Gefitinib and Radiation Therapy in Treating Children With Newly Diagnosed Gliomas

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00042991
• Collaborator: (none)
• Enrollment: 69
• Location: 1
• Arm: 1
• Duration (Months): 92
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

Biological therapies such as gefitinib may interfere with the growth of the tumor cells and may make the tumor cells more sensitive to radiation therapy. This phase I/II trial is studying how well giving gefitinib together with radiation therapy works in treating children with newly diagnosed glioma.

Condition or Disease	Intervention/Treatment	Phase
Untreated Childhood Anaplastic Astrocytoma; Untreated Childhood Anaplastic Oligodendroglioma; Untreated Childhood Brain Stem Glioma; Untreated Childhood Giant Cell Glioblastoma; Untreated Childhood Glioblastoma; Untreated Childhood Gliomatosis Cerebri; Untreated Childhood Gliosarcoma; Untreated Childhood Oligodendroglioma	Drug: gefitinib; Radiation: radiation therapy; Other: pharmacological study; Other: laboratory biomarker analysis	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To define the safety of gefitinib administered in conjunction with irradiation in children with newly diagnosed non-disseminated diffuse intrinsic brainstem gliomas and newly diagnosed incompletely resected supratentorial malignant gliomas (STMG) not receiving enzyme inducing anticonvulsant drugs (EIACDs).

2. To define the safety of gefitinib in children with newly diagnosed, incompletely resected STMG receiving EIACDs.

3. To assess the safety and efficacy of gefitinib given with radiation therapy in children newly diagnosed with a brainstem glioma as measured by progression-free survival and to estimate the survival distribution.

SECONDARY OBJECTIVES:

1. To compare hemodynamic magnetic resonance (MR) parameters to metabolic fludeoxyglucose F 18 (FDG)-positron emission tomography (PET) scanning and correlate both with clinical response or progression in this population.

2. To characterize the expression of ErbB1 receptors in tissue from STMG patients using immunohistochemistry and western blot assays.

3. To characterize the pharmacokinetics of gefitinib in the above patient groups and determine the effects of EIACD on the pharmacokinetics.

4. To explore the pharmacogenetic polymorphisms for gefitinib (e.g., CYP3A4/5 and BCRP) and relate them to gefitinib pharmacokinetics and pharmacodynamics (phenotype-genotype).

OUTLINE: This is a multicenter, dose-escalation study of gefitinib (Phase I closed to accrual effective 10/27/2003). Patients are stratified according to the following:

Stratum 1A: Intrinsic brain stem glioma; not receiving concurrent enzyme-inducing anticonvulsant drugs (EIACDs) Stratum 1B: Incompletely resected supratentorial malignant gliomas (STMG); not receiving concurrent EIACDs Stratum 2: Incompletely resected STMG; receiving concurrent EIACDs.

Phase I portion (patients in strata 1A, 1B, and 2) (phase I closed to accrual effective 10/27/2003): Patients receive oral gefitinib once daily. Treatment repeats every 4 weeks for 13 courses (1 year). Patients also receive standard brain irradiation once daily, 5 days a week, for 6 weeks beginning concurrently with initiation of the first course of gefitinib. Treatment continues in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of gefitinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity.

Phase II portion (patients in stratum 1A): Once the MTD or the recommended Phase-II dose is determined, additional patients who have newly diagnosed brain stem gliomas (BSG) are treated at the MTD or the recommended Phase-II dose.

Patients are followed for three months after the last protocol treatment for those enrolled strictly on the phase I component. Patients contributing to the phase II portion are followed until the earliest of date of death or three years after initiation of protocol therapy.

PROJECTED ACCRUAL: Considering the seven dose levels to be investigated in three strata, where each dose level can accrue up to six patients, a total of 126 patients (42 for each strata) may be accrued for this study within 2 years. (Phase I closed to accrual effective 10/27/2003). A total of 40 patients including the patients treated at the maximum tolerated dose or the recommended Phase-II dose during Phase I will be accrued for phase II of this study within 10 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 69 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I/II Trial of Gefitinib and Radiation in Pediatric Patients Newly Diagnosed With Brain Stem Tumors or Incompletely Resected Supratentorial Malignant Gliomas With Phase II Limited to Brain Stem Tumors
• Study Start Date: Jul 1, 2002
• Actual Primary Completion Date: Feb 1, 2010
• Actual Study Completion Date: Mar 1, 2010

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (gefitinib and radiation therapy) Phase I portion: Patients receive oral gefitinib once daily. Treatment repeats every 4 weeks for 13 courses (1 year). Patients also receive standard brain irradiation once daily, 5 days a week, for 6 weeks beginning concurrently with initiation of the first course of gefitinib. Treatment continues in the absence of disease progression or unacceptable toxicity. Phase II portion: Once the MTD or the recommended Phase-II dose is determined, additional patients who have newly diagnosed BSG are treated at the MTD or the recommended Phase-II dose.

