Erlotinib and Radiation Therapy in Treating Young Patients With Newly Diagnosed Glioma

• Sponsor: St. Jude Children's Research Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT00124657
• Collaborator: Rady Children's Hospital, San Diego (Other), Duke University (Other)
• Enrollment: 62
• Locations: 3
• Arm: 1
• Duration (Months): 114
• Patients Per Site: 20.7
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Erlotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. It may also make tumor cells more sensitive to radiation therapy. Giving radiation therapy together with erlotinib may kill more tumor cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of erlotinib when given together with radiation therapy and to see how well they work in treating young patients with newly diagnosed glioma.

Condition or Disease	Intervention/Treatment	Phase
Brain and Central Nervous System Tumors	Drug: Erlotinib hydrochloride	Phase 1/Phase 2

Detailed Description

OBJECTIVES:

Primary

• Determine the maximum tolerated dose and dose-limiting toxicity of erlotinib when administered during and after radiotherapy in young patients with newly diagnosed high-grade glioma and unfavorable low-grade glioma.

• Determine the 1- and 2-year progression-free survival of patients treated with this regimen.

Secondary

• Determine the toxic effects of this regimen in these patients.

• Correlate genetic abnormalities in epidermal growth factor receptor (EGFR) and components of downstream pathways with treatment response in patients treated with this regimen.

• Determine the ability of erlotinib to inhibit EGFR signaling in patients with high-grade glioma who require second surgery.

• Determine the pharmacokinetics of erlotinib and its metabolites in these patients.

• Correlate plasma and cerebrospinal fluid levels of vascular endothelial growth factor and basic fibroblast growth factor with tumor response in patients treated with this regimen.

• Correlate irradiation dosimetry with patterns of failure, standard and investigational imaging, and toxicity in patients treated with this regimen.

OUTLINE: This is a phase I dose-escalation study of erlotinib followed by a phase II study.

• Phase I: Patients undergo radiotherapy once daily, 5 days week, for approximately 6½ weeks. Beginning on the first day of radiotherapy, patients receive oral erlotinib once daily for up to 2 years.

Cohorts of patients receive escalating doses of erlotinib until the maximum tolerated dose (MTD) is determined.

• Phase II: Patients will receive erlotinib as in phase I at the MTD and undergo radiotherapy as in phase I.

PROJECTED ACCRUAL: A total of 75-80 patients (15-20 for the phase I portion and 60 for the phase II portion) will be accrued for this study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 62 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Trial of a New Tyrosine Kinase Inhibitor (Tarceva; Erlotinib Hydrochloride; OSI-774) During and After Radiotherapy in the Treatment of Patients With Newly Diagnosed High Grade Glioma and Unfavorable Low-Grade Glioma
• Study Start Date: Mar 1, 2005
• Actual Primary Completion Date: Jul 1, 2012
• Actual Study Completion Date: Sep 1, 2014

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Patients with High-Grade/Low-Grade Glioma Patients with newly diagnosed high-grade glioma (excluding those originating in the brain stem) and unfavorable low-grade glioma who are ≥ 3 years and <26 years of age. Patients receiving enzyme-inducing anticonvulsants (EIACs) are not eligible for this study. Patients with spinal cord tumors will be eligible for the Phase I and Phase II component of this study, but they will not be taken into consideration to estimate PFS in the Phase II component of this trial because of their notoriously worse prognosis. Patients receive erlotinib hydrochloride.

Drug: Erlotinib hydrochloride; This study has 2 components: a Phase I component which estimated the MTD and DLT(s) of erlotinib given once a day during and after conventionally fractionated RT for a period of 8 weeks (DLT-evaluation period), followed by continuous administration of this medication for up to 3 years; and a Phase II component where erlotinib will be given at the MTD during and after RT for 2 years. The recommended dose of erlotinib for the Phase II component of the current study is 120mg/m2 per day (maximum dose of 200mg per day).; Other Names: Tarceva OSI-774 NSC#718781

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Dose-limiting Toxicity (DLT) [During the first 8 weeks of therapy]

   DLT was defined as any of the following toxicities attributable to erlotinib therapy: thrombocytopenia grade 3 and 4; neutropenia grade 4; or any grade 3 and 4 non-hematologic toxicity except for grade 3 diarrhea and grade 3 nausea and vomiting lasting ≤48 hours in participants not receiving optimal supportive therapy, grade 3 skin rash, which did not affect normal daily activities, grade 3 fever or nonneutropenic infection, grade 3 seizures, grade 3 weight gain or loss, and grade 3 transaminase elevation that returned to grade 1 or baseline within 7 days. After enrollment of the first 4 participants, grade 3 and 4 electrolyte abnormalities that resolved to ≤grade 2 within 7 days were excluded as DLT. Toxicities were graded according to the Common Terminology Criteria for Adverse Events version 3.0.

2. Maximum Tolerated Dose (MTD) of Erlotinib [During the first 8 weeks of therapy.]

   MTD was defined as the highest dosage level in which no more than one of six assessable participants experienced dose-limiting toxicities (DLT). The dosage of erlotinib was increased by approximately 30% in each dosage level starting at 80% of the MTD in adults with solid tumors. A traditional 3+3 dose escalation scheme was used to estimate the MTD.

3. Progression Free Survival (PFS) [1 and 2 years after end of therapy]

   Progression-free survival (PFS) distributions for the Phase II participants with anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM) were calculated using Kaplan-Meier estimates (n=41). PFS was defined as the interval between treatment start and initial failure, including clinical or radiologic progression or death from any cause. PFS was not calculated for the other disease types.

Secondary Outcome Measures

1. Cmax of Erlotinib and Its Metabolite OSI-420 [After first dose of therapy, and Day 8 of therapy]

   Although the calculated dose of erlotinib was rounded to the nearest 25 mg, the actual dosage administered to patients was within 12% of the prescribed dosage in all but 1 patient. The latter patient received erlotinib at the lowest dosage level and the actual dosage was 19% higher than the calculated dose.

2. Erlotinib Tmax [After first dose of therapy]

   Although the calculated dose of erlotinib was rounded to the nearest 25 mg, the actual dosage administered to patients was within 12% of the prescribed dosage in all but 1 patient. The latter patient received erlotinib at the lowest dosage level and the actual dosage was 19% higher than the calculated dose.

3. AUC Time 0-infinite (AUCinf) of Erlotinib and Its Metabolite OSI-420 [After first dose of therapy, and Day 8 of therapy]

   Although the calculated dose of erlotinib was rounded to the nearest 25 mg, the actual dosage administered to patients was within 12% of the prescribed dosage in all but 1 patient. The latter patient received erlotinib at the lowest dosage level and the actual dosage was 19% higher than the calculated dose.

4. Number of Positive Mutations of EGFR and Downstream Pathways [Once at tumor resection and diagnosis]

   Statistical analyses of genomic changes, expression profiles and validation studies should be considered in an exploratory and hypothesis-generating context. Fresh frozen tumor tissue was obtained at the time of tumor resection and diagnosis. DNA was extracted from formalin-fixed, paraffin-embedded tissue. The entire PTEN coding sequence (exons 1-9), exons 1, 9 and 20 of PIK3CA, and exons 17-24 of EGFR were evaluated using exon-specific PCR amplification, and immunohistochemistry was done. Tumor lesions were considered positive if >25% cells were immunoreactive.

