Temozolomide Alone or in Combination With Thalidomide and/or Isotretinoin and/or Celecoxib in Treating Patients Who Have Undergone Radiation Therapy for Glioblastoma Multiforme

Sponsor

M.D. Anderson Cancer Center (Other)

Overall Status

Completed

CT.gov ID

NCT00112502

Collaborator

National Cancer Institute (NCI) (NIH)

178

Enrollment

Locations

Arms

108

Duration (Months)

14.8

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Thalidomide may stop the growth of glioblastoma multiforme by blocking blood flow to the tumor. Isotretinoin may help cells that are involved in the body's immune response to work better. Celecoxib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known which temozolomide-containing regimen is more effective in treating glioblastoma multiforme.

PURPOSE: This randomized phase II trial is studying eight different temozolomide-containing regimens to compare how well they work in treating patients who have undergone radiation therapy for glioblastoma multiforme.

Condition or Disease	Intervention/Treatment	Phase
Brain and Central Nervous System Tumors Glioblastoma Multiforme	Drug: Celecoxib Drug: Isotretinoin Drug: Temozolomide Drug: Thalidomide	Phase 2

Detailed Description

OBJECTIVES:

Compare the efficacy of adjuvant temozolomide (TMZ) alone or in combination with thalidomide and/or isotretinoin and/or celecoxib, in terms of 6-month progression-free survival, in patients who have undergone radiotherapy for supratentorial glioblastoma multiforme.
Compare the toxicity of these regimens in these patients.

OUTLINE: This is a randomized, multicenter study. Patients are randomized to 1 of 8 treatment arms.

Arm I: Patients receive oral temozolomide once daily on days 1-7 and 15-21.
Arm II: Patients receive temozolomide as in arm I and oral thalidomide once daily on days 1-28.
Arm III: Patients receive temozolomide as in arm I and oral isotretinoin twice daily on days 1-21.
Arm IV: Patients receive temozolomide as in arm I and oral celecoxib twice daily on days 1-28.
Arm V: Patients receive temozolomide as in arm I, thalidomide as in arm II, and isotretinoin as in arm III.
Arm VI: Patients receive temozolomide as in arm I, thalidomide as in arm II, and celecoxib as in arm IV.
Arm VII: Patients receive temozolomide as in arm I, isotretinoin as in arm III, and celecoxib as in arm IV.
Arm VIII: Patients receive temozolomide as in arm I, thalidomide as in arm II, isotretinoin as in arm III, and celecoxib as in arm IV.

In all arms, treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Patient may receive additional courses of therapy at the discretion of the treating physician.

After completion of study treatment, patients are followed for at least 30 days and then every 3 months thereafter.

PROJECTED ACCRUAL: A total of 180 patients will be accrued for this study.

Study Design

Study Type:

Interventional

Actual Enrollment :

178 participants

Allocation:

Randomized

Intervention Model:

Factorial Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

Official Title:

A Randomized, Factorial-Design, Phase II Trial of Temozolomide Alone and in Combination With Possible Permutations of Thalidomide, Isotretinoin and/or Celecoxib as Post-Radiation Adjuvant Therapy of Glioblastoma Multiforme

Study Start Date :

Sep 1, 2005

Actual Primary Completion Date :

Sep 1, 2014

Actual Study Completion Date :

Sep 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm I: TMZ Oral Temozolomide (TMZ) 150 mg/m^2 once daily on days 1-7 and 15-21.	Drug: Temozolomide 150 mg/m2 orally daily, 7 days on treatment, 7 days off. Other Names: Temodar
Experimental: Arm II: TMZ + Thalidomide Temozolomide as in arm I and oral Thalidomide (Thal) once daily on days 1-28 (starting dose 200 mg).	Drug: Temozolomide 150 mg/m2 orally daily, 7 days on treatment, 7 days off. Other Names: Temodar Drug: Thalidomide 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved) Other Names: Thalomid
Experimental: Arm III: TMZ + Isotretinoin Temozolomide as in Arm I and oral Isotretinoin 40 mg/m^2 twice daily on days 1-21.	Drug: Isotretinoin 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle. Other Names: Accutane 13-Cis-Retinoic Acid Drug: Temozolomide 150 mg/m2 orally daily, 7 days on treatment, 7 days off. Other Names: Temodar
Experimental: Arm IV: TMZ + Celecoxib Temozolomide as in arm I and oral Celecoxib 400 mg twice daily on days 1-28.	Drug: Celecoxib 400 mg orally twice a day continuous dosing Other Names: Celebrex Drug: Temozolomide 150 mg/m2 orally daily, 7 days on treatment, 7 days off. Other Names: Temodar
Experimental: Arm V: TMZ + Thalidomide + Isotretinoin Temozolomide as in arm I, Thalidomide as in arm II, and Isotretinoin as in arm III.	Drug: Isotretinoin 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle. Other Names: Accutane 13-Cis-Retinoic Acid Drug: Temozolomide 150 mg/m2 orally daily, 7 days on treatment, 7 days off. Other Names: Temodar Drug: Thalidomide 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved) Other Names: Thalomid
Experimental: Arm VI: TMZ + Thalidomide + Celecoxib Temozolomide as in Arm I, Thalidomide as in Arm II, and Celecoxib as in Arm IV.	Drug: Celecoxib 400 mg orally twice a day continuous dosing Other Names: Celebrex Drug: Temozolomide 150 mg/m2 orally daily, 7 days on treatment, 7 days off. Other Names: Temodar Drug: Thalidomide 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved) Other Names: Thalomid
Experimental: Arm VII: TMZ + Isotretinoin + Celecoxib Temozolomide as in Arm I, Isotretinoin as in Arm III, and Celecoxib as in Arm IV.	Drug: Celecoxib 400 mg orally twice a day continuous dosing Other Names: Celebrex Drug: Isotretinoin 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle. Other Names: Accutane 13-Cis-Retinoic Acid Drug: Temozolomide 150 mg/m2 orally daily, 7 days on treatment, 7 days off. Other Names: Temodar
Experimental: Arm VIII: TMZ + Thalidomide + Isotretinoin + Celecoxib Temozolomide as in Arm I, Thalidomide as in Arm II, Isotretinoin as in Arm III, and Celecoxib as in Arm IV.	Drug: Celecoxib 400 mg orally twice a day continuous dosing Other Names: Celebrex Drug: Isotretinoin 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle. Other Names: Accutane 13-Cis-Retinoic Acid Drug: Temozolomide 150 mg/m2 orally daily, 7 days on treatment, 7 days off. Other Names: Temodar Drug: Thalidomide 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved) Other Names: Thalomid

Outcome Measures

Primary Outcome Measures

Median Progression-Free Survival (PFS) Comparison of Thalidomide Arms Versus no Thalidomide Arms [Every 2 cycles (1 cycle = 28 days) from randomization until progression of disease, death or last follow-up, up to one year (12 study cycles).]
Thalidomide versus not Thalidomide analysis: Comparison of median PFS outcome of participants in arms II, VI, VII and VIII, versus participants in arms I, III, IV and V. Median PFS was estimated using the Kaplan-Meier method from time of randomization to time of progression, death, or last follow-up. Progression defined as 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).
Median Progression-Free Survival (PFS) Comparison of Celecoxib Arms Versus no Celecoxib Arms [Every 2 cycles (1 cycle = 28 days) from randomization until progression of disease, death or last follow-up.]
Celecoxib versus not Celecoxib analysis: We compared the median PFS outcome of participants in arms III, V, VI and VIII, versus participants in arms I, II, IV and VII. Median PFS was estimated using the Kaplan-Meier method from time of randomization to time of progression, death, or last follow-up. Progression defined as 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).
Median Progression-Free Survival (PFS) Comparison of Isotretinoin Arms Versus no Isotretinoin Arms [Every 2 cycles (1 cycle = 28 days) from randomization until progression of disease, death or last follow-up.]
Isotretinoin versus not Isotretinoin analysis: We compared the median PFS outcome of participants in arms IV, V, VII and VIII, versus participants in arms I, II, III and VI. Median PFS was estimated using the Kaplan-Meier method from time of randomization to time of progression, death, or last follow-up. Progression defined as 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).

Secondary Outcome Measures

Median Progression-Free Survival (PFS) Comparison of Doublet Versus Triplet Therapy [Every 2 cycles (1 cycle = 28 days) from randomization until progression of disease, death or last follow-up.]
Doublet (2 agents) versus Triplet (3 agents) therapy analysis: We compared the median PFS outcome of participants in arms II, III, IV, versus participants in arms V, VI and VII. Median PFS was estimated using the Kaplan-Meier method from time of randomization to time of progression, death, or last follow-up. Progression defined as 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).
Median Progression-Free Survival (PFS) of Individual Arms [Every 2 cycles (1 cycle = 28 days) from randomization until progression of disease, death or last follow-up.]
Median PFS was estimated using the Kaplan-Meier method from time of randomization to time of progression, death, or last follow-up. Progression defined as 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).
Median Overall Survival (OS) Comparison of Thalidomide Arms Versus no Thalidomide Arms [Every 3 months from randomization until progression of disease, death or last follow-up.]
Thalidomide versus not Thalidomide analysis: We compared the median OS outcome of participants in arms II, VI, VII and VIII, versus participants in arms I, III, IV and V. Median OS was estimated using the Kaplan-Meier method from time of randomization to time of progression, death, or last follow-up. Progression defined as 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).
Median Overall Survival (OS) Comparison of Celecoxib Arms Versus no Celecoxib Arms [Every 3 months from randomization until progression of disease, death or last follow-up.]
Celecoxib versus not Celecoxib analysis: We compared the median OS outcome of participants in arms III, V, VI and VIII, versus participants in arms I, II, IV and VII. Median OS was estimated using the Kaplan-Meier method from time of randomization to time of progression, death, or last follow-up. Progression defined as 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).
Median Overall Survival (OS) Comparison of Isotretinoin Arms Versus no Isotretinoin Arms [Every 3 months from randomization until progression of disease, death or last follow-up.]
Isotretinoin versus not Isotretinoin analysis: We compared the median OS outcome of participants in arms IV, V, VII and VIII, versus participants in arms I, II, III and VI. Median OS was estimated using the Kaplan-Meier method from time of randomization to time of progression, death, or last follow-up. Progression defined as 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).
Median Overall Survival (OS) Comparison of Doublet Versus Triplet Therapy [Every 3 months from randomization until progression of disease, death or last follow-up.]
Doublet (2 agents) versus Triplet (3 agents) therapy analysis: We compared the median OS outcome of participants in arms II, III, IV, versus participants in arms V, VI and VII. Median OS was estimated using the Kaplan-Meier method from time of randomization to time of progression, death, or last follow-up. Progression defined as 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).
Overall Survival of Individual Arms [Every 3 months from randomization until progression of disease, death or last follow-up.]
Overall Survival (OS) was estimated using the Kaplan-Meier method from time of randomization to time of progression, death, or last follow-up. Progression defined as 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Histologically confirmed supratentorial glioblastoma multiforme
Must have undergone a biopsy OR subtotal or gross total resection of the tumor
Must have completed post-operative (or post-biopsy) radiotherapy within the past 5 weeks
No progressive disease after radiotherapy