Drug: gefitinib; Given orally; Other Names: Iressa ; Radiation: radiation therapy; Undergo standard brain irradiation; Other Names: irradiation radiotherapy therapy, radiation ; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies ; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Number of Participants in Phase I Stratum 1A With Dose-limiting Toxicities (DLT) Observed During the First 8 Weeks of Gefitinib Therapy [Day 1 of gefitinib therapy to end of week 8]

   The dose limiting toxicity (DLT) analysis population consists of stratum 1A phase I participants who developed DLT during the maximum tolerated dose (MTD) estimation period (course 1 and 2) or who completed the MTD estimation period without DLTs. DLTs observed during courses 1 and 2 were used to estimate the MTD based on the tradional 3+3 design, where a dose is considered a safe dose only when 0 out of 3, or at most 1 out of 6 patients has DLTs. When two or more patients in a group of 2 to 6 patients had DLTs, then that dose level was considered to be too toxic.

2. Median Progression-free Survival in Newly Diagnosed Brain Stem Gliomas [Assessed pre-radiation, every 8 weeks for 13 courses of therapy, and then every 12 weeks]

   Progression-free survival is defined as the interval from intiation of treatment to the earliest of disease progression (tumor increase of 25% over baseline tumor measurement; appearance of new lesion(s); or progressive/worsening neurlogical status) or death for patients who failed or to the last date of follow-up for patients without failure

3. Median Survival in Newly Diagnosed Brain Stem Gliomas [Assessed from the start of therapy until three years after initiation of gefitinib therapy]

   Overall survival is defined as the interval from initiation of treatment to death or date of last contact for surviving patients

Secondary Outcome Measures

1. Change in Tumor Volume Measured on Fluid Attenuated Inversion Recovery (FLAIR) Imaging at Before the Protocol Therapy Started and at Two Weeks After Completion of Radiation [Baseline and two weeks post completion of radiation]

   This study attempted to investigate in an exploratory manner the effect of treatment on changes in various neuroimaging variables. In this particular objective, the study aimed to investigate how radiation+gefitinib affect the tumor volume. Tumor volume is measured using Fluid Attenuated Inversion Recovery (FLAIR) before and after the radiation therapy.

2. Change From Baseline in Volume Enhancing at Two Weeks After Completion of Radiation [Baseline and two weeks post completion of radiation]

   This study attempted to investigate in an exploratory manner the effect of treatment on changes in various neuroimaging variables. Neuroimaging changes may have some association with outcome (response,survival, etc.). Volume enhancing is one parameter obtained from standard magnetic resonance imaging (MRI) studies of the brain.

3. Change From Baseline in Diffusion Ratio at Two Weeks After Completion of Radiation [Baseline and two weeks post completion of radiation]

   This study attempted to investigate in an exploratory manner the effect of treatment on changes in various neuroimaging variables. Neuroimaging changes may have some association with outcome (response,survival, etc.). Diffusion ratio is one parameter obtained from standard magnetic resonance imaging (MRI) studies of the brain.

4. Change From Baseline in Perfusion Ratio at Two Weeks After Completion of Radiation [Baseline and two weeks post completion of radiation]

   This study attempted to investigate in an exploratory manner the effect of treatment on changes in various neuroimaging variables. Neuroimaging changes may have some association with outcome (response,survival, etc.). Perfusion ratio is one parameter obtained from standard magnetic resonance imaging (MRI) studies of the brain.

5. Mean Tumor to Gray Matter Ratio Measured at Baseline [Baseline]

   This study attempts to characterize neuroimaging parameters from positron emission tomography. For each patient, the axial image through the tumor containing the maximum activity per pixel corresponding to the highest FluoroDeoxyGlucose (FDG) uptake was identified and a region of interest (ROI) was drawn based on the FDG definition of the tumor. The mean pixel values within the tumor ROI were normalized by those for normal gray matter to provide ratios of tumor/gray matter. Each patient has a mean tumor to gray matter ratio value and the median of these values across patients is reported.

