Phase II: Temozolomide 100 mg
Measure Participants	53
Median (95% Confidence Interval) [years]	5.4

Adverse Events

Adverse Event Reporting Description	Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Arm/Group Title	Phase I: Temozolomide 100 mg		Phase I: Temozolomide 150 mg		Phase II: Temozolomide 100 mg
Arm/Group 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 100 mg/m^2, followed by radiation therapy, then post-radiation therapy temozolomide 200 mg/m^2.
All Cause Mortality
	Phase I: Temozolomide 100 mg		Phase I: Temozolomide 150 mg		Phase II: Temozolomide 100 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Phase I: Temozolomide 100 mg		Phase I: Temozolomide 150 mg		Phase II: Temozolomide 100 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/6 (50%)		4/6 (66.7%)		16/47 (34%)
Blood and lymphatic system disorders
Febrile neutropenia	0/6 (0%)		0/6 (0%)		1/47 (2.1%)
Hemoglobin decreased	0/6 (0%)		0/6 (0%)		1/47 (2.1%)
Gastrointestinal disorders
Vomiting NOS	0/6 (0%)		0/6 (0%)		1/47 (2.1%)
General disorders
Fatigue	0/6 (0%)		0/6 (0%)		1/47 (2.1%)
Late RT Toxicity:Other NOS	0/6 (0%)		0/6 (0%)		1/47 (2.1%)
Pain-other	0/6 (0%)		1/6 (16.7%)		0/47 (0%)
Investigations
Alanine aminotransferase increased	0/6 (0%)		1/6 (16.7%)		0/47 (0%)
Aspartate aminotransferase increased	0/6 (0%)		1/6 (16.7%)		0/47 (0%)
Leukopenia NOS	2/6 (33.3%)		1/6 (16.7%)		5/47 (10.6%)
Neutropenia	3/6 (50%)		2/6 (33.3%)		5/47 (10.6%)
Platelet count decreased	1/6 (16.7%)		1/6 (16.7%)		7/47 (14.9%)
Metabolism and nutrition disorders
Alkalosis NOS	0/6 (0%)		0/6 (0%)		1/47 (2.1%)
Hyperglycemia NOS	0/6 (0%)		0/6 (0%)		2/47 (4.3%)
Nervous system disorders
Ataxia NEC	0/6 (0%)		0/6 (0%)		1/47 (2.1%)
Convulsions NOS	0/6 (0%)		1/6 (16.7%)		0/47 (0%)
Encephalopathy NOS	0/6 (0%)		0/6 (0%)		1/47 (2.1%)
Headache NOS	0/6 (0%)		0/6 (0%)		1/47 (2.1%)
Learning disorder NOS	0/6 (0%)		0/6 (0%)		1/47 (2.1%)
Peripheral motor neuropathy	0/6 (0%)		0/6 (0%)		1/47 (2.1%)
Speech disorder NEC	0/6 (0%)		0/6 (0%)		2/47 (4.3%)
Renal and urinary disorders
Renal failure NOS	1/6 (16.7%)		0/6 (0%)		0/47 (0%)
Vascular disorders
Thrombosis NOS	0/6 (0%)		0/6 (0%)		1/47 (2.1%)
Other (Not Including Serious) Adverse Events
	Phase I: Temozolomide 100 mg		Phase I: Temozolomide 150 mg		Phase II: Temozolomide 100 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/6 (100%)		6/6 (100%)		47/47 (100%)
Blood and lymphatic system disorders
Hematologic-Other	0/6 (0%)		1/6 (16.7%)		2/47 (4.3%)
Hemoglobin decreased	5/6 (83.3%)		6/6 (100%)		39/47 (83%)
Hemolysis NOS	0/6 (0%)		1/6 (16.7%)		0/47 (0%)
Platelet transfusion	2/6 (33.3%)		0/6 (0%)		3/47 (6.4%)
Cardiac disorders
Arrhythmia NOS	0/6 (0%)		1/6 (16.7%)		2/47 (4.3%)
Edema NOS	3/6 (50%)		2/6 (33.3%)		12/47 (25.5%)
Endocrine disorders