PATIENT CHARACTERISTICS:

Age

18 and over

Performance status

Karnofsky 60-100%

Life expectancy

Not specified

Hematopoietic

Absolute neutrophil count ≥ 1,500/mm^3
Platelet count ≥ 100,000/mm^3

Hepatic

Serum glutamate pyruvate transaminase (SGPT) < 2 times upper limit of normal (ULN)
Alkaline phosphatase < 2 times ULN
Bilirubin ≤ 1.5 mg/dL

Renal

blood urea nitrogen (BUN) ≤ 1.5 times ULN
Creatinine ≤ 1.5 times ULN

Immunologic

No history of allergic reactions attributed to compounds of similar chemical or biological composition to celecoxib or to sulfonamides
No asthma, urticaria, or allergic reactions to aspirin or other NSAIDs
No active infection

Gastrointestinal

No inflammatory bowel disease
No history of peptic ulcer disease
No gastrointestinal bleeding within past 3 months

Other

Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective double-method contraception during and for 2 months after study participation
Fertile female patients randomized to receive thalidomide must use effective double-method contraception for ≥ 4 weeks before, during, and ≥ 4 weeks after completion of study therapy
Fertile male patients randomized to receive thalidomide must use effective contraception during and for ≥ 4 weeks after completion of study therapy
No blood donation (for patients randomized to receive thalidomide)
No history of any other cancer except nonmelanoma skin cancer or carcinoma in situ of the cervix or cancer that is in complete remission and patient completed all therapy for that disease ≥ 3 years ago
No other disease that would obscure toxicity or dangerously alter drug metabolism (e.g., severe connective tissue disease)
No other serious medical illness

PRIOR CONCURRENT THERAPY:

Biologic therapy

Not specified

Chemotherapy

Prior temozolomide in combination with radiotherapy allowed
No other prior or concurrent chemotherapy

Endocrine therapy

Not specified

Radiotherapy

See Disease Characteristics
See Chemotherapy

Surgery

See Disease Characteristics
No concurrent surgery

Other

No other concurrent non-steroidal anti-inflammatory drugs (NSAIDs) (for patients randomized to receive celecoxib)
No other concurrent investigational drugs
No other concurrent anticancer therapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hembree Mercy Cancer Center at St. Edward Mercy Medical Center	Fort Smith	Arkansas	United States	72913
2	University of Texas MD Anderson Cancer Center at Orlando	Orlando	Florida	United States	32806-2134
3	CCOP - Atlanta Regional	Atlanta	Georgia	United States	30342-1701
4	CCOP - Central Illinois	Decatur	Illinois	United States	62526
5	CCOP - Wichita	Wichita	Kansas	United States	67214-3882
6	CCOP - Grand Rapids	Grand Rapids	Michigan	United States	49503
7	CCOP - Kalamazoo	Kalamazoo	Michigan	United States	49007-3731
8	CCOP - Kansas City	Kansas City	Missouri	United States	64131
9	Cancer Research for the Ozarks	Springfield	Missouri	United States	65804
10	Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210-1240
11	CCOP - Upstate Carolina	Spartanburg	South Carolina	United States	29303
12	University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030-4009

Sponsors and Collaborators

M.D. Anderson Cancer Center
National Cancer Institute (NCI)

Investigators

Study Chair: Marta Penas-Prado, MD, M.D. Anderson Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

University of Texas (UT) MD Anderson Cancer Center Official Website

Publications

None provided.

Responsible Party:

M.D. Anderson Cancer Center

ClinicalTrials.gov Identifier:

NCT00112502

Other Study ID Numbers:

2004-0662
MDA-ID-02586
NCI-6636
MDA-2004-0662
CDR0000432954
NCI-2009-00076

First Posted:

Jun 3, 2005

Last Update Posted:

Oct 18, 2021

Last Verified:

Sep 1, 2021

Keywords provided by M.D. Anderson Cancer Center

adult giant cell glioblastoma

adult gliosarcoma

adult glioblastoma

Additional relevant MeSH terms:

Glioblastoma

Nervous System Neoplasms

Central Nervous System Neoplasms

Study Results

Participant Flow

Recruitment Details	Recruitment Period: September 2005 to February 2011 from various hospitals and institutions representing the Community Clinical Oncology Program (CCOP). A total of 146 participants were accrued at MD Anderson Cancer Center and 32 at the remaining participating sites.
Pre-assignment Detail

Arm/Group Title	Arm I: TMZ	Arm II: TMZ + Thalidomide	Arm III: TMZ + Celecoxib	Arm IV: TMZ + Isotretinoin	Arm V: TMZ + Isotretinoin + Celecoxib	Arm VI: TMZ + Thalidomide + Celecoxib	Arm VII: TMZ + Thalidomide + Isotretinoin	Arm VIII: TMZ + Thalidomide + Isotretinoin + Celecoxib
Arm/Group Description	Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21.	Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Thalidomide: 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved).	Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Celecoxib: 400 mg orally twice a day continuous dosing.	Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Isotretinoin: 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle.	Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Celecoxib: 400 mg orally twice a day continuous dosing. Isotretinoin: 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle.	Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Celecoxib: 400 mg orally twice a day continuous dosing. Thalidomide: 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved).	Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Isotretinoin: 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle. Thalidomide: 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved).	Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Celecoxib: 400 mg orally twice a day continuous dosing. Isotretinoin: 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle. Thalidomide: 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved).
Period Title: Overall Study
STARTED	22	22	22	22	23	22	23	22
COMPLETED	22	21	21	18	21	17	20	15
NOT COMPLETED	0	1	1	4	2	5	3	7

Baseline Characteristics

Arm/Group Title	Arm I: TMZ	Arm II: TMZ + Thalidomide	Arm III: TMZ + Celecoxib	Arm IV: TMZ + Isotretinoin	Arm V: TMZ + Isotretinoin + Celecoxib	Arm VI: TMZ + Thalidomide + Celecoxib	Arm VII: TMZ + Thalidomide + Isotretinoin	Arm VIII: TMZ + Thalidomide + Isotretinoin + Celecoxib	Total
Arm/Group Description	Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21.	Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Thalidomide: 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved).	Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Celecoxib: 400 mg orally twice a day continuous dosing.	Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Isotretinoin: 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle.	Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Celecoxib: 400 mg orally twice a day continuous dosing. Isotretinoin: 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle.	Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Celecoxib: 400 mg orally twice a day continuous dosing. Thalidomide: 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved).	Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Isotretinoin: 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle. Thalidomide: 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved).	Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Celecoxib: 400 mg orally twice a day continuous dosing. Isotretinoin: 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle. Thalidomide: 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved).	Total of all reporting groups
Overall Participants	22	22	22	22	23	22	23	22	178
Age, Customized (participants) [Number]
<=19 years:	0 0%	0 0%	0 0%	1 4.5%	0 0%	0 0%	0 0%	0 0%	1 0.6%
Between 20 and 59 years:	17 77.3%	12 54.5%	17 77.3%	14 63.6%	20 87%	18 81.8%	15 65.2%	17 77.3%	130 73%
>=60 years:	5 22.7%	10 45.5%	5 22.7%	7 31.8%	3 13%	4 18.2%	8 34.8%	5 22.7%	47 26.4%
Sex: Female, Male (Count of Participants)
Female	7 31.8%	10 45.5%	5 22.7%	8 36.4%	4 17.4%	6 27.3%	6 26.1%	9 40.9%	55 30.9%
Male	15 68.2%	12 54.5%	17 77.3%	14 63.6%	19 82.6%	16 72.7%	17 73.9%	13 59.1%	123 69.1%
Region of Enrollment (participants) [Number]
United States	22 100%	22 100%	22 100%	22 100%	23 100%	22 100%	23 100%	22 100%	178 100%

Outcome Measures

1. Primary Outcome

Title	Median Progression-Free Survival (PFS) Comparison of Thalidomide Arms Versus no Thalidomide Arms
Description	Thalidomide versus not Thalidomide analysis: Comparison of median PFS outcome of participants in arms II, VI, VII and VIII, versus participants in arms I, III, IV and V. Median PFS was estimated using the Kaplan-Meier method from time of randomization to time of progression, death, or last follow-up. Progression defined as 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).
Time Frame	Every 2 cycles (1 cycle = 28 days) from randomization until progression of disease, death or last follow-up, up to one year (12 study cycles).

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Thalidomide: Arm II, Arm VI, Arm VII and Arm VIII	No Thalidomide: Arm I, Arm III, Arm IV and Arm V
Arm/Group Description	Arm II: TMZ + Thalidomide, Arm VI: TMZ + Thalidomide + Celecoxib, Arm VII: TMZ + Thalidomide + Isotretinoin and Arm VIII: TMZ + Thalidomide + Isotretinoin + Celecoxib Thalidomide: 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved). Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Celecoxib: 400 mg orally twice a day continuous dosing. Isotretinoin: 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle.	Arm I: TMZ, Arm III: TMZ + Celecoxib, Arm IV: TMZ + Isotretinoin and Arm V: TMZ + Isotretinoin + Celecoxib Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Celecoxib: 400 mg orally twice a day continuous dosing. Isotretinoin: 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle.
Measure Participants	70	85
Median (95% Confidence Interval) [months]	7.6	8.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Thalidomide: Arm II, Arm VI, Arm VII and Arm VIII, No Thalidomide: Arm I, Arm III, Arm IV and Arm V
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.2
	Confidence Interval	(2-Sided) 95% 0.8 to 1.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Median Progression-Free Survival (PFS) Comparison of Celecoxib Arms Versus no Celecoxib Arms
Description	Celecoxib versus not Celecoxib analysis: We compared the median PFS outcome of participants in arms III, V, VI and VIII, versus participants in arms I, II, IV and VII. Median PFS was estimated using the Kaplan-Meier method from time of randomization to time of progression, death, or last follow-up. Progression defined as 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).
Time Frame	Every 2 cycles (1 cycle = 28 days) from randomization until progression of disease, death or last follow-up.

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Celecoxib: Arm III, Arm V, Arm VI and Arm VIII	No Celecoxib: Arm I, Arm II, Arm IV and Arm VII
Arm/Group Description	Arm III: TMZ + Celecoxib, Arm V: TMZ + Isotretinoin + Celecoxib, Arm VI: TMZ + Thalidomide + Celecoxib and Arm VIII: TMZ + Thalidomide + Isotretinoin + Celecoxib Thalidomide: 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved). Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Celecoxib: 400 mg orally twice a day continuous dosing. Isotretinoin: 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle.	Arm I: TMZ, Arm II: TMZ + Thalidomide, Arm IV: TMZ + Isotretinoin and Arm VII: TMZ + Thalidomide + Isotretinoin. Thalidomide: 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved). Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Isotretinoin: 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle.
Measure Participants	74	81
Median (95% Confidence Interval) [months]	8.3	7.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Thalidomide: Arm II, Arm VI, Arm VII and Arm VIII, No Thalidomide: Arm I, Arm III, Arm IV and Arm V
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.8
	Confidence Interval	(2-Sided) 95% 0.6 to 1.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Median Progression-Free Survival (PFS) Comparison of Isotretinoin Arms Versus no Isotretinoin Arms
Description	Isotretinoin versus not Isotretinoin analysis: We compared the median PFS outcome of participants in arms IV, V, VII and VIII, versus participants in arms I, II, III and VI. Median PFS was estimated using the Kaplan-Meier method from time of randomization to time of progression, death, or last follow-up. Progression defined as 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).
Time Frame	Every 2 cycles (1 cycle = 28 days) from randomization until progression of disease, death or last follow-up.