6. Mean Tumor to White Matter Ratio Measured at Baseline [Baseline]

   This study attempts to characterize neuroimaging parameters from positron emission tomography. For each patient, the axial image through the tumor containing the maximum activity per pixel corresponding to the highest FluoroDeoxyGlucose (FDG) uptake was identified and a region of interest (ROI) was drawn based on the FDG definition of the tumor. The mean pixel values within the tumor ROI were normalized by those for normal white matter to provide ratios of tumor/gray matter. Each patient has a mean tumor to white matter ratio value and the median of these values across patients is reported.

7. Peak Serum Concentration of Gefitinib (Cmax) [Week 2 of course 1]

8. Elimination Half Life of Gefitinib (t1/2) [Week 2 of course 1]

9. Clearance of Gefitinib (Cl) [Week 2 of course 1]

10. Time of Maximum Clearance of Gefitinib (Tmax) [Week 2 of course 1]

11. Gefitinib Area Under the Concentration Curve From 0-24 Hours (AUC) [Week 2 of course 1]

12. Number of Patients With Epidermal Growth Factor Receptor (EGFR) Amplification [Pre-treatment]

    Epidermal growth factor receptor (EFGR) is a protein found on the surface of cells to which epidermal growth factor (EGF) binds. When EGF attaches to EGFR, it activates the enzyme tyrosine kinase, triggering reactions that cause the cells to grow and multiply.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Tumor:

• Phase I: newly diagnosed non-disseminated diffuse intrinsic brainstem tumor or newly diagnosed (diagnostic scan must be within 4 weeks prior to treatment initiation), incompletely resected supratentorial malignant glioma (anaplastic astrocytoma, glioblastoma multiforme or other high-grade glioma) (STMG); the STMG group must have residual tumor evident on postoperative MRI or CT

• Phase II: only newly diagnosed non-disseminated diffuse intrinsic brain stem glioma patients are eligible

• Performance status: Karnofsky or Lansky >= 50% assessed within two weeks prior to registration

• Prior/concurrent therapy:

• Chemotherapy: no prior therapy allowed, including prior gefitinib treatment

• Radiation therapy (XRT): no prior therapy allowed

• Bone marrow transplant: none prior

• Anti-convulsants: patients with brain stem glioma (BSG) receiving EIACD will not be eligible; patients with STMG will be eligible for this study even if they are receiving enzyme inducting anti-convulsant drugs (EIACD) and will be stratified by use of EIACDs

• Growth factors: off all colony forming growth factor(s) > 2 weeks prior to registration (G-CSF, GM-CSF, erythropoietin)

• ANC > 1,000/ul

• Platelets > 100,000/ul (transfusion independent)

• Hemoglobin > 8g/dl (may be transfused)

• Patients may have bone marrow involvement by disease

• Creatinine < 2 x normal for age or GFR > 70 ml/min/1.73m^2

• Bilirubin < 1.5 x normal institutional normal for age

• SGPT (ALT) < 3 x institutional normal for age

• Pregnant and/or lactating patients are excluded; patients of childbearing potential should not become pregnant and should not father a child during treatment with gefitinib; pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method

• Signed informed consent according to institutional guidelines must be obtained prior to study entry

Exclusion Criteria:

• Patients with evidence of intramural hemorrhage on a scan obtained prior to enrollment or after enrollment, before treatment

• Patients with BSG must not be taking enzyme-inducing anticonvulsant drugs

• Patient must not be receiving any other anticancer or experimental drug therapy

• Patient must have no uncontrolled infection

• Patients with significant cardiac, hepatic, gastrointestinal, renal, pulmonary, or psychiatric disease are ineligible; patients with deep venous or arterial thrombosis within 6 weeks of study entry are ineligible

• Patients with disseminated disease are not permitted

• Patients with spinal disease requiring craniospinal radiation are not eligible

• Patients with completely resected supratentorial malignant gliomas patients are ineligible

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pediatric Brain Tumor Consortium	Memphis	Tennessee	United States	38105

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Jeffrey Geyer, Pediatric Brain Tumor Consortium