5. Ability of Erlotinib to Inhibit EGFR Signaling [5 Years]

   The objective was to test the ability of erlotinib to inhibit the EGFR signaling in patients with high-grade glioma who required a second surgery. This outcome was not assessed due to insufficient availability of tumor and control samples for analysis.

6. Correlation Between Standard Magnetic Resonance Imaging and Investigational Radiologic Techniques in Assessing Tumor Response to This Treatment [at diagnosis and regular intervals during therapy (up to 2 years after start of therapy)]

   This objective was to prospectively investigate the correlation between standard magnetic resonance imaging (MRI) and investigational radiologic techniques (MR spectroscopy, perfusion/diffusion, PET scan, DEMRI/BLAST) in assessing tumor response to this treatment.

7. To Prospectively Investigate the Technical Factors Involved in Planning and Administering Conformal Fractionated RT as Outlined in This Study, and to Correlate RT Dosimetry With Patterns of Failure, Standard and Investigational Imaging and Toxicity [5 Years]

8. Plasma and CSF Levels of VEGF, bFGF, and SDF1 [at diagnosis and regular intervals during therapy (up to 2 years after start of therapy)]

   This objective was to determine the plasma and CSF levels of the VEGF, bFGF, and SDF1 at diagnosis, and the plasma levels of these factors at regular intervals during therapy, and to analyze the association of these results with tumor response.

9. Number of Participants Experiencing Grade 3 or 4 Toxicity Events [From start of therapy through 2 years.]

   Adverse events were collected systematically for each of the 44 Phase II participants from the time of enrollment to the completion of therapy (approximately 2 years from start of therapy).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 3 Years to 21 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Diagnosis of high-grade glioma of 1 of the following types:

• Unfavorable low-grade glioma

• Gliomatosis cerebri or bithalamic involvement

• Histologically confirmed high-grade glioma (WHO grade III or IV) of 1 of the following subtypes:

• Anaplastic astrocytoma

• Anaplastic oligodendroglioma

• Anaplastic oligoastrocytoma

• Anaplastic ganglioglioma

• Pleomorphic xanthoastrocytoma with anaplastic features

• Malignant glioneuronal tumor

• Glioblastoma multiforme

• Gliosarcoma

• Newly diagnosed disease

• Intracranial or spinal cord tumors allowed

PATIENT CHARACTERISTICS:

Age

• 3 to 21

Performance status

• Karnofsky 40-100% (age 17 to 21 years) OR

• Lansky 40-100% (age 3 to 16 years)

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count ≥ 1,000/mm^3

• Platelet count ≥ 100,000/mm^3 (transfusion independent)

• Hemoglobin ≥ 8 g/dL (transfusion allowed)

Hepatic

• Bilirubin < 1.5 times upper limit of normal (ULN)

• SGPT < 5 times ULN

• Albumin ≥ 2 g/dL

Renal

• Creatinine < 2 times normal OR

• Glomerular filtration rate > 70 mL/min

Cardiovascular

• No significant cardiovascular problem

Pulmonary

• No significant pulmonary problem

Other

• Not pregnant or nursing

• Fertile patients must use effective contraception

• No uncontrolled infection

• No significant medical illness

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No prior or concurrent biologic agents

Chemotherapy

• No prior or concurrent chemotherapy

Endocrine therapy

• Not specified

Radiotherapy

• No prior radiotherapy

Surgery

• No more than 42 days since prior surgery

Other

• No other prior or concurrent anticancer or experimental treatment

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California San Diego	San Diego	California	United States	92123-4282
2	Duke Children's Hospital and Health Center	Durham	North Carolina	United States	27710
3	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105

Sponsors and Collaborators

• St. Jude Children's Research Hospital
• Rady Children's Hospital, San Diego
• Duke University

Investigators

• Principal Investigator: Alberto Broniscer, MD, St. Jude Children's Research Hospital

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude

Publications

None provided.

• Responsible Party: St. Jude Children's Research Hospital
• ClinicalTrials.gov Identifier: NCT00124657
• Other Study ID Numbers: SJHG04
• First Posted: Jul 28, 2005
• Last Update Posted: Dec 4, 2015
• Last Verified: Oct 1, 2015

• Keywords provided by St. Jude Children's Research Hospital: adult anaplastic astrocytoma; adult anaplastic oligodendroglioma; adult glioblastoma; adult giant cell glioblastoma; adult gliosarcoma; adult mixed glioma; childhood mixed glioma; untreated childhood cerebellar astrocytoma; childhood high-grade cerebral astrocytoma; childhood low-grade cerebral astrocytoma; childhood oligodendroglioma; childhood spinal cord neoplasm
• Additional relevant MeSH terms: Glioma; Nervous System Neoplasms; Central Nervous System Neoplasms; Erlotinib Hydrochloride

Study Results

Participant Flow

Recruitment Details	Overall accrual included 62 unique subjects. Five subjects participated in both Phase I and Phase II. Phase I enrolled 23 (03/2005-06/2007). Phase II enrolled an additional 39 participants (08/2007-11/2010) plus 5 carried over from Phase I for a total of 44. One of the 39 accrued to Phase II was enrolled at Rady Children's Hospital.
Pre-assignment Detail	Participants had newly diagnosed high-grade glioma (except those originating in the brain stem) and unfavorable low-grade glioma and were ≥ 3 and ≤21 years of age. Participants receiving enzyme-inducing anticonvulsants (EIACs) were not eligible for this study. Patients with spinal cord tumors were eligible for the Phase II component of this study.

Arm/Group Title	Phase I Only	Phase I and Phase II	Phase II Only
Arm/Group Description	18 participants were enrolled on the Phase I portion of the trial only.	5 patients participated in both the Phase I portion and the Phase II portion of the study.	39 participants were enrolled on the Phase II portion of the trial only.
Period Title: Overall Study
STARTED	18	5	39
COMPLETED	2	0	7
NOT COMPLETED	16	5	32

Baseline Characteristics

Arm/Group Title	Phase I Only	Phase I and Phase II	Phase II Only	Total
Arm/Group Description	18 participants were enrolled on the Phase I portion of the trial only.	5 patients participated in both the Phase I portion and the Phase II portion of the study.	39 participants were enrolled on the Phase II portion of the trial only.	Total of all reporting groups
Overall Participants	18	5	39	62
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	11.49 (4.31)	11.47 (6.05)	10.55 (4.85)	11.12 (4.81)
Sex: Female, Male (Count of Participants)
Female	8 44.4%	2 40%	23 59%	33 53.2%
Male	10 55.6%	3 60%	16 41%	29 46.8%
Diagnosis (participants) [Number]
Anaplastic astrocytoma (AA)	7 38.9%	1 20%	19 48.7%	27 43.5%
Glioblastoma multiforme (GBM)	8 44.4%	4 80%	17 43.6%	29 46.8%
Anaplastic oligoastrocytoma	2 11.1%	0 0%	1 2.6%	3 4.8%
Anaplastic ganglioglioma	1 5.6%	0 0%	0 0%	1 1.6%
Unfavorable fibrillary astrocytoma	0 0%	0 0%	1 2.6%	1 1.6%
Spinal GBM	0 0%	0 0%	1 2.6%	1 1.6%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Dose-limiting Toxicity (DLT)
Description	DLT was defined as any of the following toxicities attributable to erlotinib therapy: thrombocytopenia grade 3 and 4; neutropenia grade 4; or any grade 3 and 4 non-hematologic toxicity except for grade 3 diarrhea and grade 3 nausea and vomiting lasting ≤48 hours in participants not receiving optimal supportive therapy, grade 3 skin rash, which did not affect normal daily activities, grade 3 fever or nonneutropenic infection, grade 3 seizures, grade 3 weight gain or loss, and grade 3 transaminase elevation that returned to grade 1 or baseline within 7 days. After enrollment of the first 4 participants, grade 3 and 4 electrolyte abnormalities that resolved to ≤grade 2 within 7 days were excluded as DLT. Toxicities were graded according to the Common Terminology Criteria for Adverse Events version 3.0.
Time Frame	During the first 8 weeks of therapy

Outcome Measure Data

Analysis Population Description

23 participants were enrolled on Phase I component; 22 were analyzed for DLT over 4 dose levels. 1 treated at dose level 120mg/m^2 was not assessable for DLT due to early tumor progression. 4 were treated before and 19 after the study was amended to exclude grade 3 and 4 electrolyte abnormalities that resolved to ≤ grade 2 within 7 days.