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Isotretinoin: Arm IV, Arm V, Arm VII and Arm VIII	No Isotretinoin: Arm I, Arm II, Arm III and Arm VI
Arm/Group Description	Arm IV: TMZ + Isotretinoin, Arm V: TMZ + Isotretinoin + Celecoxib, Arm VII: TMZ + Thalidomide + Isotretinoin and Arm VIII: TMZ + Thalidomide + Isotretinoin + Celecoxib Thalidomide: 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved). Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Celecoxib: 400 mg orally twice a day continuous dosing. Isotretinoin: 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle.	Arm I: TMZ, Arm II: TMZ + Thalidomide, Arm III: TMZ + Celecoxib and Arm VI: TMZ + Thalidomide + Celecoxib Thalidomide: 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved). Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Celecoxib: 400 mg orally twice a day continuous dosing.
Measure Participants	74	81
Median (95% Confidence Interval) [months]	6.6	9.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Thalidomide: Arm II, Arm VI, Arm VII and Arm VIII, No Thalidomide: Arm I, Arm III, Arm IV and Arm V
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.3
	Confidence Interval	(2-Sided) 95% 0.9 to 1.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Median Progression-Free Survival (PFS) Comparison of Doublet Versus Triplet Therapy
Description	Doublet (2 agents) versus Triplet (3 agents) therapy analysis: We compared the median PFS outcome of participants in arms II, III, IV, versus participants in arms V, VI and VII. Median PFS was estimated using the Kaplan-Meier method from time of randomization to time of progression, death, or last follow-up. Progression defined as 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).
Time Frame	Every 2 cycles (1 cycle = 28 days) from randomization until progression of disease, death or last follow-up.

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Doublet (2 Agents): Arm II, Arm III and Arm IV	Triplet (3 Agents): Arm V, Arm VI and Arm VII
Arm/Group Description	Arm II: TMZ + Thalidomide, Arm III: TMZ + Celecoxib and Arm IV: TMZ + Isotretinoin Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Thalidomide: 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved). Celecoxib: 400 mg orally twice a day continuous dosing. Isotretinoin: 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle.	Arm V: TMZ + Isotretinoin + Celecoxib, Arm VI: TMZ + Thalidomide + Celecoxib and Arm VII: Thalidomide + Celecoxib + Isotretinoin Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Thalidomide: 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved). Celecoxib: 400 mg orally twice a day continuous dosing. Isotretinoin: 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle.
Measure Participants	60	58
Median (95% Confidence Interval) [months]	8.3	8.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Thalidomide: Arm II, Arm VI, Arm VII and Arm VIII, No Thalidomide: Arm I, Arm III, Arm IV and Arm V
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.9
	Confidence Interval	(2-Sided) 95% 0.6 to 1.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Median Progression-Free Survival (PFS) of Individual Arms
Description	Median PFS was estimated using the Kaplan-Meier method from time of randomization to time of progression, death, or last follow-up. Progression defined as 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).
Time Frame	Every 2 cycles (1 cycle = 28 days) from randomization until progression of disease, death or last follow-up.

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Arm I: TMZ	Arm II: TMZ + Thalidomide	Arm III: TMZ + Celecoxib	Arm IV: TMZ + Isotretinoin	Arm V: TMZ + Isotretinoin + Celecoxib	Arm VI: TMZ + Thalidomide + Celecoxib	Arm VII: TMZ + Thalidomide + Isotretinoin	Arm VIII: TMZ + Thalidomide + Isotretinoin + Celecoxib
Arm/Group Description	Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21.	Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Thalidomide: 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved).	Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Celecoxib: 400 mg orally twice a day continuous dosing.	Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Isotretinoin: 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle.	Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Celecoxib: 400 mg orally twice a day continuous dosing. Isotretinoin: 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle.	Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Celecoxib: 400 mg orally twice a day continuous dosing. Thalidomide: 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved).	Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Isotretinoin: 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle. Thalidomide: 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved).	Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Celecoxib: 400 mg orally twice a day continuous dosing. Isotretinoin: 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle. Thalidomide: 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved).
Measure Participants	22	18	21	21	21	20	17	15
Median (95% Confidence Interval) [months]	10.5	7.7	13.4	6.5	11.6	7.9	6.2	5.8

6. Secondary Outcome

Title	Median Overall Survival (OS) Comparison of Thalidomide Arms Versus no Thalidomide Arms
Description	Thalidomide versus not Thalidomide analysis: We compared the median OS outcome of participants in arms II, VI, VII and VIII, versus participants in arms I, III, IV and V. Median OS was estimated using the Kaplan-Meier method from time of randomization to time of progression, death, or last follow-up. Progression defined as 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).
Time Frame	Every 3 months from randomization until progression of disease, death or last follow-up.

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Thalidomide: Arm II, Arm VI, Arm VII and Arm VIII	No Thalidomide: Arm I, Arm III, Arm IV and Arm V
Arm/Group Description	Arm II: TMZ + Thalidomide, Arm VI: TMZ + Thalidomide + Celecoxib, Arm VII: TMZ + Thalidomide + Isotretinoin and Arm VIII: TMZ + Thalidomide + Isotretinoin + Celecoxib Thalidomide: 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved). Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Celecoxib: 400 mg orally twice a day continuous dosing. Isotretinoin: 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle.	Arm I: TMZ, Arm III: TMZ + Celecoxib, Arm IV: TMZ + Isotretinoin and Arm V: TMZ + Isotretinoin + Celecoxib Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Celecoxib: 400 mg orally twice a day continuous dosing. Isotretinoin: 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle.
Measure Participants	70	85
Median (95% Confidence Interval) [months]	18.3	17.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Thalidomide: Arm II, Arm VI, Arm VII and Arm VIII, No Thalidomide: Arm I, Arm III, Arm IV and Arm V
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.0
	Confidence Interval	(2-Sided) 95% 0.7 to 1.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Median Overall Survival (OS) Comparison of Celecoxib Arms Versus no Celecoxib Arms
Description	Celecoxib versus not Celecoxib analysis: We compared the median OS outcome of participants in arms III, V, VI and VIII, versus participants in arms I, II, IV and VII. Median OS was estimated using the Kaplan-Meier method from time of randomization to time of progression, death, or last follow-up. Progression defined as 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).
Time Frame	Every 3 months from randomization until progression of disease, death or last follow-up.

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Celecoxib: Arm III, Arm V, Arm VI and Arm VIII	No Celecoxib: Arm I, Arm II, Arm IV and Arm VII
Arm/Group Description	Arm III: TMZ + Celecoxib, Arm V: TMZ + Isotretinoin + Celecoxib, Arm VI: TMZ + Thalidomide + Celecoxib and Arm VIII: TMZ + Thalidomide + Isotretinoin + Celecoxib Thalidomide: 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved). Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Celecoxib: 400 mg orally twice a day continuous dosing. Isotretinoin: 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle.	Arm I: TMZ, Arm II: TMZ + Thalidomide, Arm IV: TMZ + Isotretinoin and Arm VII: TMZ + Thalidomide + Isotretinoin. Thalidomide: 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved). Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Isotretinoin: 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle.
Measure Participants	74	81
Median (95% Confidence Interval) [months]	20.2	17.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Thalidomide: Arm II, Arm VI, Arm VII and Arm VIII, No Thalidomide: Arm I, Arm III, Arm IV and Arm V
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.8
	Confidence Interval	(2-Sided) 95% 0.5 to 1.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Median Overall Survival (OS) Comparison of Isotretinoin Arms Versus no Isotretinoin Arms
Description	Isotretinoin versus not Isotretinoin analysis: We compared the median OS outcome of participants in arms IV, V, VII and VIII, versus participants in arms I, II, III and VI. Median OS was estimated using the Kaplan-Meier method from time of randomization to time of progression, death, or last follow-up. Progression defined as 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).
Time Frame	Every 3 months from randomization until progression of disease, death or last follow-up.

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Isotretinoin: Arm IV, Arm V, Arm VII and ARM VIII	No Isotretinoin: Arm I, Arm II, Arm III and ARM VI
Arm/Group Description	Arm IV: TMZ + Isotretinoin, Arm V: TMZ + Isotretinoin + Celecoxib, Arm VII: TMZ + Thalidomide + Isotretinoin and Arm VIII: TMZ + Thalidomide + Isotretinoin + Celecoxib Thalidomide: 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved). Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Celecoxib: 400 mg orally twice a day continuous dosing. Isotretinoin: 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle.	Arm I: TMZ, Arm II: TMZ + Thalidomide, Arm III: TMZ + Celecoxib and Arm VI: TMZ + Thalidomide + Celecoxib Thalidomide: 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved). Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Celecoxib: 400 mg orally twice a day continuous dosing.
Measure Participants	74	81
Median (95% Confidence Interval) [months]	17.1	19.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Thalidomide: Arm II, Arm VI, Arm VII and Arm VIII, No Thalidomide: Arm I, Arm III, Arm IV and Arm V
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.2
	Confidence Interval	(2-Sided) 95% 0.8 to 1.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Median Overall Survival (OS) Comparison of Doublet Versus Triplet Therapy
Description	Doublet (2 agents) versus Triplet (3 agents) therapy analysis: We compared the median OS outcome of participants in arms II, III, IV, versus participants in arms V, VI and VII. Median OS was estimated using the Kaplan-Meier method from time of randomization to time of progression, death, or last follow-up. Progression defined as 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).
Time Frame	Every 3 months from randomization until progression of disease, death or last follow-up.

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Doublet (2 Agents): Arm II, Arm III and Arm IV	Triplet (3 Agents): Arm V, Arm VI and Arm VII
Arm/Group Description	Arm II: TMZ + Thalidomide, Arm III: TMZ + Celecoxib and Arm IV: TMZ + Isotretinoin Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Thalidomide: 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved). Celecoxib: 400 mg orally twice a day continuous dosing. Isotretinoin: 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle.	Arm V: TMZ + Isotretinoin + Celecoxib, Arm VI: TMZ + Thalidomide + Celecoxib and Arm VII: Thalidomide + Celecoxib + Isotretinoin Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Thalidomide: 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved). Celecoxib: 400 mg orally twice a day continuous dosing. Isotretinoin: 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle.
Measure Participants	60	58
Median (95% Confidence Interval) [months]	17.0	20.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Thalidomide: Arm II, Arm VI, Arm VII and Arm VIII, No Thalidomide: Arm I, Arm III, Arm IV and Arm V
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.7
	Confidence Interval	(2-Sided) 95% 0.5 to 1.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Overall Survival of Individual Arms
Description	Overall Survival (OS) was estimated using the Kaplan-Meier method from time of randomization to time of progression, death, or last follow-up. Progression defined as 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).
Time Frame	Every 3 months from randomization until progression of disease, death or last follow-up.