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00042991
• Other Study ID Numbers: NCI-2012-03022; NCI-2012-03022; PBTC-007; PBTC-007; U01CA081457
• First Posted: Jan 27, 2003
• Last Update Posted: May 28, 2014
• Last Verified: Dec 1, 2012

• Additional relevant MeSH terms: Glioblastoma; Glioma; Astrocytoma; Gliosarcoma; Oligodendroglioma; Neoplasms, Neuroepithelial; Gefitinib

Study Results

Participant Flow

Recruitment Details	Accrual to this study started with the first patient who enrolled on 07/01/2002 and ended with the last patient who enrolled on 05/31/2006. Nine institutions enrolled patients on the study.
Pre-assignment Detail	There was no randomization to the three strata, which were distinct based on diagnosis and the use of enzyme inducing anti-convulsants (EIACD).

Arm/Group Title	Stratum 1A-100 mg/m^2 of Gefitinib + Radiation	Stratum 1A-250 mg/m^2 of Gefitinib + Radiation	Stratum 1A-375 mg/m^2 of Gefitinib + Radiation	Stratum-1B: 100 mg/m^2 of Gefitinib + Radiation	Stratum-1B: 250 mg/m^2 of Gefitinib + Radiation	Stratum-1B: 375 mg/m^2 of Gefitinib + Radiation	Stratum-2: 100 mg/m^2 of Gefitinib + Radiation + EIACD
Arm/Group Description	These are patients with newly diagnosed brain stem glioma who were treated at Dose 100 mg/m^2 of Gefitinib+Radiation, where Gefitinib was administered orally once daily.	These are patients with newly diagnosed brain stem glioma who were treated at Dose 250 mg/m^2 of Gefitinib+Radiation, where Gefitinib was administered orally once daily.	These are patients with newly diagnosed brain stem glioma who were treated at Dose 375 mg/m^2 of Gefitinib+Radiation, where Gefitinib was administered orally once daily.	These are patients with newly diagnosed, incompletely resected supertentorial malignant gliomas and NOT receiving enzyme inducing anticonvulsant drugs (EIACD), who were treated at Dose 100 mg/m^2 of Gefitinib+Radiation, where Gefitinib was administered orally once daily.	These are patients with newly diagnosed, incompletely resected supertentorial malignant gliomas and NOT receiving enzyme inducing anticonvulsant drugs (EIACD), who were treated at Dose 250 mg/m^2 of Gefitinib+Radiation, where Gefitinib was administered orally once daily.	These are patients with newly diagnosed, incompletely resected supertentorial malignant gliomas and NOT receiving enzyme inducing anticonvulsant drugs (EIACD), who were treated at Dose 375 mg/m^2 of Gefitinib+Radiation, where Gefitinib was administered orally once daily.	These are patients with newly diagnosed, incompletely resected supertentorial malignant gliomas and receiving enzyme inducing anticonvulsant drugs (EIACD), who were treated at Dose 100 mg/m^2 of Gefitinib+Radiation, where Gefitinib was administered orally once daily.
Period Title: Overall Study
STARTED	6	43	7	2	3	5	3
Phase-I Trial	6	7	7	2	3	5	3
Phase-II Trial	0	36	0	0	0	0	0
COMPLETED	0	3	1	0	0	0	1
NOT COMPLETED	6	40	6	2	3	5	2