Arm/Group Title	70 mg/m^2	90 mg/m^2	120 mg/m^2	160 mg/m^2
Arm/Group Description	Dose level 1 was 70 mg/m^2, range of actual dosage was 68-83 mg/m^2.	Dose level 2 was 90 mg/m^2, range of actual dosage was 85-87.5 mg/m^2.	Dose level 3 was 120 mg/m^2, range of actual dosage was 107-128 mg/m^2.	Dose level 4 was 160 mg/m^2, range of actual dosage was 151.5-167 mg/m^2.
Measure Participants	7	3	6	6
Number [participants]	0 0%	0 0%	1 2.6%	2 3.2%

2. Secondary Outcome

Title	Cmax of Erlotinib and Its Metabolite OSI-420
Description	Although the calculated dose of erlotinib was rounded to the nearest 25 mg, the actual dosage administered to patients was within 12% of the prescribed dosage in all but 1 patient. The latter patient received erlotinib at the lowest dosage level and the actual dosage was 19% higher than the calculated dose.
Time Frame	After first dose of therapy, and Day 8 of therapy

Outcome Measure Data

Analysis Population Description

Pharmacokinetic variables were obtained in 17 patients enrolled on the Phase I portion of the study.

Arm/Group Title	70 mg/m^2	90 mg/m^2	120 mg/m^2	160 mg/m^2
Arm/Group Description	Dose level 1 was 70 mg/m^2, range of actual dosage was 68-83 mg/m^2.	Dose level 2 was 90 mg/m^2, range of actual dosage was 85-87.5 mg/m^2.	Dose level 3 was 120 mg/m^2, range of actual dosage was 107-128 mg/m^2.	Dose level 4 was 160 mg/m^2, range of actual dosage was 151.5-167 mg/m^2.
Measure Participants	7	2	5	3
Erlotinib, after first dose of therapy	1.3	1.6	1.2	1.8
Erlotinib, Day 8 of therapy	1.8	1.3	1.4	2
OSI-420, after first dose of therapy	0.13	0.16	0.14	0.32
OSI-420, Day 8 of therapy	0.25	0.17	0.3	0.3

3. Secondary Outcome

Title	Erlotinib Tmax
Description	Although the calculated dose of erlotinib was rounded to the nearest 25 mg, the actual dosage administered to patients was within 12% of the prescribed dosage in all but 1 patient. The latter patient received erlotinib at the lowest dosage level and the actual dosage was 19% higher than the calculated dose.
Time Frame	After first dose of therapy

Outcome Measure Data

Analysis Population Description

Pharmacokinetic variables were obtained in 17 patients enrolled on the Phase I portion of the study.

Arm/Group Title	70 mg/m^2	90 mg/m^2	120 mg/m^2	160 mg/m^2
Arm/Group Description	Dose level 1 was 70 mg/m^2, range of actual dosage was 68-83 mg/m^2.	Dose level 2 was 90 mg/m^2, range of actual dosage was 85-87.5 mg/m^2.	Dose level 3 was 120 mg/m^2, range of actual dosage was 107-128 mg/m^2.	Dose level 4 was 160 mg/m^2, range of actual dosage was 151.5-167 mg/m^2.
Measure Participants	7	2	5	3
Erlotinib, after first dose of therapy	4	3.1	2.2	2.2
Erlotinib, Day 8 of therapy	2.1	2.6	1.75	2.2

4. Secondary Outcome

Title	AUC Time 0-infinite (AUCinf) of Erlotinib and Its Metabolite OSI-420
Description	Although the calculated dose of erlotinib was rounded to the nearest 25 mg, the actual dosage administered to patients was within 12% of the prescribed dosage in all but 1 patient. The latter patient received erlotinib at the lowest dosage level and the actual dosage was 19% higher than the calculated dose.
Time Frame	After first dose of therapy, and Day 8 of therapy

Outcome Measure Data

Analysis Population Description

Pharmacokinetic variables were obtained in 17 patients enrolled on the Phase I portion of the study.

Arm/Group Title	70 mg/m^2	90 mg/m^2	120 mg/m^2	160 mg/m^2
Arm/Group Description	Dose level 1 was 70 mg/m^2, range of actual dosage was 68-83 mg/m^2.	Dose level 2 was 90 mg/m^2, range of actual dosage was 85-87.5 mg/m^2.	Dose level 3 was 120 mg/m^2, range of actual dosage was 107-128 mg/m^2.	Dose level 4 was 160 mg/m^2, range of actual dosage was 151.5-167 mg/m^2.
Measure Participants	7	2	5	3
Erlotinib, after first dose of therapy	34.9	23.9	27.8	37.1
Erlotinib, Day 8 of therapy	28.8	21.2	23.1	35.5
OSI-420, after first dose of therapy	2.1	1.9	2.5	4.2
OSI-420, Day 8 of therapy	3.3	2.1	2.8	4.3

5. Secondary Outcome

Title	Number of Positive Mutations of EGFR and Downstream Pathways
Description	Statistical analyses of genomic changes, expression profiles and validation studies should be considered in an exploratory and hypothesis-generating context. Fresh frozen tumor tissue was obtained at the time of tumor resection and diagnosis. DNA was extracted from formalin-fixed, paraffin-embedded tissue. The entire PTEN coding sequence (exons 1-9), exons 1, 9 and 20 of PIK3CA, and exons 17-24 of EGFR were evaluated using exon-specific PCR amplification, and immunohistochemistry was done. Tumor lesions were considered positive if >25% cells were immunoreactive.
Time Frame	Once at tumor resection and diagnosis

Outcome Measure Data

Analysis Population Description

Unstained slides were available for immunohistochemistry analysis in 21 of the 23 Phase I participants.

Arm/Group Title	Phase I
Arm/Group Description	Phase I participants
Measure Participants	21
Positive for PTEN (R130*)	1 5.6%
Positive PIK3CA (H1047R)	1 5.6%
Positive EGFR kinase domain	0 0%

6. Primary Outcome

Title	Maximum Tolerated Dose (MTD) of Erlotinib
Description	MTD was defined as the highest dosage level in which no more than one of six assessable participants experienced dose-limiting toxicities (DLT). The dosage of erlotinib was increased by approximately 30% in each dosage level starting at 80% of the MTD in adults with solid tumors. A traditional 3+3 dose escalation scheme was used to estimate the MTD.
Time Frame	During the first 8 weeks of therapy.

Outcome Measure Data

Analysis Population Description

22 participants were analyzed for MTD over 4 dose levels. One of 23 enrolled participants was not evaluable due to early disease progression.