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Arm I: TMZ	Arm II: TMZ + Thalidomide	Arm III: TMZ + Celecoxib	Arm IV: TMZ + Isotretinoin	Arm V: TMZ + Isotretinoin + Celecoxib	Arm VI: TMZ + Thalidomide + Celecoxib	Arm VII: TMZ + Thalidomide + Isotretinoin	Arm VIII: TMZ + Thalidomide + Isotretinoin + Celecoxib
Arm/Group Description	Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21.	Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Thalidomide: 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved).	Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Celecoxib: 400 mg orally twice a day continuous dosing.	Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Isotretinoin: 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle.	Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Celecoxib: 400 mg orally twice a day continuous dosing. Isotretinoin: 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle.	Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Celecoxib: 400 mg orally twice a day continuous dosing. Thalidomide: 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved).	Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Isotretinoin: 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle. Thalidomide: 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved).	Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Celecoxib: 400 mg orally twice a day continuous dosing. Isotretinoin: 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle. Thalidomide: 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved).
Measure Participants	22	18	21	21	21	20	17	15
Median (95% Confidence Interval) [months]	21.2	17.4	18.1	11.7	23.1	20.2	17.9	18.5

Adverse Events

	Arm I: TMZ		Arm II: TMZ + Thalidomide		Arm III: TMZ + Celecoxib		Arm IV: TMZ + Isotretinoin		Arm V: TMZ + Isotretinoin + Celecoxib		Arm VI: TMZ + Thalidomide + Celecoxib		Arm VII: TMZ + Thalidomide + Isotretinoin		Arm VIII: TMZ + Thalidomide + Isotretinoin + Celecoxib
Time Frame	Adverse Events (AEs) and Serious Adverse Events (SAEs) were collected from study drug administration to time of progression, death, or last follow-up,1 year", "Adverse Events (AEs) and Serious Adverse Events (SAEs) were collected from study drug administration to time of progression, death, or last follow-up, up to 5 years.
Adverse Event Reporting Description