Cushingoid	1/6 (16.7%)		0/6 (0%)		1/47 (2.1%)
Eye disorders
Cataract NEC	1/6 (16.7%)		0/6 (0%)		1/47 (2.1%)
Diplopia	0/6 (0%)		1/6 (16.7%)		5/47 (10.6%)
Dry eye NEC	1/6 (16.7%)		0/6 (0%)		3/47 (6.4%)
Late RT Toxicity:Eye NOS	2/6 (33.3%)		0/6 (0%)		5/47 (10.6%)
Ocular-Other	1/6 (16.7%)		0/6 (0%)		5/47 (10.6%)
Vision blurred	1/6 (16.7%)		1/6 (16.7%)		15/47 (31.9%)
Gastrointestinal disorders
Constipation	3/6 (50%)		1/6 (16.7%)		11/47 (23.4%)
Diarrhea NOS	1/6 (16.7%)		2/6 (33.3%)		11/47 (23.4%)
Esophageal spasm	0/6 (0%)		1/6 (16.7%)		1/47 (2.1%)
Esophagitis NOS	1/6 (16.7%)		0/6 (0%)		7/47 (14.9%)
Nausea	5/6 (83.3%)		4/6 (66.7%)		32/47 (68.1%)
Stomatitis	2/6 (33.3%)		1/6 (16.7%)		11/47 (23.4%)
Vomiting NOS	5/6 (83.3%)		1/6 (16.7%)		25/47 (53.2%)
General disorders
Fatigue	6/6 (100%)		6/6 (100%)		42/47 (89.4%)
Late RT Toxicity:Other NOS	2/6 (33.3%)		1/6 (16.7%)		10/47 (21.3%)
Pain-other	0/6 (0%)		2/6 (33.3%)		16/47 (34%)
Rigors	1/6 (16.7%)		0/6 (0%)		5/47 (10.6%)
Hepatobiliary disorders
Hepatic-Other	2/6 (33.3%)		1/6 (16.7%)		2/47 (4.3%)
Immune system disorders
Allergy-Other	3/6 (50%)		0/6 (0%)		0/47 (0%)
Infections and infestations
Infection NOS	2/6 (33.3%)		0/6 (0%)		9/47 (19.1%)
Infection with grade 3 or 4 neutropenia	0/6 (0%)		1/6 (16.7%)		5/47 (10.6%)
Injury, poisoning and procedural complications
Dermatitis radiation NOS	3/6 (50%)		3/6 (50%)		17/47 (36.2%)
Ecchymosis	0/6 (0%)		1/6 (16.7%)		5/47 (10.6%)
Late RT Toxicity:Skin(within RT field)NOS	3/6 (50%)		0/6 (0%)		9/47 (19.1%)
Operative injury of vein/artery	0/6 (0%)		1/6 (16.7%)		0/47 (0%)
Investigations
Alanine aminotransferase increased	5/6 (83.3%)		3/6 (50%)		27/47 (57.4%)
Aspartate aminotransferase increased	4/6 (66.7%)		2/6 (33.3%)		24/47 (51.1%)
Blood alkaline phosphatase NOS increased	2/6 (33.3%)		1/6 (16.7%)		6/47 (12.8%)
Blood bilirubin increased	0/6 (0%)		1/6 (16.7%)		6/47 (12.8%)
Blood creatinine increased	3/6 (50%)		1/6 (16.7%)		15/47 (31.9%)
Gamma-glutamyltransferase increased	1/6 (16.7%)		1/6 (16.7%)		1/47 (2.1%)
Leukopenia NOS	4/6 (66.7%)		5/6 (83.3%)		26/47 (55.3%)
Lymphopenia	1/6 (16.7%)		2/6 (33.3%)		20/47 (42.6%)
Metabolic-Other	1/6 (16.7%)		1/6 (16.7%)		5/47 (10.6%)
Neutropenia	2/6 (33.3%)		3/6 (50%)		19/47 (40.4%)
Platelet count decreased	4/6 (66.7%)		1/6 (16.7%)		30/47 (63.8%)
Prothrombin time prolonged	0/6 (0%)		1/6 (16.7%)		2/47 (4.3%)
Weight decreased	2/6 (33.3%)		3/6 (50%)		10/47 (21.3%)
Weight increased	1/6 (16.7%)		0/6 (0%)		6/47 (12.8%)
Metabolism and nutrition disorders
Anorexia	3/6 (50%)		3/6 (50%)		17/47 (36.2%)
Blood albumin decreased	2/6 (33.3%)		0/6 (0%)		5/47 (10.6%)
Blood bicarbonate decreased	1/6 (16.7%)		0/6 (0%)		1/47 (2.1%)
Blood magnesium decreased	0/6 (0%)		2/6 (33.3%)		1/47 (2.1%)
Dehydration	1/6 (16.7%)		0/6 (0%)		5/47 (10.6%)