Arm/Group Title	Phase I
Arm/Group Description	22 participants were analyzed for MLT over 4 dose levels.
Measure Participants	22
Number [mg/m^2]	120

7. Primary Outcome

Title	Progression Free Survival (PFS)
Description	Progression-free survival (PFS) distributions for the Phase II participants with anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM) were calculated using Kaplan-Meier estimates (n=41). PFS was defined as the interval between treatment start and initial failure, including clinical or radiologic progression or death from any cause. PFS was not calculated for the other disease types.
Time Frame	1 and 2 years after end of therapy

Outcome Measure Data

Analysis Population Description

Per protocol, 41 participants with either anaplastic astrocytoma or glioblastoma multiforme were analyzed for this outcome.

Arm/Group Title	Phase I AA	Phase I GBM	Phase II AA	Phase II GBM
Arm/Group Description	All participants with a diagnosis of anaplastic astrocytoma (AA) and treated on Phase I.	All participants with a diagnosis of glioblastoma multiforme (GBM) and treated on Phase I.	Participants with a diagnosis of intracranial anaplastic astrocytoma (AA) treated with a combination of maximum safe surgical resection, local RT, and erlotinib.	Participants with a diagnosis of intracranial glioblastoma multiforme (GBM) treated with a combination of maximum safe surgical resection, local RT, and erlotinib.
Measure Participants	8	12	20	21
1-year PFS	0.75 (0.14)	0.33 (0.12)	0.45 (0.106)	0.19 (0.077)
2-year PFS	NA (NA)	NA (NA)	0.15 (0.069)	0.19 (0.077)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	70 mg/m^2
	Comments	1-year progression-free survival (n=8)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Kaplan-Meier
	Estimated Value	0.75
	Confidence Interval	(2-Sided) 95%; 0.48 to 1.00
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.14
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	90 mg/m^2
	Comments	1-year progression-free survival (n=12)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Kaplan-Meier
	Estimated Value	0.33
	Confidence Interval	(2-Sided) 95%; 0.09 to 0.57
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.12
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	120 mg/m^2
	Comments	1-year progression free survival (n=20)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Kaplan-Meier
	Estimated Value	0.45
	Confidence Interval	(2-Sided) 95%; 0.198 to 0.602
	Parameter Dispersion	Type: Standard Deviation; Value: 0.106
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	120 mg/m^2
	Comments	2-year progression free survival (n=20)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Kaplan-Meier
	Estimated Value	0.150
	Confidence Interval	(2-Sided) 95%; 0.015 to 0.285
	Parameter Dispersion	Type: Standard Deviation; Value: 0.069
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	160 mg/m^2
	Comments	1-year progression free survival (n=21)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Kaplan-Meier
	Estimated Value	0.190
	Confidence Interval	(2-Sided) 95%; 0.039 to 0.341
	Parameter Dispersion	Type: Standard Deviation; Value: 0.077
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	160 mg/m^2
	Comments	2-year progression free survival (n=21)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Kaplan-Meier
	Estimated Value	0.190
	Confidence Interval	(2-Sided) 95%; 0.039 to 0.341
	Parameter Dispersion	Type: Standard Deviation; Value: 0.077
	Estimation Comments

8. Secondary Outcome

Title	Ability of Erlotinib to Inhibit EGFR Signaling
Description	The objective was to test the ability of erlotinib to inhibit the EGFR signaling in patients with high-grade glioma who required a second surgery. This outcome was not assessed due to insufficient availability of tumor and control samples for analysis.
Time Frame	5 Years

Outcome Measure Data

Analysis Population Description

This outcome was not assessed due to insufficient availability of tumor and control samples for analysis.

Arm/Group Title	Patients With High-Grade/Low-Grade Glioma
Arm/Group Description	Participants included patients with newly diagnosed high-grade glioma (excluding those originating in the brain stem) and unfavorable low-grade glioma who are ≥ 3 years and <26 years of age. Patients receiving enzyme-inducing anticonvulsants (EIACs) were not eligible for this study. Patients received erlotinib hydrochloride: In the Phase II component of this study, erlotinib was given at the MTD during and after RT for 2 years. The recommended dose of erlotinib for the Phase II component of the current study was 120mg/m^2 per day (maximum dose of 200mg per day).
Measure Participants	0

9. Secondary Outcome

Title	Correlation Between Standard Magnetic Resonance Imaging and Investigational Radiologic Techniques in Assessing Tumor Response to This Treatment
Description	This objective was to prospectively investigate the correlation between standard magnetic resonance imaging (MRI) and investigational radiologic techniques (MR spectroscopy, perfusion/diffusion, PET scan, DEMRI/BLAST) in assessing tumor response to this treatment.
Time Frame	at diagnosis and regular intervals during therapy (up to 2 years after start of therapy)

Outcome Measure Data

Analysis Population Description

This objective became obsolete over the course of the protocol, and data was not collected.

Arm/Group Title	Patients With High-Grade/Low-Grade Glioma
Arm/Group Description	Participants included patients with newly diagnosed high-grade glioma (excluding those originating in the brain stem) and unfavorable low-grade glioma who are ≥ 3 years and <26 years of age. Patients receiving enzyme-inducing anticonvulsants (EIACs) were not eligible for this study. Patients received erlotinib hydrochloride: In the Phase II component of this study, erlotinib was given at the MTD during and after RT for 2 years. The recommended dose of erlotinib for the Phase II component of the current study was 120mg/m^2 per day (maximum dose of 200mg per day).
Measure Participants	0

10. Secondary Outcome

Title	To Prospectively Investigate the Technical Factors Involved in Planning and Administering Conformal Fractionated RT as Outlined in This Study, and to Correlate RT Dosimetry With Patterns of Failure, Standard and Investigational Imaging and Toxicity
Time Frame	5 Years

Outcome Measure Data

Analysis Population Description

This objective became obsolete over the course of the protocol, and data was not collected.

Arm/Group Title	Patients With High-Grade/Low-Grade Glioma
Arm/Group Description	Patients with newly diagnosed high-grade glioma (excluding those originating in the brain stem) and unfavorable low-grade glioma who are ≥ 3 years and <26 years of age. Patients receiving enzyme-inducing anticonvulsants (EIACs) are not eligible for this study. Patients with spinal cord tumors will be eligible for the Phase I and Phase II component of this study, but they will not be taken into consideration to estimate PFS in the Phase II component of this trial because of their notoriously worse prognosis. Patients receive erlotinib hydrochloride. Erlotinib hydrochloride: This study had 2 components: a Phase I component which estimated the MTD and DLT(s) of erlotinib given once a day during and after conventionally fractionated RT for a period of 8 weeks (DLT-evaluation period), followed by continuous administration of this medication for up to 3 years; and a Phase II component where erlotinib was given at the MTD during and after RT for 2 years.
Measure Participants	0

11. Secondary Outcome

Title	Plasma and CSF Levels of VEGF, bFGF, and SDF1
Description	This objective was to determine the plasma and CSF levels of the VEGF, bFGF, and SDF1 at diagnosis, and the plasma levels of these factors at regular intervals during therapy, and to analyze the association of these results with tumor response.
Time Frame	at diagnosis and regular intervals during therapy (up to 2 years after start of therapy)

Outcome Measure Data

Analysis Population Description

This objective became obsolete over the course of the protocol, and data was not collected.