Arm/Group Title	Arm I: TMZ		Arm II: TMZ + Thalidomide		Arm III: TMZ + Celecoxib		Arm IV: TMZ + Isotretinoin		Arm V: TMZ + Isotretinoin + Celecoxib		Arm VI: TMZ + Thalidomide + Celecoxib		Arm VII: TMZ + Thalidomide + Isotretinoin		Arm VIII: TMZ + Thalidomide + Isotretinoin + Celecoxib
Arm/Group Description	Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21.		Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Thalidomide: 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved).		Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Celecoxib: 400 mg orally twice a day continuous dosing.		Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Isotretinoin: 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle.		Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Celecoxib: 400 mg orally twice a day continuous dosing. Isotretinoin: 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle.		Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Celecoxib: 400 mg orally twice a day continuous dosing. Thalidomide: 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved).		Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Isotretinoin: 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle. Thalidomide: 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved).		Oral Temozolomide (TMZ): 150 mg/m^2 once daily on days 1-7 and 15-21. Celecoxib: 400 mg orally twice a day continuous dosing. Isotretinoin: 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle. Thalidomide: 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved).
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm I: TMZ		Arm II: TMZ + Thalidomide		Arm III: TMZ + Celecoxib		Arm IV: TMZ + Isotretinoin		Arm V: TMZ + Isotretinoin + Celecoxib		Arm VI: TMZ + Thalidomide + Celecoxib		Arm VII: TMZ + Thalidomide + Isotretinoin		Arm VIII: TMZ + Thalidomide + Isotretinoin + Celecoxib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/22 (50%)		9/21 (42.9%)		7/21 (33.3%)		8/18 (44.4%)		12/21 (57.1%)		15/17 (88.2%)		8/20 (40%)		7/15 (46.7%)
Blood and lymphatic system disorders
Lymphopenia	10/22 (45.5%)	10	5/21 (23.8%)	5	5/21 (23.8%)	5	5/18 (27.8%)	5	11/21 (52.4%)	11	10/17 (58.8%)	10	3/20 (15%)	3	4/15 (26.7%)	4
Platelets	1/22 (4.5%)	1	1/21 (4.8%)	1	1/21 (4.8%)	1	1/18 (5.6%)	1	0/21 (0%)	0	2/17 (11.8%)	2	1/20 (5%)	1	0/15 (0%)	0
Leukocytes	0/22 (0%)	0	2/21 (9.5%)	2	0/21 (0%)	0	2/18 (11.1%)	2	0/21 (0%)	0	1/17 (5.9%)	1	2/20 (10%)	2	0/15 (0%)	0
Neutrophils	0/22 (0%)	0	3/21 (14.3%)	3	0/21 (0%)	0	2/18 (11.1%)	2	0/21 (0%)	0	2/17 (11.8%)	2	3/20 (15%)	3	1/15 (6.7%)	1
Hemoglobin	0/22 (0%)	0	0/21 (0%)	0	1/21 (4.8%)	1	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Thrombocytopenia	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	1/21 (4.8%)	1	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Cardiac disorders
Sinus Bradycardia	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0	0/15 (0%)	0
General disorders
Death	0/22 (0%)	0	1/21 (4.8%)	1	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1	1/20 (5%)	1	0/15 (0%)	0
Fatigue	0/22 (0%)	0	0/21 (0%)	0	1/21 (4.8%)	1	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Obesity	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	1/21 (4.8%)	1	0/17 (0%)	0	0/20 (0%)	0	1/15 (6.7%)	1
Metabolism and nutrition disorders
Hyperkalemia	0/22 (0%)	0	0/21 (0%)	0	1/21 (4.8%)	1	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Hyperglycemia	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	1/18 (5.6%)	1	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Musculoskeletal and connective tissue disorders
Gait/Walking	0/22 (0%)	0	1/21 (4.8%)	1	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lymphoma	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	1/18 (5.6%)	1	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Nervous system disorders
Pyramidal Tract Dysfunction	0/22 (0%)	0	1/21 (4.8%)	1	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pneumonia	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	1/21 (4.8%)	1	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Dyspnea	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	1/15 (6.7%)	1
Skin and subcutaneous tissue disorders
Erythema Multiforme	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	1/15 (6.7%)	1
Vascular disorders
Thrombosis	1/22 (4.5%)	1	0/21 (0%)	0	0/21 (0%)	0	1/18 (5.6%)	1	0/21 (0%)	0	1/17 (5.9%)	1	2/20 (10%)	2	1/15 (6.7%)	1
Pulmonary Embolism	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0	0/15 (0%)	0
Other (Not Including Serious) Adverse Events
	Arm I: TMZ		Arm II: TMZ + Thalidomide		Arm III: TMZ + Celecoxib		Arm IV: TMZ + Isotretinoin		Arm V: TMZ + Isotretinoin + Celecoxib		Arm VI: TMZ + Thalidomide + Celecoxib		Arm VII: TMZ + Thalidomide + Isotretinoin		Arm VIII: TMZ + Thalidomide + Isotretinoin + Celecoxib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/22 (100%)		21/21 (100%)		21/21 (100%)		18/18 (100%)		21/21 (100%)		17/17 (100%)		20/20 (100%)		15/15 (100%)
Blood and lymphatic system disorders
Leukocytes	16/22 (72.7%)	54	14/21 (66.7%)	28	16/21 (76.2%)	43	15/18 (83.3%)	34	16/21 (76.2%)	66	17/17 (100%)	35	11/20 (55%)	36	14/15 (93.3%)	32
Lymphopenia	22/22 (100%)	99	21/21 (100%)	35	21/21 (100%)	70	18/18 (100%)	50	21/21 (100%)	74	17/17 (100%)	69	12/20 (60%)	23	12/15 (80%)	17
Neutrophils	13/22 (59.1%)	37	11/21 (52.4%)	25	9/21 (42.9%)	30	10/18 (55.6%)	21	11/21 (52.4%)	19	17/17 (100%)	24	7/20 (35%)	27	12/15 (80%)	22
Platelets	13/22 (59.1%)	35	5/21 (23.8%)	8	12/21 (57.1%)	28	13/18 (72.2%)	17	11/21 (52.4%)	31	14/17 (82.4%)	26	9/20 (45%)	22	11/15 (73.3%)	14
Hemoglobin	16/22 (72.7%)	39	8/21 (38.1%)	12	17/21 (81%)	39	14/18 (77.8%)	31	15/21 (71.4%)	39	17/17 (100%)	45	9/20 (45%)	25	11/15 (73.3%)	26
Anemia	1/22 (4.5%)	1	0/21 (0%)	0	2/21 (9.5%)	3	0/18 (0%)	0	1/21 (4.8%)	1	1/17 (5.9%)	1	0/20 (0%)	0	2/15 (13.3%)	4
Hematocrit	1/22 (4.5%)	1	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
CO2 Serum High	4/22 (18.2%)	5	2/21 (9.5%)	2	5/21 (23.8%)	6	1/18 (5.6%)	1	2/21 (9.5%)	2	4/17 (23.5%)	7	4/20 (20%)	4	2/15 (13.3%)	2
Edema	4/22 (18.2%)	4	2/21 (9.5%)	2	6/21 (28.6%)	6	2/18 (11.1%)	2	3/21 (14.3%)	4	6/17 (35.3%)	9	3/20 (15%)	4	6/15 (40%)	6
Leukocytosis	1/22 (4.5%)	1	0/21 (0%)	0	2/21 (9.5%)	3	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
High Lactate Dehydrogenase	8/22 (36.4%)	10	3/21 (14.3%)	3	4/21 (19%)	5	5/18 (27.8%)	7	3/21 (14.3%)	3	3/17 (17.6%)	4	2/20 (10%)	2	3/15 (20%)	4
High BUN Serum	5/22 (22.7%)	9	2/21 (9.5%)	2	8/21 (38.1%)	13	4/18 (22.2%)	6	6/21 (28.6%)	8	2/17 (11.8%)	2	2/20 (10%)	2	1/15 (6.7%)	1
Edema	1/22 (4.5%)	1	0/21 (0%)	0	1/21 (4.8%)	1	1/18 (5.6%)	1	0/21 (0%)	0	1/17 (5.9%)	1	1/20 (5%)	1	1/15 (6.7%)	1
Edema	0/22 (0%)	0	1/21 (4.8%)	1	3/21 (14.3%)	3	0/18 (0%)	0	2/21 (9.5%)	2	1/17 (5.9%)	1	0/20 (0%)	0	0/15 (0%)	0
Thrombotic Thrombocytopenic Purpura	0/22 (0%)	0	0/21 (0%)	0	1/21 (4.8%)	1	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Low BUN Serum	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	1/18 (5.6%)	1	1/21 (4.8%)	1	2/17 (11.8%)	2	1/20 (5%)	1	1/15 (6.7%)	1
Bilateral Ankle Swelling	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	1/18 (5.6%)	1	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Low Lactate Dehydrogenase	0/22 (0%)	0	1/21 (4.8%)	2	0/21 (0%)	0	0/18 (0%)	0	1/21 (4.8%)	1	2/17 (11.8%)	4	0/20 (0%)	0	0/15 (0%)	0
Partial Thromboplastin Time	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0	0/15 (0%)	0
Cardiac disorders
Sinus Bradycardia	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0	0/15 (0%)	0
Supraventricular Arrhythmia-Sinus Tachycardia	1/22 (4.5%)	1	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Hypertension	4/22 (18.2%)	6	4/21 (19%)	4	1/21 (4.8%)	2	4/18 (22.2%)	4	2/21 (9.5%)	2	1/17 (5.9%)	1	4/20 (20%)	5	2/15 (13.3%)	2
Hypotension	1/22 (4.5%)	1	1/21 (4.8%)	1	2/21 (9.5%)	2	2/18 (11.1%)	2	0/21 (0%)	0	2/17 (11.8%)	2	1/20 (5%)	1	0/15 (0%)	0
Palpitations	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	2/18 (11.1%)	2	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	0/15 (0%)	0
Supraventricular Arrhythmia-Atrial Fibrillation	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	1/18 (5.6%)	1	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Chest Tightness	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1	1/20 (5%)	1	0/15 (0%)	0
Cardiac Arrhythmia	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	2/20 (10%)	2	0/15 (0%)	0
Ear and labyrinth disorders
Hearing Loss	1/22 (4.5%)	1	1/21 (4.8%)	1	5/21 (23.8%)	5	3/18 (16.7%)	3	1/21 (4.8%)	1	3/17 (17.6%)	3	3/20 (15%)	3	2/15 (13.3%)	2
Left Ear Drainage	1/22 (4.5%)	1	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Otitis	1/22 (4.5%)	1	1/21 (4.8%)	1	0/21 (0%)	0	2/18 (11.1%)	2	2/21 (9.5%)	3	1/17 (5.9%)	1	1/20 (5%)	1	0/15 (0%)	0
Ear Pain	4/22 (18.2%)	5	1/21 (4.8%)	1	1/21 (4.8%)	1	1/18 (5.6%)	1	1/21 (4.8%)	1	2/17 (11.8%)	2	1/20 (5%)	1	0/15 (0%)	0
Tinnitus	1/22 (4.5%)	1	0/21 (0%)	0	0/21 (0%)	0	3/18 (16.7%)	3	2/21 (9.5%)	2	2/17 (11.8%)	2	1/20 (5%)	1	1/15 (6.7%)	1
Ear Wax	0/22 (0%)	0	1/21 (4.8%)	1	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Tympanic Membrane Perforation	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0	0/15 (0%)	0
Otosclerosis	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	0/15 (0%)	0
Endocrine disorders
Hot Flashes	1/22 (4.5%)	1	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Cushingoid	0/22 (0%)	0	1/21 (4.8%)	1	1/21 (4.8%)	1	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	0/15 (0%)	0
Diabetes	0/22 (0%)	0	1/21 (4.8%)	1	1/21 (4.8%)	1	1/18 (5.6%)	1	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	0/15 (0%)	0
Hypothyroidism	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	1/18 (5.6%)	1	0/21 (0%)	0	1/17 (5.9%)	1	2/20 (10%)	2	1/15 (6.7%)	1
Low Testosterone	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0	0/15 (0%)	0
Thyroid Problems	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	1/15 (6.7%)	1
Eye disorders
Blurred Vision	4/22 (18.2%)	6	1/21 (4.8%)	1	4/21 (19%)	4	2/18 (11.1%)	2	4/21 (19%)	4	4/17 (23.5%)	4	3/20 (15%)	4	4/15 (26.7%)	4
Anopsia	2/22 (9.1%)	2	2/21 (9.5%)	2	3/21 (14.3%)	3	2/18 (11.1%)	2	3/21 (14.3%)	3	4/17 (23.5%)	4	3/20 (15%)	4	6/15 (40%)	6
Lowered Visual Acuity	1/22 (4.5%)	1	0/21 (0%)	0	0/21 (0%)	0	1/18 (5.6%)	1	2/21 (9.5%)	2	1/17 (5.9%)	1	1/20 (5%)	1	0/15 (0%)	0
Loss of Vision	2/22 (9.1%)	2	0/21 (0%)	0	2/21 (9.5%)	2	2/18 (11.1%)	2	1/21 (4.8%)	1	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Photophobia	1/22 (4.5%)	1	0/21 (0%)	0	0/21 (0%)	0	1/18 (5.6%)	1	0/21 (0%)	0	2/17 (11.8%)	2	0/20 (0%)	0	1/15 (6.7%)	1
Retinopathy	1/22 (4.5%)	1	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Watery Eye	1/22 (4.5%)	1	0/21 (0%)	0	0/21 (0%)	0	1/18 (5.6%)	1	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Diplopia	0/22 (0%)	0	0/21 (0%)	0	2/21 (9.5%)	2	2/18 (11.1%)	2	0/21 (0%)	0	0/17 (0%)	0	3/20 (15%)	4	0/15 (0%)	0
Dry Eye	0/22 (0%)	0	2/21 (9.5%)	2	1/21 (4.8%)	1	2/18 (11.1%)	2	1/21 (4.8%)	1	0/17 (0%)	0	2/20 (10%)	2	1/15 (6.7%)	1
Eyelid Dysfunction	0/22 (0%)	0	1/21 (4.8%)	1	1/21 (4.8%)	1	0/18 (0%)	0	2/21 (9.5%)	2	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Nystagmus	0/22 (0%)	0	1/21 (4.8%)	1	1/21 (4.8%)	1	0/18 (0%)	0	1/21 (4.8%)	1	0/17 (0%)	0	1/20 (5%)	2	1/15 (6.7%)	1
Extraocular Movement	0/22 (0%)	0	0/21 (0%)	0	1/21 (4.8%)	1	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	0/15 (0%)	0
Exophoria	0/22 (0%)	0	1/21 (4.8%)	1	0/21 (0%)	0	1/18 (5.6%)	1	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	0/15 (0%)	0
Esotropia	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	1/18 (5.6%)	1	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	0/15 (0%)	0
Astigmatism	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	1/21 (4.8%)	1	0/17 (0%)	0	1/20 (5%)	1	0/15 (0%)	0
Conjunctival Infection	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	2/21 (9.5%)	2	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Eye Pain	0/22 (0%)	0	1/21 (4.8%)	1	0/21 (0%)	0	0/18 (0%)	0	1/21 (4.8%)	1	0/17 (0%)	0	2/20 (10%)	2	1/15 (6.7%)	1
Photosensitivity	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	1/21 (4.8%)	1	0/17 (0%)	0	1/20 (5%)	1	0/15 (0%)	0
Asymmetrical Optic Cup	0/22 (0%)	0	1/21 (4.8%)	1	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Anisocoria	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0	0/15 (0%)	0
Swollen Eyes	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	1/15 (6.7%)	1
Gastrointestinal disorders
Anorexia	8/22 (36.4%)	9	2/21 (9.5%)	2	3/21 (14.3%)	3	7/18 (38.9%)	10	3/21 (14.3%)	3	9/17 (52.9%)	10	4/20 (20%)	4	3/15 (20%)	3
Constipation	13/22 (59.1%)	13	11/21 (52.4%)	11	9/21 (42.9%)	9	11/18 (61.1%)	12	8/21 (38.1%)	8	12/17 (70.6%)	14	10/20 (50%)	10	8/15 (53.3%)	8
Colitis	1/22 (4.5%)	1	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Diarrhea	1/22 (4.5%)	1	0/21 (0%)	0	3/21 (14.3%)	5	4/18 (22.2%)	4	1/21 (4.8%)	1	4/17 (23.5%)	4	5/20 (25%)	6	3/15 (20%)	3