Baseline Characteristics

Arm/Group Title	Stratum 1A-100 mg/m^2 of Gefitinib + Radiation	Stratum 1A-250 mg/m^2 of Gefitinib + Radiation	Stratum 1A-375 mg/m^2 of Gefitinib + Radiation	Stratum-1B: 100 mg/m^2 of Gefitinib + Radiation	Stratum-1B: 250 mg/m^2 of Gefitinib + Radiation	Stratum-1B: 375 mg/m^2 of Gefitinib + Radiation	Stratum-2: 100 mg/m^2 of Gefitinib + Radiation + EIACD	Total
Arm/Group Description	These are patients with newly diagnosed brain stem glioma who were treated at Dose 100 mg/m^2 of Gefitinib+Radiation, where Gefitinib was administered orally once daily.	These are patients with newly diagnosed brain stem glioma who were treated at Dose 250 mg/m^2 of Gefitinib+Radiation, where Gefitinib was administered orally once daily.	These are patients with newly diagnosed brain stem glioma who were treated at Dose 375 mg/m^2 of Gefitinib+Radiation, where Gefitinib was administered orally once daily.	These are patients with newly diagnosed, incompletely resected supertentorial malignant gliomas and NOT receiving enzyme inducing anticonvulsant drugs (EIACD), who were treated at Dose 100 mg/m^2 of Gefitinib+Radiation, where Gefitinib was administered orally once daily.	These are patients with newly diagnosed, incompletely resected supertentorial malignant gliomas and NOT receiving enzyme inducing anticonvulsant drugs (EIACD), who were treated at Dose 250 mg/m^2 of Gefitinib+Radiation, where Gefitinib was administered orally once daily.	These are patients with newly diagnosed, incompletely resected supertentorial malignant gliomas and NOT receiving enzyme inducing anticonvulsant drugs (EIACD), who were treated at Dose 375 mg/m^2 of Gefitinib+Radiation, where Gefitinib was administered orally once daily.	These are patients with newly diagnosed, incompletely resected supertentorial malignant gliomas and receiving enzyme inducing anticonvulsant drugs (EIACD), who were treated at Dose 100 mg/m^2 of Gefitinib+Radiation, where Gefitinib was administered orally once daily.	Total of all reporting groups
Overall Participants	6	43	7	2	3	5	3	69
Age (Count of Participants)
<=18 years	6 100%	43 100%	7 100%	2 100%	2 66.7%	5 100%	3 100%	68 98.6%
Between 18 and 65 years	0 0%	0 0%	0 0%	0 0%	1 33.3%	0 0%	0 0%	1 1.4%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	7.25 (2.92)	8.02 (3.87)	10.07 (4.71)	9.17 (8.56)	15.91 (5.61)	11.69 (5.40)	12.82 (2.37)	9.01 (4.47)
Sex: Female, Male (Count of Participants)
Female	3 50%	29 67.4%	4 57.1%	0 0%	0 0%	2 40%	2 66.7%	40 58%
Male	3 50%	14 32.6%	3 42.9%	2 100%	3 100%	3 60%	1 33.3%	29 42%
Region of Enrollment (participants) [Number]
United States	6 100%	43 100%	7 100%	2 100%	3 100%	5 100%	3 100%	69 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants in Phase I Stratum 1A With Dose-limiting Toxicities (DLT) Observed During the First 8 Weeks of Gefitinib Therapy
Description	The dose limiting toxicity (DLT) analysis population consists of stratum 1A phase I participants who developed DLT during the maximum tolerated dose (MTD) estimation period (course 1 and 2) or who completed the MTD estimation period without DLTs. DLTs observed during courses 1 and 2 were used to estimate the MTD based on the tradional 3+3 design, where a dose is considered a safe dose only when 0 out of 3, or at most 1 out of 6 patients has DLTs. When two or more patients in a group of 2 to 6 patients had DLTs, then that dose level was considered to be too toxic.
Time Frame	Day 1 of gefitinib therapy to end of week 8

Outcome Measure Data

Analysis Population Description

This cohort includes only the patients who were enrolled and treated on Gefitinib+Radiation during the Phase I component of the trial, where the safety of Gefitinib was assedded at Dose Levels 100 mg/m^2, 250 mg/m^2, and 375 mg/m^2.

Arm/Group Title	Stratum 1A-100 mg/m^2 of Gefitinib + Radiation	Stratum 1A-250 mg/m^2 of Gefitinib + Radiation	Stratum 1A-375 mg/m^2 of Gefitinib + Radiation
Arm/Group Description	These are patients with brain stem glioma who were treated during the Phase-I trial of Radiation+Dose 100 mg/m^2 of Gefitinib, where Gefitinib was administered orally once daily.	These are patients with brain stem glioma who were treated during the Phase-I trial of Radiation+Dose 250 mg/m^2 of Gefitinib, where Gefitinib was administered orally once daily.	These are patients with brain stem glioma who were treated during the Phase-I trial of Radiation+Dose 375 mg/m^2 of Gefitinib, where Gefitinib was administered orally once daily.
Measure Participants	6	7	7
Number [Participants]	2 33.3%	0 0%	1 14.3%

2. Primary Outcome

Title	Median Progression-free Survival in Newly Diagnosed Brain Stem Gliomas
Description	Progression-free survival is defined as the interval from intiation of treatment to the earliest of disease progression (tumor increase of 25% over baseline tumor measurement; appearance of new lesion(s); or progressive/worsening neurlogical status) or death for patients who failed or to the last date of follow-up for patients without failure
Time Frame	Assessed pre-radiation, every 8 weeks for 13 courses of therapy, and then every 12 weeks

Outcome Measure Data

Analysis Population Description

Here, we only report the results for Phase-II trial as this objective was specifically for the Phase-II trial. This cohort includes seven patients who were treated during Phase-I at Dose 250 mg/m^2 of Gefitinib.