Arm/Group Title	Patients With High-Grade/Low-Grade Glioma
Arm/Group Description	Participants included patients with newly diagnosed high-grade glioma (excluding those originating in the brain stem) and unfavorable low-grade glioma who are ≥ 3 years and <26 years of age. Patients receiving enzyme-inducing anticonvulsants (EIACs) were not eligible for this study. Patients received erlotinib hydrochloride: In the Phase II component of this study, erlotinib was given at the MTD during and after RT for 2 years. The recommended dose of erlotinib for the Phase II component of the current study was 120mg/m^2 per day (maximum dose of 200mg per day).
Measure Participants	0

12. Secondary Outcome

Title	Number of Participants Experiencing Grade 3 or 4 Toxicity Events
Description	Adverse events were collected systematically for each of the 44 Phase II participants from the time of enrollment to the completion of therapy (approximately 2 years from start of therapy).
Time Frame	From start of therapy through 2 years.

Outcome Measure Data

Analysis Population Description

All 44 Phase II participants were evaluated. Eight of 16 participants with lymphopenia received dexamethasone within 4 weeks of the recorded toxicity. In both participants with headache, there was a documented progressive disease within 3 days of the recorded headache.

Arm/Group Title	Grade 3 Toxicity	Grade 4 Toxicity
Arm/Group Description	Grade 3 toxicity per CTCAE 3.0.	Grade 4 toxicity per CTCAE 3.0.
Measure Participants	44	44
Blood: Hemoglobin	2 11.1%	1 20%
Blood: Lymphopenia	7 38.9%	8 160%
Blood: Neutrophils	2 11.1%	1 20%
Blood: Platelets	0 0%	1 20%
Dermatologic: Pruritus	3 16.7%	0 0%
Dermatologic: Rash/Desquamation	1 5.6%	0 0%
Dermatologic: Rash/acne	2 11.1%	0 0%
Gastrointestinal: Anorexia	3 16.7%	0 0%
Gastrointestinal: Diarrhea	5 27.8%	0 0%
Gastrointestinal: Dysphagia	1 5.6%	0 0%
Gastrointestinal: Mucositis	1 5.6%	0 0%
Gastrointestinal: Nausea	2 11.1%	0 0%
Gastrointestinal: Vomiting	4 22.2%	0 0%
Metabolic: ALT/AST	2 11.1%	0 0%
Metabolic: Hypokalemia	2 11.1%	0 0%
Metabolic: Bilirubin	1 5.6%	0 0%
Pain: Headache	1 5.6%	1 20%
Constitutional: Fatigue	1 5.6%	0 0%
Constitutional: Weight Loss	2 11.1%	0 0%