Xerostomia	1/22 (4.5%)	1	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	0/15 (0%)	0
Dysphagia	2/22 (9.1%)	2	1/21 (4.8%)	1	1/21 (4.8%)	1	2/18 (11.1%)	2	1/21 (4.8%)	1	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Bloating	1/22 (4.5%)	1	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	1/15 (6.7%)	1
Heartburn	1/22 (4.5%)	1	1/21 (4.8%)	1	2/21 (9.5%)	2	1/18 (5.6%)	1	1/21 (4.8%)	1	1/17 (5.9%)	1	0/20 (0%)	0	2/15 (13.3%)	2
Gingivitis	1/22 (4.5%)	1	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1	1/20 (5%)	1	0/15 (0%)	0
Nausea	11/22 (50%)	14	6/21 (28.6%)	7	9/21 (42.9%)	11	10/18 (55.6%)	12	11/21 (52.4%)	12	10/17 (58.8%)	13	11/20 (55%)	12	8/15 (53.3%)	8
Abdomen/GI Pain	2/22 (9.1%)	2	1/21 (4.8%)	1	2/21 (9.5%)	2	5/18 (27.8%)	6	2/21 (9.5%)	2	1/17 (5.9%)	1	2/20 (10%)	2	4/15 (26.7%)	5
Taste Alteration	2/22 (9.1%)	2	0/21 (0%)	0	2/21 (9.5%)	2	0/18 (0%)	0	1/21 (4.8%)	1	1/17 (5.9%)	1	0/20 (0%)	0	0/15 (0%)	0
Vomiting	5/22 (22.7%)	5	4/21 (19%)	4	4/21 (19%)	5	4/18 (22.2%)	5	1/21 (4.8%)	1	4/17 (23.5%)	4	5/20 (25%)	5	3/15 (20%)	3
Dehydration	0/22 (0%)	0	0/21 (0%)	0	2/21 (9.5%)	2	0/18 (0%)	0	1/21 (4.8%)	1	1/17 (5.9%)	1	1/20 (5%)	1	1/15 (6.7%)	1
Distension	0/22 (0%)	0	0/21 (0%)	0	1/21 (4.8%)	1	1/18 (5.6%)	1	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	0/15 (0%)	0
Dry Mouth	0/22 (0%)	0	1/21 (4.8%)	1	1/21 (4.8%)	1	0/18 (0%)	0	4/21 (19%)	4	0/17 (0%)	0	3/20 (15%)	3	1/15 (6.7%)	1
Thrush	0/22 (0%)	0	0/21 (0%)	0	1/21 (4.8%)	2	1/18 (5.6%)	1	1/21 (4.8%)	1	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Mucositis	0/22 (0%)	0	0/21 (0%)	0	1/21 (4.8%)	1	1/18 (5.6%)	2	1/21 (4.8%)	1	0/17 (0%)	0	0/20 (0%)	0	1/15 (6.7%)	1
Mouth Sores	0/22 (0%)	0	0/21 (0%)	0	1/21 (4.8%)	1	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Ulcer	0/22 (0%)	0	0/21 (0%)	0	1/21 (4.8%)	1	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Ascites	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	1/18 (5.6%)	1	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Periodontal Disease	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	1/18 (5.6%)	1	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Gastritis	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	1/18 (5.6%)	1	1/21 (4.8%)	1	2/17 (11.8%)	2	0/20 (0%)	0	1/15 (6.7%)	1
Dysgeusia	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	1/21 (4.8%)	1	2/17 (11.8%)	2	0/20 (0%)	0	0/15 (0%)	0
Dyspepsia	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	1/21 (4.8%)	1	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Indigestion	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	1/21 (4.8%)	1	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Diverticulitis	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	1/21 (4.8%)	1	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Intermittent Appetite Change	0/22 (0%)	0	1/21 (4.8%)	1	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0	0/15 (0%)	0
GERD	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0	2/15 (13.3%)	2
Hemorrhoids	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1	2/20 (10%)	3	1/15 (6.7%)	1
Flatulence	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	0/15 (0%)	0
Anal Incontinence	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	0/15 (0%)	0
General disorders
Fatigue	19/22 (86.4%)	27	13/21 (61.9%)	16	16/21 (76.2%)	20	14/18 (77.8%)	15	17/21 (81%)	20	17/17 (100%)	26	14/20 (70%)	16	14/15 (93.3%)	16
Pain	1/22 (4.5%)	1	2/21 (9.5%)	2	2/21 (9.5%)	2	5/18 (27.8%)	7	1/21 (4.8%)	1	4/17 (23.5%)	4	4/20 (20%)	5	5/15 (33.3%)	6
Speech Impairment	2/22 (9.1%)	2	6/21 (28.6%)	6	4/21 (19%)	4	4/18 (22.2%)	4	7/21 (33.3%)	7	4/17 (23.5%)	5	8/20 (40%)	8	1/15 (6.7%)	1
Weight Loss	10/22 (45.5%)	11	1/21 (4.8%)	1	5/21 (23.8%)	5	3/18 (16.7%)	4	7/21 (33.3%)	8	4/17 (23.5%)	4	4/20 (20%)	4	5/15 (33.3%)	5
Fever	4/22 (18.2%)	5	1/21 (4.8%)	1	0/21 (0%)	0	3/18 (16.7%)	5	1/21 (4.8%)	1	2/17 (11.8%)	2	3/20 (15%)	4	2/15 (13.3%)	2
Insomnia	7/22 (31.8%)	8	2/21 (9.5%)	2	5/21 (23.8%)	5	4/18 (22.2%)	5	7/21 (33.3%)	7	6/17 (35.3%)	6	3/20 (15%)	3	4/15 (26.7%)	4
Chills	1/22 (4.5%)	1	1/21 (4.8%)	1	1/21 (4.8%)	1	2/18 (11.1%)	4	0/21 (0%)	0	3/17 (17.6%)	3	3/20 (15%)	3	0/15 (0%)	0
Weight Gain	2/22 (9.1%)	2	1/21 (4.8%)	1	1/21 (4.8%)	1	0/18 (0%)	0	1/21 (4.8%)	1	1/17 (5.9%)	1	0/20 (0%)	0	0/15 (0%)	0
Obesity	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	1/21 (4.8%)	1	0/17 (0%)	0	3/20 (15%)	4	1/15 (6.7%)	1
Flu-Like Syndrome	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1	2/20 (10%)	3	0/15 (0%)	0
Hepatobiliary disorders
ALT, SGPT	6/22 (27.3%)	7	5/21 (23.8%)	6	8/21 (38.1%)	14	7/18 (38.9%)	7	6/21 (28.6%)	9	4/17 (23.5%)	5	8/20 (40%)	8	7/15 (46.7%)	9
AST, SGOT	4/22 (18.2%)	4	5/21 (23.8%)	8	9/21 (42.9%)	10	3/18 (16.7%)	3	5/21 (23.8%)	5	6/17 (35.3%)	10	6/20 (30%)	6	6/15 (40%)	7
Gilbert's Disease	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0	0/15 (0%)	0
Immune system disorders
Allergic Reaction	1/22 (4.5%)	1	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	2	0/20 (0%)	0	0/15 (0%)	0
Allergic Rhinitis	2/22 (9.1%)	2	0/21 (0%)	0	0/21 (0%)	0	3/18 (16.7%)	3	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Rhinitis	2/22 (9.1%)	3	0/21 (0%)	0	1/21 (4.8%)	1	1/18 (5.6%)	1	3/21 (14.3%)	3	2/17 (11.8%)	4	4/20 (20%)	4	2/15 (13.3%)	2
Allergy	0/22 (0%)	0	0/21 (0%)	0	1/21 (4.8%)	1	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Allergy	0/22 (0%)	0	0/21 (0%)	0	1/21 (4.8%)	1	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Sarcoidosis	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	0/15 (0%)	0
Infections and infestations
Infection	1/22 (4.5%)	1	3/21 (14.3%)	3	0/21 (0%)	0	1/18 (5.6%)	1	3/21 (14.3%)	3	2/17 (11.8%)	2	1/20 (5%)	1	1/15 (6.7%)	1
Opportunistic Infection	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	1/18 (5.6%)	1	1/21 (4.8%)	1	1/17 (5.9%)	1	1/20 (5%)	1	0/15 (0%)	0
Herpes	1/22 (4.5%)	1	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Infection with Unknown ANC	1/22 (4.5%)	1	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Infection with Normal ANC	1/22 (4.5%)	1	0/21 (0%)	0	0/21 (0%)	0	1/18 (5.6%)	1	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	0/15 (0%)	0
Infection with Normal ANC	1/22 (4.5%)	3	1/21 (4.8%)	1	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Oral Candidiasis	0/22 (0%)	0	1/21 (4.8%)	1	1/21 (4.8%)	1	0/18 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1	1/20 (5%)	1	0/15 (0%)	0
Toe Infection	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	1/18 (5.6%)	1	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Sore Throat	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	2/18 (11.1%)	2	1/21 (4.8%)	1	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Infection with Normal ANC	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	1/18 (5.6%)	1	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Metabolism and nutrition disorders
Hyperglycemia	18/22 (81.8%)	35	8/21 (38.1%)	10	17/21 (81%)	38	10/18 (55.6%)	20	11/21 (52.4%)	17	9/17 (52.9%)	18	10/20 (50%)	20	9/15 (60%)	10
Amylase	1/22 (4.5%)	1	0/21 (0%)	0	1/21 (4.8%)	1	2/18 (11.1%)	4	5/21 (23.8%)	15	0/17 (0%)	0	1/20 (5%)	2	0/15 (0%)	0
Hypertriglyceridemia	6/22 (27.3%)	7	7/21 (33.3%)	7	7/21 (33.3%)	7	10/18 (55.6%)	21	16/21 (76.2%)	30	3/17 (17.6%)	3	11/20 (55%)	17	11/15 (73.3%)	14
Hypoalbuminemia	2/22 (9.1%)	3	3/21 (14.3%)	8	3/21 (14.3%)	4	3/18 (16.7%)	3	2/21 (9.5%)	3	4/17 (23.5%)	5	2/20 (10%)	2	4/15 (26.7%)	5
Hypophosphatemia	0/22 (0%)	0	0/21 (0%)	0	1/21 (4.8%)	1	5/18 (27.8%)	5	0/21 (0%)	0	2/17 (11.8%)	2	0/20 (0%)	0	1/15 (6.7%)	1
Lipase	1/22 (4.5%)	1	0/21 (0%)	0	1/21 (4.8%)	1	7/18 (38.9%)	8	9/21 (42.9%)	23	1/17 (5.9%)	1	3/20 (15%)	3	3/15 (20%)	5
Hypokalemia	3/22 (13.6%)	4	1/21 (4.8%)	1	3/21 (14.3%)	4	3/18 (16.7%)	3	4/21 (19%)	6	4/17 (23.5%)	5	4/20 (20%)	7	3/15 (20%)	4
Hypercholesteremia	9/22 (40.9%)	12	6/21 (28.6%)	6	3/21 (14.3%)	3	13/18 (72.2%)	17	16/21 (76.2%)	22	4/17 (23.5%)	4	8/20 (40%)	8	9/15 (60%)	10
Alkaline Phosphatase	6/22 (27.3%)	14	2/21 (9.5%)	2	2/21 (9.5%)	4	4/18 (22.2%)	5	5/21 (23.8%)	11	2/17 (11.8%)	2	2/20 (10%)	2	1/15 (6.7%)	1
Low Bicarbonate	2/22 (9.1%)	2	2/21 (9.5%)	5	2/21 (9.5%)	2	7/18 (38.9%)	7	2/21 (9.5%)	2	1/17 (5.9%)	1	1/20 (5%)	1	2/15 (13.3%)	2
Hyperbilirubinemia	2/22 (9.1%)	3	3/21 (14.3%)	3	3/21 (14.3%)	5	3/18 (16.7%)	7	3/21 (14.3%)	6	1/17 (5.9%)	1	1/20 (5%)	1	3/15 (20%)	3
Creatinine	6/22 (27.3%)	7	3/21 (14.3%)	3	2/21 (9.5%)	2	5/18 (27.8%)	5	4/21 (19%)	6	5/17 (29.4%)	5	4/20 (20%)	4	2/15 (13.3%)	3
Hypoglycemia	3/22 (13.6%)	3	0/21 (0%)	0	5/21 (23.8%)	5	1/18 (5.6%)	2	1/21 (4.8%)	1	1/17 (5.9%)	1	2/20 (10%)	2	0/15 (0%)	0
Hypercalcemia	1/22 (4.5%)	1	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	1/21 (4.8%)	1	0/17 (0%)	0	1/20 (5%)	1	1/15 (6.7%)	1
Hyperkalemia	2/22 (9.1%)	2	0/21 (0%)	0	3/21 (14.3%)	3	1/18 (5.6%)	1	4/21 (19%)	6	1/17 (5.9%)	1	2/20 (10%)	2	2/15 (13.3%)	3
Hypermagnesemia	1/22 (4.5%)	1	0/21 (0%)	0	0/21 (0%)	0	1/18 (5.6%)	1	1/21 (4.8%)	1	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Hyperuricemia	5/22 (22.7%)	5	1/21 (4.8%)	1	5/21 (23.8%)	6	2/18 (11.1%)	2	6/21 (28.6%)	9	1/17 (5.9%)	1	1/20 (5%)	2	0/15 (0%)	0
Hypocalcemia	1/22 (4.5%)	1	1/21 (4.8%)	3	3/21 (14.3%)	7	1/18 (5.6%)	1	2/21 (9.5%)	2	3/17 (17.6%)	3	2/20 (10%)	2	1/15 (6.7%)	1
Hyponatremia	5/22 (22.7%)	6	3/21 (14.3%)	4	2/21 (9.5%)	2	3/18 (16.7%)	3	4/21 (19%)	6	1/17 (5.9%)	1	0/20 (0%)	0	1/15 (6.7%)	1
Hypomagnesemia	1/22 (4.5%)	1	3/21 (14.3%)	3	2/21 (9.5%)	2	1/18 (5.6%)	1	1/21 (4.8%)	1	0/17 (0%)	0	1/20 (5%)	1	1/15 (6.7%)	1
Hyperlipidemia	1/22 (4.5%)	1	0/21 (0%)	0	0/21 (0%)	0	1/18 (5.6%)	1	1/21 (4.8%)	1	0/17 (0%)	0	1/20 (5%)	1	0/15 (0%)	0
High Chloride Serum	3/22 (13.6%)	4	3/21 (14.3%)	6	5/21 (23.8%)	7	6/18 (33.3%)	9	2/21 (9.5%)	4	5/17 (29.4%)	9	2/20 (10%)	3	2/15 (13.3%)	2
Hyperphosphatemia	4/22 (18.2%)	7	1/21 (4.8%)	1	2/21 (9.5%)	2	1/18 (5.6%)	1	3/21 (14.3%)	4	2/17 (11.8%)	2	4/20 (20%)	4	0/15 (0%)	0
High Bicarbonate	2/22 (9.1%)	2	0/21 (0%)	0	1/21 (4.8%)	1	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	2/20 (10%)	2	0/15 (0%)	0
Low Chloride Serum	2/22 (9.1%)	2	1/21 (4.8%)	1	1/21 (4.8%)	1	1/18 (5.6%)	1	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	2	0/15 (0%)	0
Low Protein Serum	2/22 (9.1%)	2	1/21 (4.8%)	2	3/21 (14.3%)	5	1/18 (5.6%)	1	1/21 (4.8%)	1	3/17 (17.6%)	6	2/20 (10%)	3	2/15 (13.3%)	2
High Protein Serum	2/22 (9.1%)	2	0/21 (0%)	0	1/21 (4.8%)	1	0/18 (0%)	0	2/21 (9.5%)	2	1/17 (5.9%)	1	0/20 (0%)	0	0/15 (0%)	0
Low Uric Acid	2/22 (9.1%)	3	0/21 (0%)	0	2/21 (9.5%)	2	1/18 (5.6%)	1	0/21 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0	0/15 (0%)	0
Hypernatremia	2/22 (9.1%)	3	2/21 (9.5%)	2	2/21 (9.5%)	2	2/18 (11.1%)	2	1/21 (4.8%)	1	3/17 (17.6%)	4	0/20 (0%)	0	2/15 (13.3%)	2
Proteinuria	0/22 (0%)	0	0/21 (0%)	0	2/21 (9.5%)	3	0/18 (0%)	0	1/21 (4.8%)	1	3/17 (17.6%)	6	2/20 (10%)	2	0/15 (0%)	0
Hyperalbuminenia	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	1/21 (4.8%)	2	0/17 (0%)	0	0/20 (0%)	0	2/15 (13.3%)	2
Creatine Phosphokinase	0/22 (0%)	0	1/21 (4.8%)	1	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Musculoskeletal and connective tissue disorders
Muscle Weakness	11/22 (50%)	16	5/21 (23.8%)	5	9/21 (42.9%)	10	11/18 (61.1%)	14	7/21 (33.3%)	7	11/17 (64.7%)	14	4/20 (20%)	4	4/15 (26.7%)	5
Gait/Walking	5/22 (22.7%)	5	5/21 (23.8%)	5	7/21 (33.3%)	8	6/18 (33.3%)	7	6/21 (28.6%)	7	8/17 (47.1%)	8	10/20 (50%)	10	4/15 (26.7%)	4
Involuntary Movement	1/22 (4.5%)	1	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	0/15 (0%)	0
Unsteady Gait	2/22 (9.1%)	2	0/21 (0%)	0	1/21 (4.8%)	1	1/18 (5.6%)	1	1/21 (4.8%)	1	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Back Pain	5/22 (22.7%)	5	2/21 (9.5%)	2	1/21 (4.8%)	1	3/18 (16.7%)	3	1/21 (4.8%)	1	1/17 (5.9%)	1	1/20 (5%)	1	2/15 (13.3%)	2
Joint Pain	2/22 (9.1%)	2	0/21 (0%)	0	2/21 (9.5%)	2	5/18 (27.8%)	6	0/21 (0%)	0	3/17 (17.6%)	4	0/20 (0%)	0	2/15 (13.3%)	2
Knee Pain	1/22 (4.5%)	1	1/21 (4.8%)	1	0/21 (0%)	0	2/18 (11.1%)	2	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Ankle Pain	1/22 (4.5%)	1	1/21 (4.8%)	1	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	1/15 (6.7%)	1
Shoulder Pain	2/22 (9.1%)	2	0/21 (0%)	0	1/21 (4.8%)	1	0/18 (0%)	0	2/21 (9.5%)	2	1/17 (5.9%)	1	1/20 (5%)	1	0/15 (0%)	0
Jaw Pain	2/22 (9.1%)	2	1/21 (4.8%)	1	0/21 (0%)	0	1/18 (5.6%)	1	0/21 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0	2/15 (13.3%)	2
Wrist Pain	2/22 (9.1%)	2	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Muscle Cramps	0/22 (0%)	0	0/21 (0%)	0	1/21 (4.8%)	1	0/18 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0	0/15 (0%)	0
Hip Pain	0/22 (0%)	0	0/21 (0%)	0	1/21 (4.8%)	1	1/18 (5.6%)	1	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	1/15 (6.7%)	1
Neck Pain	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	3/18 (16.7%)	3	1/21 (4.8%)	1	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Fracture	0/22 (0%)	0	1/21 (4.8%)	1	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Bilateral Hands/Feet Swelling	0/22 (0%)	0	1/21 (4.8%)	1	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	2/17 (11.8%)	2	0/20 (0%)	0	0/15 (0%)	0