Hyperglycemia NOS	2/6 (33.3%)		2/6 (33.3%)		12/47 (25.5%)
Hyperkalemia	0/6 (0%)		1/6 (16.7%)		5/47 (10.6%)
Hypernatremia	1/6 (16.7%)		0/6 (0%)		4/47 (8.5%)
Hyperuricemia	0/6 (0%)		1/6 (16.7%)		0/47 (0%)
Hypocalcemia	5/6 (83.3%)		4/6 (66.7%)		26/47 (55.3%)
Hypoglycaemia NOS	0/6 (0%)		1/6 (16.7%)		4/47 (8.5%)
Hypokalemia	1/6 (16.7%)		1/6 (16.7%)		14/47 (29.8%)
Hyponatremia	1/6 (16.7%)		1/6 (16.7%)		8/47 (17%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/6 (16.7%)		1/6 (16.7%)		6/47 (12.8%)
Bone pain	0/6 (0%)		1/6 (16.7%)		0/47 (0%)
Joint, muscle, or bone-Other	0/6 (0%)		1/6 (16.7%)		3/47 (6.4%)
Muscle weakness NOS	2/6 (33.3%)		1/6 (16.7%)		10/47 (21.3%)
Nervous system disorders
Amnesia NEC	2/6 (33.3%)		2/6 (33.3%)		14/47 (29.8%)
Ataxia NEC	2/6 (33.3%)		2/6 (33.3%)		13/47 (27.7%)
Cerebral ischaemia	1/6 (16.7%)		0/6 (0%)		0/47 (0%)
Convulsions NOS	0/6 (0%)		1/6 (16.7%)		5/47 (10.6%)
Dizziness (exc vertigo)	0/6 (0%)		1/6 (16.7%)		7/47 (14.9%)
Headache NOS	4/6 (66.7%)		2/6 (33.3%)		30/47 (63.8%)
Late RT Toxicity:Brain NOS	2/6 (33.3%)		1/6 (16.7%)		5/47 (10.6%)
Late RT Toxicity:Encephalopathy NOS	0/6 (0%)		1/6 (16.7%)		2/47 (4.3%)
Neuralgia NOS	0/6 (0%)		1/6 (16.7%)		7/47 (14.9%)
Neurologic-Other	1/6 (16.7%)		1/6 (16.7%)		3/47 (6.4%)
Peripheral motor neuropathy	3/6 (50%)		3/6 (50%)		15/47 (31.9%)
Peripheral sensory neuropathy	3/6 (50%)		2/6 (33.3%)		10/47 (21.3%)
Speech disorder NEC	3/6 (50%)		0/6 (0%)		6/47 (12.8%)
Taste disturbance	3/6 (50%)		0/6 (0%)		14/47 (29.8%)
Tremor NEC	1/6 (16.7%)		0/6 (0%)		0/47 (0%)
Psychiatric disorders
Anxiety NEC	1/6 (16.7%)		1/6 (16.7%)		9/47 (19.1%)
Confusion	0/6 (0%)		1/6 (16.7%)		9/47 (19.1%)
Depression NEC	2/6 (33.3%)		2/6 (33.3%)		9/47 (19.1%)
Insomnia NEC	2/6 (33.3%)		0/6 (0%)		10/47 (21.3%)
Renal and urinary disorders
Renal/GU-Other	1/6 (16.7%)		1/6 (16.7%)		1/47 (2.1%)
Urinary incontinence	2/6 (33.3%)		1/6 (16.7%)		5/47 (10.6%)
Respiratory, thoracic and mediastinal disorders
Cough	1/6 (16.7%)		0/6 (0%)		6/47 (12.8%)
Dysphonia	1/6 (16.7%)		0/6 (0%)		0/47 (0%)
Skin and subcutaneous tissue disorders
Alopecia	4/6 (66.7%)		2/6 (33.3%)		24/47 (51.1%)
Dermatitis exfoliative NOS	1/6 (16.7%)		1/6 (16.7%)		11/47 (23.4%)
Erythema multiforme	0/6 (0%)		1/6 (16.7%)		0/47 (0%)
Petechiae	0/6 (0%)		1/6 (16.7%)		1/47 (2.1%)
Pruritus NOS	1/6 (16.7%)		1/6 (16.7%)		0/47 (0%)
Skin-Other	1/6 (16.7%)		0/6 (0%)		2/47 (4.3%)
Vascular disorders
Hypertension NOS	3/6 (50%)		0/6 (0%)		6/47 (12.8%)
Thrombosis NOS	1/6 (16.7%)		0/6 (0%)		5/47 (10.6%)

Limitations/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.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

PI's are required to abide by the sponsor's publication guidelines which require review by coauthors and subsequent review and approval by the sponsor.