Adverse Events

Time Frame	Adverse events were collected systematically for each of the 23 Phase I and 44 Phase II participants from the time of enrollment to the completion of therapy (approximately 2 years from start of therapy).
Arm/Group Title	70 mg/m^2 (Phase I)		90 mg/m^2 (Phase I)		120 mg/m^2 (Phase I)		160 mg/m^2 (Phase I)		Phase II
Arm/Group Description	Participants received dose of 70 mg/m^2, range of actual dose was 68-83 mg/m^2.		Participants received dose of 90 mg/m^2, range of actual dose was 85-87.5 mg/m^2.		Participants received dose of 120 mg/m^2, range of actual dose was 107-128 mg/m^2.		Participants received dose of 160 mg/m^2, range of actual dose was 151.5-167 mg/m^2.		Phase II participants received 120 mg/m^2.
All Cause Mortality
	70 mg/m^2 (Phase I)		90 mg/m^2 (Phase I)		120 mg/m^2 (Phase I)		160 mg/m^2 (Phase I)		Phase II
	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)
Serious Adverse Events
	70 mg/m^2 (Phase I)		90 mg/m^2 (Phase I)		120 mg/m^2 (Phase I)		160 mg/m^2 (Phase I)		Phase II
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/7 (57.1%)		1/3 (33.3%)		2/7 (28.6%)		4/6 (66.7%)		26/44 (59.1%)
Blood and lymphatic system disorders
Hemoglobin	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	3/44 (6.8%)	7
Lymphopenia	2/7 (28.6%)	2	1/3 (33.3%)	1	2/7 (28.6%)	2	4/6 (66.7%)	6	16/44 (36.4%)	32
Neutrophils	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	3/44 (6.8%)	3
Platelets	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/44 (2.3%)	1
Gastrointestinal disorders
Anorexia	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	3/44 (6.8%)	4
Diarrhea	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	5/44 (11.4%)	6
Dysphagia	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/44 (2.3%)	1
Mucositis	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/44 (2.3%)	1
Nausea	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	2/44 (4.5%)	2
Vomiting	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	4/44 (9.1%)	4
General disorders
Fatigue	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/44 (2.3%)	1
Weight loss	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	2/44 (4.5%)	2
Headache	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	2/44 (4.5%)	2
Metabolism and nutrition disorders
ALT/AST	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	2/44 (4.5%)	2
Hypokalemia	2/7 (28.6%)	2	0/3 (0%)	0	1/7 (14.3%)	2	0/6 (0%)	0	2/44 (4.5%)	4
Bilirubin	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/44 (2.3%)	1
Lipase	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/44 (0%)	0
Hypophosphatemia	1/7 (14.3%)	1	1/3 (33.3%)	1	0/7 (0%)	0	0/6 (0%)	0	0/44 (0%)	0
Skin and subcutaneous tissue disorders
Pruritis	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	3/44 (6.8%)	4
Rash/Desquamation	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/44 (2.3%)	1
Rash/Acne	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	2/44 (4.5%)	2
Other (Not Including Serious) Adverse Events
	70 mg/m^2 (Phase I)		90 mg/m^2 (Phase I)		120 mg/m^2 (Phase I)		160 mg/m^2 (Phase I)		Phase II
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/7 (100%)		3/3 (100%)		7/7 (100%)		6/6 (100%)		43/44 (97.7%)
Blood and lymphatic system disorders
Hemoglobin	6/7 (85.7%)	15	2/3 (66.7%)	2	3/7 (42.9%)	3	4/6 (66.7%)	7	18/44 (40.9%)	41
Leukocytes (total WBC)	4/7 (57.1%)	10	2/3 (66.7%)	3	5/7 (71.4%)	6	3/6 (50%)	8	21/44 (47.7%)	38
Lymphopenia	7/7 (100%)	18	3/3 (100%)	8	7/7 (100%)	14	6/6 (100%)	13	27/44 (61.4%)	104
Neutrophils/granulocytes (ANC/AGC)	2/7 (28.6%)	6	1/3 (33.3%)	1	1/7 (14.3%)	1	1/6 (16.7%)	1	10/44 (22.7%)	16
Platelets	2/7 (28.6%)	2	0/3 (0%)	0	2/7 (28.6%)	3	3/6 (50%)	5	8/44 (18.2%)	10
Edema: limb	1/7 (14.3%)	1	1/3 (33.3%)	1	0/7 (0%)	0	1/6 (16.7%)	1	4/44 (9.1%)	4
Lymphatics - other	0/7 (0%)	0	1/3 (33.3%)	1	0/7 (0%)	0	0/6 (0%)	0	0/44 (0%)	0
Cardiac disorders
Supraventricular and nodal arrhythmia, sinus tachycardia	0/7 (0%)	0	1/3 (33.3%)	1	1/7 (14.3%)	1	2/6 (33.3%)	4	3/44 (6.8%)	4
Hypertension	3/7 (42.9%)	4	2/3 (66.7%)	2	2/7 (28.6%)	2	1/6 (16.7%)	1	6/44 (13.6%)	7
Hypotension	0/7 (0%)	0	1/3 (33.3%)	1	0/7 (0%)	0	0/6 (0%)	0	3/44 (6.8%)	3
Supraventricular and nodal arrhythmia, sinus bradycardia	0/7 (0%)	0	1/3 (33.3%)	1	0/7 (0%)	0	0/6 (0%)	0	0/44 (0%)	0
Palpitations	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	2/44 (4.5%)	3
Ear and labyrinth disorders
Hearing: patients wihtout baseline audiogram and not enrolled in a monitoring program	1/7 (14.3%)	1	0/3 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	3/44 (6.8%)	4
Otitis, external ear (non-infectious)	1/7 (14.3%)	4	2/3 (66.7%)	4	1/7 (14.3%)	1	0/6 (0%)	0	5/44 (11.4%)	6
Auditory/Ear - other	5/7 (71.4%)	8	1/3 (33.3%)	1	0/7 (0%)	0	0/6 (0%)	0	2/44 (4.5%)	2
Otitis, middle ear (non-infectious	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	1/44 (2.3%)	1
Tinnitus	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	2/44 (4.5%)	2
Endocrine disorders
Cushingoid appearance(e.g. moon face, buffalo hump, centripetal obesity, cutaneous striae)	2/7 (28.6%)	2	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	5/44 (11.4%)	5
Eye disorders
Nystagmus	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	3/44 (6.8%)	3
Ocular/visual - other	2/7 (28.6%)	2	1/3 (33.3%)	1	0/7 (0%)	0	1/6 (16.7%)	1	10/44 (22.7%)	11
Ophthalmoplegia/diplopia (double vision)	2/7 (28.6%)	2	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	4/44 (9.1%)	5
Vision-blurred vision	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	3/44 (6.8%)	3
Ocular surface disease	1/7 (14.3%)	1	1/3 (33.3%)	1	2/7 (28.6%)	2	4/6 (66.7%)	4	2/44 (4.5%)	2
Vision-photophobia	2/7 (28.6%)	2	1/3 (33.3%)	1	1/7 (14.3%)	1	0/6 (0%)	0	1/44 (2.3%)	1
Cataract	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/44 (0%)	0
Dry eye syndrome	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/44 (2.3%)	1
Eyelid dysfunction	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/44 (0%)	0
Gastrointestinal disorders
Anorexia	4/7 (57.1%)	10	2/3 (66.7%)	3	2/7 (28.6%)	3	5/6 (83.3%)	5	26/44 (59.1%)	30
Constipation	3/7 (42.9%)	4	1/3 (33.3%)	1	1/7 (14.3%)	1	4/6 (66.7%)	4	8/44 (18.2%)	11
Dehydration	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	1/6 (16.7%)	2	7/44 (15.9%)	7
Diarrhea	6/7 (85.7%)	13	3/3 (100%)	4	7/7 (100%)	8	4/6 (66.7%)	8	28/44 (63.6%)	51
Gastrointestinal - Other	1/7 (14.3%)	2	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	8/44 (18.2%)	12
Heartburn/dyspepsia	1/7 (14.3%)	2	2/3 (66.7%)	3	0/7 (0%)	0	0/6 (0%)	0	5/44 (11.4%)	5
Mucositis/stomatitis (clinical exam), oral cavity	1/7 (14.3%)	1	3/3 (100%)	5	3/7 (42.9%)	3	1/6 (16.7%)	1	4/44 (9.1%)	4
Mucositis/stomatitis (functional/symptomatic), oral cavity	1/7 (14.3%)	1	0/3 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	3/44 (6.8%)	3
Nausea	6/7 (85.7%)	11	2/3 (66.7%)	5	3/7 (42.9%)	4	4/6 (66.7%)	6	19/44 (43.2%)	27
Taste alteration (dysgeusia)	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	5/44 (11.4%)	7
Vomiting	5/7 (71.4%)	13	1/3 (33.3%)	3	3/7 (42.9%)	4	4/6 (66.7%)	5	19/44 (43.2%)	31