Muscles Twitching	0/22 (0%)	0	1/21 (4.8%)	1	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Gout	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0	0/15 (0%)	0
Osteopenia	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	0/15 (0%)	0
Deep Tendon Reflexes - Limb	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	2/15 (13.3%)	2
Left Hemiparesis	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	1/15 (6.7%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Polyp in the Cardia	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0	0/15 (0%)	0
Hepatic Hemangioma	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	0/15 (0%)	0
Cervical Lipoma	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	0/15 (0%)	0
Asymptomatic Thyroid Nodule	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	1/15 (6.7%)	1
Nervous system disorders
Syncope	1/22 (4.5%)	1	3/21 (14.3%)	3	1/21 (4.8%)	1	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	2/15 (13.3%)	2
Headache	10/22 (45.5%)	13	9/21 (42.9%)	11	9/21 (42.9%)	9	14/18 (77.8%)	15	12/21 (57.1%)	17	8/17 (47.1%)	10	13/20 (65%)	16	8/15 (53.3%)	9
Dizziness	7/22 (31.8%)	7	6/21 (28.6%)	6	9/21 (42.9%)	10	6/18 (33.3%)	6	8/21 (38.1%)	9	11/17 (64.7%)	13	9/20 (45%)	9	3/15 (20%)	3
Ataxia	1/22 (4.5%)	1	1/21 (4.8%)	1	1/21 (4.8%)	1	0/18 (0%)	0	4/21 (19%)	4	5/17 (29.4%)	5	2/20 (10%)	2	1/15 (6.7%)	1
Pyramidal Tract Dysfunction	10/22 (45.5%)	10	5/21 (23.8%)	5	7/21 (33.3%)	7	6/18 (33.3%)	6	7/21 (33.3%)	7	8/17 (47.1%)	8	8/20 (40%)	8	4/15 (26.7%)	4
Cognitive Disturbance	6/22 (27.3%)	7	4/21 (19%)	4	7/21 (33.3%)	7	5/18 (27.8%)	5	5/21 (23.8%)	5	5/17 (29.4%)	5	5/20 (25%)	5	3/15 (20%)	3
Confusion	3/22 (13.6%)	4	0/21 (0%)	0	4/21 (19%)	5	5/18 (27.8%)	5	1/21 (4.8%)	1	4/17 (23.5%)	4	4/20 (20%)	4	3/15 (20%)	3
Memory Impairment	9/22 (40.9%)	9	5/21 (23.8%)	5	7/21 (33.3%)	7	8/18 (44.4%)	9	8/21 (38.1%)	8	7/17 (41.2%)	7	4/20 (20%)	4	4/15 (26.7%)	4
Anxiety	3/22 (13.6%)	3	1/21 (4.8%)	1	3/21 (14.3%)	3	2/18 (11.1%)	2	3/21 (14.3%)	3	5/17 (29.4%)	5	4/20 (20%)	4	0/15 (0%)	0
Agitation	1/22 (4.5%)	1	0/21 (0%)	0	0/21 (0%)	0	2/18 (11.1%)	2	2/21 (9.5%)	2	2/17 (11.8%)	2	1/20 (5%)	1	0/15 (0%)	0
Neuropathy	2/22 (9.1%)	2	0/21 (0%)	0	2/21 (9.5%)	2	0/18 (0%)	0	1/21 (4.8%)	1	1/17 (5.9%)	1	1/20 (5%)	2	1/15 (6.7%)	1
Neuropathy - Motor	1/22 (4.5%)	1	2/21 (9.5%)	2	2/21 (9.5%)	2	1/18 (5.6%)	1	0/21 (0%)	0	2/17 (11.8%)	2	0/20 (0%)	0	0/15 (0%)	0
Neuropathy - Sensory	4/22 (18.2%)	4	3/21 (14.3%)	4	2/21 (9.5%)	2	2/18 (11.1%)	4	2/21 (9.5%)	2	4/17 (23.5%)	4	4/20 (20%)	4	4/15 (26.7%)	4
Tingling	3/22 (13.6%)	3	2/21 (9.5%)	2	0/21 (0%)	0	0/18 (0%)	0	3/21 (14.3%)	3	3/17 (17.6%)	3	4/20 (20%)	5	1/15 (6.7%)	1
Dysesthesias	1/22 (4.5%)	1	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Numbness	4/22 (18.2%)	4	2/21 (9.5%)	2	3/21 (14.3%)	3	3/18 (16.7%)	4	2/21 (9.5%)	2	4/17 (23.5%)	5	7/20 (35%)	8	1/15 (6.7%)	1
Radiculopathy	1/22 (4.5%)	1	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Neuralgia	1/22 (4.5%)	1	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Seizure	5/22 (22.7%)	5	6/21 (28.6%)	6	5/21 (23.8%)	14	7/18 (38.9%)	10	11/21 (52.4%)	13	8/17 (47.1%)	12	8/20 (40%)	8	2/15 (13.3%)	2
Somnolence	2/22 (9.1%)	2	1/21 (4.8%)	1	1/21 (4.8%)	1	1/18 (5.6%)	1	0/21 (0%)	0	3/17 (17.6%)	4	5/20 (25%)	5	4/15 (26.7%)	4
Tremor	2/22 (9.1%)	2	3/21 (14.3%)	3	2/21 (9.5%)	2	2/18 (11.1%)	2	2/21 (9.5%)	2	3/17 (17.6%)	3	3/20 (15%)	3	7/15 (46.7%)	7
Low Phenytoin	0/22 (0%)	0	0/21 (0%)	0	1/21 (4.8%)	1	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Psychosis	0/22 (0%)	0	0/21 (0%)	0	1/21 (4.8%)	1	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Mood Changes	0/22 (0%)	0	1/21 (4.8%)	1	2/21 (9.5%)	2	0/18 (0%)	0	1/21 (4.8%)	1	1/17 (5.9%)	1	0/20 (0%)	0	0/15 (0%)	0
CN VI Palsy	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	1/18 (5.6%)	1	0/21 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0	0/15 (0%)	0
Short Term Memory	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	1/21 (4.8%)	1	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Dystonic Meige Syndrome	0/22 (0%)	0	1/21 (4.8%)	1	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Left VII CN Palsy	0/22 (0%)	0	1/21 (4.8%)	1	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Disorientation	0/22 (0%)	0	1/21 (4.8%)	1	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Light Headedness	0/22 (0%)	0	1/21 (4.8%)	1	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Restlessness	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	2/17 (11.8%)	2	0/20 (0%)	0	0/15 (0%)	0
Hyperreflexia	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0	0/15 (0%)	0
Apraxia	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	1/15 (6.7%)	1
Facial Droop	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	0/15 (0%)	0
Psychiatric disorders
Depression	3/22 (13.6%)	4	2/21 (9.5%)	2	2/21 (9.5%)	2	4/18 (22.2%)	5	8/21 (38.1%)	8	5/17 (29.4%)	6	2/20 (10%)	2	4/15 (26.7%)	4
Renal and urinary disorders
Urinary Tract Infection	1/22 (4.5%)	1	1/21 (4.8%)	1	1/21 (4.8%)	1	3/18 (16.7%)	3	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	0/15 (0%)	0
Pain	1/22 (4.5%)	1	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Urinary Frequency	4/22 (18.2%)	5	2/21 (9.5%)	3	1/21 (4.8%)	1	5/18 (27.8%)	6	2/21 (9.5%)	2	3/17 (17.6%)	4	3/20 (15%)	3	2/15 (13.3%)	2
Renal Pain	0/22 (0%)	0	0/21 (0%)	0	1/21 (4.8%)	1	0/18 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1	1/20 (5%)	1	0/15 (0%)	0
Membranous Glomerulonephritis	0/22 (0%)	0	0/21 (0%)	0	1/21 (4.8%)	1	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Stress Incontinence	0/22 (0%)	0	0/21 (0%)	0	1/21 (4.8%)	1	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Hematuria	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	1/18 (5.6%)	1	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Dysuria	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	1/21 (4.8%)	1	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Urinary Incontinence	0/22 (0%)	0	2/21 (9.5%)	3	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	1/15 (6.7%)	1
Bladder Spasms	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0	0/15 (0%)	0
Burning During Urination	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0	0/15 (0%)	0
Kidney Stones	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	0/15 (0%)	0
Reproductive system and breast disorders
Erectile Dysfunction	1/22 (4.5%)	1	0/21 (0%)	0	1/21 (4.8%)	1	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	0/15 (0%)	0
Libido	1/22 (4.5%)	1	1/21 (4.8%)	1	2/21 (9.5%)	2	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	0/15 (0%)	0
Breast Pain	1/22 (4.5%)	1	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Irregular Menses	0/22 (0%)	0	1/21 (4.8%)	1	1/21 (4.8%)	1	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Orgasmic dyfunction	0/22 (0%)	0	0/21 (0%)	0	1/21 (4.8%)	1	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Vaginal Dryness	0/22 (0%)	0	0/21 (0%)	0	1/21 (4.8%)	1	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Breast Tenderness	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0	0/15 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnea	3/22 (13.6%)	3	1/21 (4.8%)	1	1/21 (4.8%)	1	4/18 (22.2%)	5	3/21 (14.3%)	4	5/17 (29.4%)	6	3/20 (15%)	5	2/15 (13.3%)	2
Pneumonitis	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1	4/20 (20%)	4	0/15 (0%)	0
Bronchospasm	2/22 (9.1%)	3	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Cough	8/22 (36.4%)	10	3/21 (14.3%)	3	3/21 (14.3%)	4	7/18 (38.9%)	8	3/21 (14.3%)	4	2/17 (11.8%)	2	6/20 (30%)	8	3/15 (20%)	4
Upper Respiratory Infection	3/22 (13.6%)	6	3/21 (14.3%)	3	0/21 (0%)	0	3/18 (16.7%)	3	1/21 (4.8%)	1	1/17 (5.9%)	1	1/20 (5%)	1	2/15 (13.3%)	2
Paranasal Sinus Reactions	1/22 (4.5%)	1	0/21 (0%)	0	1/21 (4.8%)	1	0/18 (0%)	0	1/21 (4.8%)	1	0/17 (0%)	0	0/20 (0%)	0	1/15 (6.7%)	1
Chest Pain	5/22 (22.7%)	6	1/21 (4.8%)	1	0/21 (0%)	0	2/18 (11.1%)	2	1/21 (4.8%)	1	3/17 (17.6%)	3	1/20 (5%)	1	1/15 (6.7%)	1
Wheezing	1/22 (4.5%)	2	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	1/15 (6.7%)	1
Vital Capacity	1/22 (4.5%)	1	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Voice Changes	2/22 (9.1%)	2	1/21 (4.8%)	1	1/21 (4.8%)	1	1/18 (5.6%)	1	0/21 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0	1/15 (6.7%)	1
Hiccoughs	0/22 (0%)	0	0/21 (0%)	0	2/21 (9.5%)	2	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Sinus Congestion	0/22 (0%)	0	0/21 (0%)	0	1/21 (4.8%)	1	1/18 (5.6%)	1	0/21 (0%)	0	1/17 (5.9%)	1	1/20 (5%)	1	1/15 (6.7%)	1
Throat Pain	0/22 (0%)	0	1/21 (4.8%)	1	0/21 (0%)	0	2/18 (11.1%)	3	0/21 (0%)	0	2/17 (11.8%)	2	1/20 (5%)	1	0/15 (0%)	0
Pleural Effusion	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	1/18 (5.6%)	1	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	0/15 (0%)	0
Pneumothorax	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	1/21 (4.8%)	1	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Aspiration	0/22 (0%)	0	1/21 (4.8%)	1	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Edema	0/22 (0%)	0	1/21 (4.8%)	1	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Bronchitis	0/22 (0%)	0	1/21 (4.8%)	1	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	1/15 (6.7%)	1
Tachycardia	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0	0/15 (0%)	0
CO2 Serum Low	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	1/15 (6.7%)	1
Skin and subcutaneous tissue disorders
Rash	8/22 (36.4%)	8	5/21 (23.8%)	5	6/21 (28.6%)	10	1/18 (5.6%)	1	4/21 (19%)	4	11/17 (64.7%)	12	6/20 (30%)	7	4/15 (26.7%)	4
Pruritus	4/22 (18.2%)	4	0/21 (0%)	0	3/21 (14.3%)	3	3/18 (16.7%)	3	2/21 (9.5%)	2	1/17 (5.9%)	2	2/20 (10%)	2	2/15 (13.3%)	2
Dry Skin	3/22 (13.6%)	3	2/21 (9.5%)	2	4/21 (19%)	4	11/18 (61.1%)	13	19/21 (90.5%)	19	9/17 (52.9%)	9	9/20 (45%)	9	10/15 (66.7%)	10
Alopecia	3/22 (13.6%)	3	4/21 (19%)	4	5/21 (23.8%)	5	4/18 (22.2%)	4	5/21 (23.8%)	5	1/17 (5.9%)	1	3/20 (15%)	3	6/15 (40%)	6
Bruising	2/22 (9.1%)	2	1/21 (4.8%)	1	1/21 (4.8%)	1	2/18 (11.1%)	2	0/21 (0%)	0	1/17 (5.9%)	1	1/20 (5%)	1	2/15 (13.3%)	2
Cellulitis	2/22 (9.1%)	2	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	2/21 (9.5%)	2	0/17 (0%)	0	0/20 (0%)	0	1/15 (6.7%)	1
Shingles	1/22 (4.5%)	1	0/21 (0%)	0	1/21 (4.8%)	1	1/18 (5.6%)	1	2/21 (9.5%)	2	0/17 (0%)	0	0/20 (0%)	0	1/15 (6.7%)	1
Nail Changes	0/22 (0%)	0	0/21 (0%)	0	1/21 (4.8%)	1	0/18 (0%)	0	1/21 (4.8%)	1	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Acne	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	1/18 (5.6%)	1	1/21 (4.8%)	1	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Skin Lesion	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	3/18 (16.7%)	3	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Facial Hair Growth	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	1/18 (5.6%)	1	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Erythema Multiforme	0/22 (0%)	0	1/21 (4.8%)	1	0/21 (0%)	0	0/18 (0%)	0	1/21 (4.8%)	1	1/17 (5.9%)	1	0/20 (0%)	0	0/15 (0%)	0
Cheilosis	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	1/21 (4.8%)	1	0/17 (0%)	0	0/20 (0%)	0	1/15 (6.7%)	1
Ecchymosis Lower Extremity	0/22 (0%)	0	1/21 (4.8%)	1	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Uticaria	0/22 (0%)	0	1/21 (4.8%)	1	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Burn	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0	0/15 (0%)	0
Ulceration	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0	0/15 (0%)	0
Wound Complication	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0	0/15 (0%)	0
Skin Sensitivity	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	0/15 (0%)	0
Dermatitis	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	0/15 (0%)	0
Flushing	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	0/15 (0%)	0
Hyperpigmentation	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	1/15 (6.7%)	1
Agraphesthesia	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	0/15 (0%)	0
Injection Site Reaction	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	1/15 (6.7%)	1
Vascular disorders
Thrombosis	4/22 (18.2%)	5	0/21 (0%)	0	0/21 (0%)	0	1/18 (5.6%)	1	2/21 (9.5%)	2	1/17 (5.9%)	1	1/20 (5%)	1	0/15 (0%)	0
Hemorrhage	1/22 (4.5%)	1	0/21 (0%)	0	0/21 (0%)	0	3/18 (16.7%)	4	1/21 (4.8%)	2	0/17 (0%)	0	3/20 (15%)	3	1/15 (6.7%)	1
Thrombophlebitis	1/22 (4.5%)	1	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Varicosities	0/22 (0%)	0	0/21 (0%)	0	1/21 (4.8%)	1	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	0/20 (0%)	0	0/15 (0%)	0
Deep Vein Thrombosis	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	1/21 (4.8%)	1	1/17 (5.9%)	1	0/20 (0%)	0	1/15 (6.7%)	1
Necrosis	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	0/15 (0%)	0
Peripheral Vascular Disease	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	0/15 (0%)	0
Vein Injury	0/22 (0%)	0	0/21 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/17 (0%)	0	1/20 (5%)	1	0/15 (0%)	0