Arm/Group Title	Stratum 1A-Dose 250 mg/m^2 of Gefitinib+Radiation
Arm/Group Description	This analysis includes patients with newly diagnosed Brain Stem Glioma patients who received Dose 250 mg/m^2 of Gefitinib+Radiation.
Measure Participants	43
Median (Full Range) [Months]	7.43

3. Primary Outcome

Title	Median Survival in Newly Diagnosed Brain Stem Gliomas
Description	Overall survival is defined as the interval from initiation of treatment to death or date of last contact for surviving patients
Time Frame	Assessed from the start of therapy until three years after initiation of gefitinib therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Stratum 1A-Dose 250 mg/m^2 of Gefitinib+Radiation
Arm/Group Description	This analysis includes patients with newly diagnosed Brain Stem Glioma patients who received Dose 250 mg/m^2 of Gefitinib+Radiation.
Measure Participants	43
Median (Full Range) [Months]	12.12

4. Secondary Outcome

Title	Change in Tumor Volume Measured on Fluid Attenuated Inversion Recovery (FLAIR) Imaging at Before the Protocol Therapy Started and at Two Weeks After Completion of Radiation
Description	This study attempted to investigate in an exploratory manner the effect of treatment on changes in various neuroimaging variables. In this particular objective, the study aimed to investigate how radiation+gefitinib affect the tumor volume. Tumor volume is measured using Fluid Attenuated Inversion Recovery (FLAIR) before and after the radiation therapy.
Time Frame	Baseline and two weeks post completion of radiation

Outcome Measure Data

Analysis Population Description

Out of 43 patients, 35 patients had brain MRI before the treatment started and at the time of the completion of Radiation therapy. Therefore, this analysis is based on the volumetric data from these 35 patients.

Arm/Group Title	Stratum 1A-Dose 250 mg/m^2 of Gefitinib+Radiation
Arm/Group Description	This analysis includes patients with newly diagnosed Brain Stem Glioma patients who received Dose 250 mg/m^2 of Gefitinib+Radiation.
Measure Participants	35
Median (Full Range) [cc]	-14.03

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stratum 1A-100 mg/m^2 of Gefitinib + Radiation
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

5. Secondary Outcome

Title	Change From Baseline in Volume Enhancing at Two Weeks After Completion of Radiation
Description	This study attempted to investigate in an exploratory manner the effect of treatment on changes in various neuroimaging variables. Neuroimaging changes may have some association with outcome (response,survival, etc.). Volume enhancing is one parameter obtained from standard magnetic resonance imaging (MRI) studies of the brain.
Time Frame	Baseline and two weeks post completion of radiation

Outcome Measure Data

Analysis Population Description

Out of 43 patients, for only 19 patients, enhacing tumor was greater than zero based on brain MRI scans before the treatment started and at the time of the completion of Radiation therapy. Therefore, this analysis is based on the enhancing volumetric data from these 19 patients.

Arm/Group Title	Stratum 1A-Dose 250 mg/m^2 of Gefitinib+Radiation
Arm/Group Description	This analysis includes patients with newly diagnosed Brain Stem Glioma patients who received Dose 250 mg/m^2 of Gefitinib+Radiation.
Measure Participants	19
Median (Full Range) [cc]	0.35

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stratum 1A-100 mg/m^2 of Gefitinib + Radiation
	Comments	19 patients had Enhancing tumor at both Baseline and Post-RT time points. Thus, the following test was based on these 19 patients.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0546
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

6. Secondary Outcome

Title	Change From Baseline in Diffusion Ratio at Two Weeks After Completion of Radiation
Description	This study attempted to investigate in an exploratory manner the effect of treatment on changes in various neuroimaging variables. Neuroimaging changes may have some association with outcome (response,survival, etc.). Diffusion ratio is one parameter obtained from standard magnetic resonance imaging (MRI) studies of the brain.
Time Frame	Baseline and two weeks post completion of radiation

Outcome Measure Data

Analysis Population Description

Out of 43 patients, 29 patients had diffusion scans before the treatment started and at the time of the completion of Radiation therapy. Therefore, this analysis is based on the volumetric data from these 29 patients.