Dental: teeth	1/7 (14.3%)	1	1/3 (33.3%)	1	1/7 (14.3%)	1	1/6 (16.7%)	1	0/44 (0%)	0
Dysphagia (difficulty swallowing)	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/44 (2.3%)	1
Flatulence	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/44 (0%)	0
Gastritis (including bile reflex gastritis)	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	1/44 (2.3%)	1
Ulcer, GI, stomach	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/44 (0%)	0
General disorders
Fatigue (asthenia, lethargy, malaise)	5/7 (71.4%)	8	0/3 (0%)	0	2/7 (28.6%)	3	3/6 (50%)	4	18/44 (40.9%)	25
Fever (in absence of neutrophenia defined as ANC <1.0 x 10e9/L)	5/7 (71.4%)	8	1/3 (33.3%)	1	2/7 (28.6%)	2	1/6 (16.7%)	1	8/44 (18.2%)	10
Insomnia	1/7 (14.3%)	3	2/3 (66.7%)	2	1/7 (14.3%)	1	0/6 (0%)	0	3/44 (6.8%)	3
Weight loss	3/7 (42.9%)	4	0/3 (0%)	0	1/7 (14.3%)	1	2/6 (33.3%)	4	19/44 (43.2%)	27
Pain - other	1/7 (14.3%)	1	0/3 (0%)	0	1/7 (14.3%)	1	1/6 (16.7%)	1	11/44 (25%)	17
Pain, abdomen NOS	3/7 (42.9%)	3	1/3 (33.3%)	1	1/7 (14.3%)	1	2/6 (33.3%)	3	6/44 (13.6%)	7
Pain, back	1/7 (14.3%)	2	1/3 (33.3%)	2	2/7 (28.6%)	2	1/6 (16.7%)	1	4/44 (9.1%)	5
Pain, head/headache	5/7 (71.4%)	17	2/3 (66.7%)	3	3/7 (42.9%)	4	5/6 (83.3%)	6	20/44 (45.5%)	29
Pain, throat/pharynx/larynx	0/7 (0%)	0	1/3 (33.3%)	1	1/7 (14.3%)	1	0/6 (0%)	0	7/44 (15.9%)	7
Rigors/chills	2/7 (28.6%)	2	1/3 (33.3%)	1	0/7 (0%)	0	0/6 (0%)	0	2/44 (4.5%)	2
Pain, chest/thorax NOS	0/7 (0%)	0	2/3 (66.7%)	3	0/7 (0%)	0	1/6 (16.7%)	1	1/44 (2.3%)	1
Pain, external ear	0/7 (0%)	0	2/3 (66.7%)	2	0/7 (0%)	0	0/6 (0%)	0	0/44 (0%)	0
Pain, eye	1/7 (14.3%)	1	0/3 (0%)	0	1/7 (14.3%)	1	1/6 (16.7%)	1	1/44 (2.3%)	1
Pain, joint	2/7 (28.6%)	2	1/3 (33.3%)	1	0/7 (0%)	0	2/6 (33.3%)	2	1/44 (2.3%)	1
Weight gain	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/44 (0%)	0
Flu-like syndrome	0/7 (0%)	0	1/3 (33.3%)	1	0/7 (0%)	0	0/6 (0%)	0	0/44 (0%)	0
Pain, extremity-limb	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/44 (0%)	0
Pain, muscle	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/44 (0%)	0
Pain, oral cavity	1/7 (14.3%)	2	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	2/44 (4.5%)	2
Pain, pain NOS	0/7 (0%)	0	1/3 (33.3%)	2	0/7 (0%)	0	0/6 (0%)	0	0/44 (0%)	0
Pain, stomach	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	2/44 (4.5%)	2
Hepatobiliary disorders
Hepatobiliary/pancreas - other	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/44 (0%)	0
Immune system disorders
Allergic rhinitis (including sneezing, nasal stuffiness, postnasal drip)	3/7 (42.9%)	3	0/3 (0%)	0	2/7 (28.6%)	2	3/6 (50%)	3	8/44 (18.2%)	11
Allergic reaction/hypersensitivity (including drug fever)	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/44 (2.3%)	1
Infections and infestations
Infection - Other	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	3	19/44 (43.2%)	26
Infection with normal ANC or Grade 1 or 2 neurophils, external ear (otitis externa)	3/7 (42.9%)	3	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	3/44 (6.8%)	3
Infection with normal ANC or Grade 1 or 2 neutrophils, middle ear (otitis media)	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	3/44 (6.8%)	3
Infection with normal ANC or Grade 1 or 2 neutrophils, upper airway NOS	0/7 (0%)	0	2/3 (66.7%)	2	1/7 (14.3%)	1	2/6 (33.3%)	2	3/44 (6.8%)	3
Opportunistic infection associated with >=Grade 2 lymphopenia	1/7 (14.3%)	1	0/3 (0%)	0	1/7 (14.3%)	2	2/6 (33.3%)	3	5/44 (11.4%)	6
Infection with normal ANC or Grade 1 or 2 neutrophils, Anal/perianal	1/7 (14.3%)	1	1/3 (33.3%)	2	0/7 (0%)	0	0/6 (0%)	0	0/44 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils, eye NOS	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	1/6 (16.7%)	1	0/44 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils, mucosa	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	1/6 (16.7%)	1	1/44 (2.3%)	1
Infection with normal ANC or Grade 1 or 2 neutrophils, pharynx	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	1/6 (16.7%)	1	1/44 (2.3%)	1
Infection with normal ANC or Grade 1 or 2 neutrophils, sinus	0/7 (0%)	0	1/3 (33.3%)	1	1/7 (14.3%)	1	0/6 (0%)	0	1/44 (2.3%)	1
Infection with normal ANC or Grade 1 or 2 neutrophils, skin (cellulitis)	1/7 (14.3%)	1	1/3 (33.3%)	1	0/7 (0%)	0	1/6 (16.7%)	1	0/44 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils, urinary tract NOS	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	2/6 (33.3%)	2	1/44 (2.3%)	1
Infection with normal ANC or Grade 1 or 2 neutrophils, wound	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	3/6 (50%)	3	2/44 (4.5%)	3
Infection with normal ANC or Grade 1 or 2 neutrophils, lip/perioral	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	2/6 (33.3%)	2	0/44 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils, conjunctiva	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	1/44 (2.3%)	1
Infection with normal ANC or Grade 1 or 2 neutrophils, dental-tooth	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	1/44 (2.3%)	1
Infection with normal ANC or Grade 1 or 2 neutrophils, Foreign body	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/44 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils, lung (pnemonia)	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	1/44 (2.3%)	2
Infection with normal ANC or Grade 1 or 2 neutrophils, meninges (meningitis)	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/44 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils, nose	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	1/44 (2.3%)	1
Infection with normal ANC or Grade 1 or 2 neutrophils, oral cavity-gums (gingivitis)	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/44 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils, rectum	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/44 (0%)	0
Injury, poisoning and procedural complications
Death not associated with CTCAE term, disease progression NOS	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/44 (0%)	0
Intra-operative injury, brain	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/44 (0%)	0
Metabolism and nutrition disorders
ALT, SGPT (serum glutamic pyruvic transaminase)	2/7 (28.6%)	2	3/3 (100%)	6	3/7 (42.9%)	3	2/6 (33.3%)	6	14/44 (31.8%)	26
AST, SGOT (serum glutamic oxaloacetic transaminase)	1/7 (14.3%)	1	2/3 (66.7%)	3	1/7 (14.3%)	1	2/6 (33.3%)	5	13/44 (29.5%)	20
Albumin, serum-low (hypoalbuminemia)	4/7 (57.1%)	5	0/3 (0%)	0	2/7 (28.6%)	2	1/6 (16.7%)	1	11/44 (25%)	19
Alkaline phosphatase	0/7 (0%)	0	2/3 (66.7%)	2	0/7 (0%)	0	0/6 (0%)	0	4/44 (9.1%)	6
Bicarbonate, serum-low	1/7 (14.3%)	2	0/3 (0%)	0	1/7 (14.3%)	1	1/6 (16.7%)	1	5/44 (11.4%)	5
Bilirubin (hyperbilirubinemia)	0/7 (0%)	0	2/3 (66.7%)	5	4/7 (57.1%)	8	2/6 (33.3%)	5	16/44 (36.4%)	25
Calcium, serum-low (hypocalcemia)	4/7 (57.1%)	4	2/3 (66.7%)	2	1/7 (14.3%)	1	1/6 (16.7%)	2	7/44 (15.9%)	12
Creatinine	0/7 (0%)	0	1/3 (33.3%)	1	1/7 (14.3%)	3	0/6 (0%)	0	4/44 (9.1%)	7
Glucose, serum-high (hyperglycemia)	6/7 (85.7%)	13	2/3 (66.7%)	2	1/7 (14.3%)	1	3/6 (50%)	5	13/44 (29.5%)	23
Glucose, serum-low (hypoglycemia)	0/7 (0%)	0	1/3 (33.3%)	1	2/7 (28.6%)	2	1/6 (16.7%)	3	8/44 (18.2%)	14