Limitations/Caveats

[Not Specified]

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Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Name/Title	John F de Groot, Chair Ad Interim, Neuro-Oncology
Organization	The University of Texas (UT) MD Anderson Cancer Center
Phone	713-745-3072
Email	jdegroot@mdanderson.org

Responsible Party:

M.D. Anderson Cancer Center

ClinicalTrials.gov Identifier:

NCT00112502

Other Study ID Numbers:

2004-0662
MDA-ID-02586
NCI-6636
MDA-2004-0662
CDR0000432954
NCI-2009-00076

First Posted:

Jun 3, 2005

Last Update Posted:

Oct 18, 2021

Last Verified:

Sep 1, 2021

Temozolomide Alone or in Combination With Thalidomide and/or Isotretinoin and/or Celecoxib in Treating Patients Who Have Undergone Radiation Therapy for Glioblastoma Multiforme

Study Details

Study Description

Brief Summary

Detailed Description

OBJECTIVES:

Study Design

Arms and Interventions

Outcome Measures

Primary Outcome Measures

Secondary Outcome Measures

Eligibility Criteria

Criteria

DISEASE CHARACTERISTICS:

PATIENT CHARACTERISTICS:

PRIOR CONCURRENT THERAPY:

Contacts and Locations

Locations

Sponsors and Collaborators

Investigators

Study Documents (Full-Text)

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Additional Information:

Publications

Study Results

Participant Flow

Baseline Characteristics

Outcome Measures

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Adverse Events

All Cause Mortality

Serious Adverse Events

Other (Not Including Serious) Adverse Events

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Results Point of Contact