Magnesium, serum-high (hypermagnesemia)	1/7 (14.3%)	1	0/3 (0%)	0	6/7 (85.7%)	13	4/6 (66.7%)	5	9/44 (20.5%)	15
Phosphate, serum-low (hypophosphatemia)	6/7 (85.7%)	10	2/3 (66.7%)	7	2/7 (28.6%)	3	4/6 (66.7%)	5	12/44 (27.3%)	22
Potassium, serum-low (hypokalemia)	5/7 (71.4%)	10	0/3 (0%)	0	2/7 (28.6%)	3	3/6 (50%)	5	12/44 (27.3%)	23
Potassium, serum-high (hyperkalemia)	1/7 (14.3%)	1	1/3 (33.3%)	2	0/7 (0%)	0	1/6 (16.7%)	1	3/44 (6.8%)	4
Sodium, serum-high (hypernatremia)	0/7 (0%)	0	1/3 (33.3%)	2	4/7 (57.1%)	10	1/6 (16.7%)	4	15/44 (34.1%)	28
Sodium, serum-low (hyponatremia)	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	3/44 (6.8%)	6
Calcium, serum-high (hypercalcemia)	1/7 (14.3%)	1	0/3 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/44 (0%)	0
Magnesium, serum-low (hypomagnesemia)	0/7 (0%)	0	1/3 (33.3%)	1	0/7 (0%)	0	1/6 (16.7%)	2	1/44 (2.3%)	1
Amylase	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	1/44 (2.3%)	1
Cholesterol, serum-high (hypercholestremia)	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/44 (0%)	0
Lipase	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	1/44 (2.3%)	1
Metabolic/laboratory - other	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/44 (0%)	0
Musculoskeletal and connective tissue disorders
Musculoskeletal/soft tissue - other	1/7 (14.3%)	2	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	3/44 (6.8%)	4
Extremity-lower (gait/walking)	3/7 (42.9%)	3	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	2/44 (4.5%)	2
Muscle weakness, generalized or specific area (not due to neuropathy), whole body/generalized	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/44 (2.3%)	1
Trismus (difficulty, restriction or pain when opening mouth)	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/44 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Secondary malignancy - possibly related to cancer treatment	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/44 (0%)	0
Nervous system disorders
Ataxia (incoordination)	2/7 (28.6%)	2	0/3 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	8/44 (18.2%)	13
Dizziness	1/7 (14.3%)	1	1/3 (33.3%)	1	1/7 (14.3%)	1	1/6 (16.7%)	2	3/44 (6.8%)	3
Mood alteration, anxiety	1/7 (14.3%)	2	0/3 (0%)	0	2/7 (28.6%)	2	0/6 (0%)	0	5/44 (11.4%)	5
Mood alteration, depression	0/7 (0%)	0	2/3 (66.7%)	3	0/7 (0%)	0	3/6 (50%)	3	6/44 (13.6%)	8
Neurology - other	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	8/44 (18.2%)	12
Neuropathy: motor	3/7 (42.9%)	7	0/3 (0%)	0	3/7 (42.9%)	3	4/6 (66.7%)	4	4/44 (9.1%)	6
Seizure	3/7 (42.9%)	4	1/3 (33.3%)	1	4/7 (57.1%)	4	3/6 (50%)	3	11/44 (25%)	25
Speech impairment (e.g., dysphasia or aphasia)	2/7 (28.6%)	3	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	3/44 (6.8%)	3
Tremor	0/7 (0%)	0	1/3 (33.3%)	1	2/7 (28.6%)	2	1/6 (16.7%)	1	3/44 (6.8%)	3
Cognitive disturbance	1/7 (14.3%)	1	1/3 (33.3%)	1	0/7 (0%)	0	0/6 (0%)	0	0/44 (0%)	0
Memory impairment	2/7 (28.6%)	2	1/3 (33.3%)	1	1/7 (14.3%)	1	0/6 (0%)	0	2/44 (4.5%)	2
Personality/behavioral	0/7 (0%)	0	1/3 (33.3%)	1	2/7 (28.6%)	2	0/6 (0%)	0	2/44 (4.5%)	2
Somnolence/depressed level of consciousness	1/7 (14.3%)	2	0/3 (0%)	0	0/7 (0%)	0	2/6 (33.3%)	2	0/44 (0%)	0
Syncope (fainting)	1/7 (14.3%)	1	1/3 (33.3%)	1	0/7 (0%)	0	0/6 (0%)	0	0/44 (0%)	0
Hydrocephalus	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	1/44 (2.3%)	1
Leak, cerebrospinal fluid (CSF)	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/44 (0%)	0
Mood alteration, agitation	0/7 (0%)	0	1/3 (33.3%)	1	0/7 (0%)	0	0/6 (0%)	0	1/44 (2.3%)	1
Neuropathy: cranial, CN VI Lateral deviation of eye	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/44 (2.3%)	1
Neuropathy: cranial, CN VII motor-face: sensory-taste	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/44 (0%)	0
Neuropathy: cranial, CN VIII hearing and balance	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	1/44 (2.3%)	1
Neuropathy: sensory	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	2/44 (4.5%)	2
Psychosis (hallucinations/delusions)	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/44 (0%)	0
Pyramidal tract dysfunction	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	1/44 (2.3%)	1
Renal and urinary disorders
Urinary retention (including neurogenic bladder)	1/7 (14.3%)	1	0/3 (0%)	0	2/7 (28.6%)	2	0/6 (0%)	0	2/44 (4.5%)	2
Cystitis	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	1/44 (2.3%)	1
Urinary frequency/urgency	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	2/44 (4.5%)	3
Reproductive system and breast disorders
Sexual/reproductive function - other	0/7 (0%)	0	1/3 (33.3%)	1	0/7 (0%)	0	0/6 (0%)	0	0/44 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	6/7 (85.7%)	8	2/3 (66.7%)	2	1/7 (14.3%)	1	2/6 (33.3%)	4	7/44 (15.9%)	7
Dyspnea (shortness of breath)	2/7 (28.6%)	3	1/3 (33.3%)	1	1/7 (14.3%)	2	0/6 (0%)	0	2/44 (4.5%)	3
Nasal cavity/paranasal sinus reactions	4/7 (57.1%)	9	1/3 (33.3%)	1	1/7 (14.3%)	1	1/6 (16.7%)	1	1/44 (2.3%)	1
Bronchospasm, wheezing	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/44 (0%)	0
Pulmonary/upper respiratory - other	1/7 (14.3%)	2	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/44 (0%)	0
Skin and subcutaneous tissue disorders
Chelitis	1/7 (14.3%)	2	1/3 (33.3%)	1	0/7 (0%)	0	0/6 (0%)	0	3/44 (6.8%)	3
Dermatology/Skin - other	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	8/44 (18.2%)	14
Dry skin	4/7 (57.1%)	6	2/3 (66.7%)	2	2/7 (28.6%)	2	4/6 (66.7%)	5	18/44 (40.9%)	19
Hair loss/alopecia (scalp or body)	6/7 (85.7%)	6	2/3 (66.7%)	2	2/7 (28.6%)	3	1/6 (16.7%)	1	13/44 (29.5%)	14
Hyperpigmentation	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	3/44 (6.8%)	3
Nail changes	2/7 (28.6%)	2	1/3 (33.3%)	1	3/7 (42.9%)	3	4/6 (66.7%)	4	7/44 (15.9%)	7
Pruritus/itching	3/7 (42.9%)	3	1/3 (33.3%)	1	2/7 (28.6%)	3	1/6 (16.7%)	1	16/44 (36.4%)	21
Rash/desquamation	5/7 (71.4%)	6	2/3 (66.7%)	2	4/7 (57.1%)	5	3/6 (50%)	4	19/44 (43.2%)	27
Rash: acne/acneiform	6/7 (85.7%)	8	3/3 (100%)	4	5/7 (71.4%)	5	2/6 (33.3%)	2	18/44 (40.9%)	29
Striae	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	2/6 (33.3%)	2	3/44 (6.8%)	3
Flushing	2/7 (28.6%)	3	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/44 (0%)	0
Rash: hand-foot skin reaction	2/7 (28.6%)	2	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/44 (0%)	0
Ulceration	0/7 (0%)	0	3/3 (100%)	4	1/7 (14.3%)	1	0/6 (0%)	0	1/44 (2.3%)	1
Bruising (in absence of Grade 3 or 4 thrombocytopenia)	0/7 (0%)	0	1/3 (33.3%)	1	0/7 (0%)	0	0/6 (0%)	0	2/44 (4.5%)	3
Burn	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/44 (0%)	0
Rash: dermatitis associated with radiation, radiation	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	1/44 (2.3%)	1
Vascular disorders
Hemorrhage, pulmonary/upper respiratory, nose	1/7 (14.3%)	1	1/3 (33.3%)	1	2/7 (28.6%)	2	1/6 (16.7%)	1	4/44 (9.1%)	6
Hemorrhage, CNS	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	2/6 (33.3%)	2	0/44 (0%)	0
Hemorrhage, GU, urinary NOS	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	1/6 (16.7%)	1	1/44 (2.3%)	1

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.