Arm/Group Title	Stratum 1A-Dose 250 mg/m^2 of Gefitinib+Radiation
Arm/Group Description	This analysis includes patients with newly diagnosed Brain Stem Glioma patients who received Dose 250 mg/m^2 of Gefitinib+Radiation.
Measure Participants	29
Median (Full Range) [Ratio]	-0.41

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stratum 1A-100 mg/m^2 of Gefitinib + Radiation
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

7. Secondary Outcome

Title	Change From Baseline in Perfusion Ratio at Two Weeks After Completion of Radiation
Description	This study attempted to investigate in an exploratory manner the effect of treatment on changes in various neuroimaging variables. Neuroimaging changes may have some association with outcome (response,survival, etc.). Perfusion ratio is one parameter obtained from standard magnetic resonance imaging (MRI) studies of the brain.
Time Frame	Baseline and two weeks post completion of radiation

Outcome Measure Data

Analysis Population Description

Out of 43 patients, 20 patients had perfusion scans before the treatment started and at the time of the completion of Radiation therapy. Therefore, this analysis is based on the volumetric data from these 20 patients.

Arm/Group Title	Stratum 1A-Dose 250 mg/m^2 of Gefitinib+Radiation
Arm/Group Description	This analysis includes patients with newly diagnosed Brain Stem Glioma patients who received Dose 250 mg/m^2 of Gefitinib+Radiation.
Measure Participants	20
Median (Full Range) [Ratio]	0.72

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stratum 1A-100 mg/m^2 of Gefitinib + Radiation
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.18
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

8. Secondary Outcome

Title	Mean Tumor to Gray Matter Ratio Measured at Baseline
Description	This study attempts to characterize neuroimaging parameters from positron emission tomography. For each patient, the axial image through the tumor containing the maximum activity per pixel corresponding to the highest FluoroDeoxyGlucose (FDG) uptake was identified and a region of interest (ROI) was drawn based on the FDG definition of the tumor. The mean pixel values within the tumor ROI were normalized by those for normal gray matter to provide ratios of tumor/gray matter. Each patient has a mean tumor to gray matter ratio value and the median of these values across patients is reported.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

Out of 43 patients, only 18 Patients had baseline PET scans. Therefore, this analysis is based on these 18 patients.

Arm/Group Title	Stratum 1A-Dose 250 mg/m^2 of Gefitinib+Radiation
Arm/Group Description	This analysis includes patients with newly diagnosed Brain Stem Glioma patients who received Dose 250 mg/m^2 of Gefitinib+Radiation.
Measure Participants	18
Median (Full Range) [Ratio]	0.55

9. Secondary Outcome

Title	Mean Tumor to White Matter Ratio Measured at Baseline
Description	This study attempts to characterize neuroimaging parameters from positron emission tomography. For each patient, the axial image through the tumor containing the maximum activity per pixel corresponding to the highest FluoroDeoxyGlucose (FDG) uptake was identified and a region of interest (ROI) was drawn based on the FDG definition of the tumor. The mean pixel values within the tumor ROI were normalized by those for normal white matter to provide ratios of tumor/gray matter. Each patient has a mean tumor to white matter ratio value and the median of these values across patients is reported.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

Out of 43 patients, only 18 Patients had baseline PET scans. Therefore, this analysis is based on these 18 patients.

Arm/Group Title	Stratum 1A-Dose 250 mg/m^2 of Gefitinib+Radiation
Arm/Group Description	This analysis includes patients with newly diagnosed Brain Stem Glioma patients who received Dose 250 mg/m^2 of Gefitinib+Radiation.
Measure Participants	18
Median (Full Range) [Ratio]	1.16

10. Secondary Outcome

Title	Peak Serum Concentration of Gefitinib (Cmax)
Time Frame	Week 2 of course 1

Outcome Measure Data

Analysis Population Description

PK Data was combined at each dose level accross strata (Stratum 1A, Stratum 1B, and Stratum 2); at Dose 250 mg/m^2 of Gefitinib accross strata, PK data from Phase-I patients was analysed earlier for the publication of the Phase-I trial. PK data for the Phase-II patients was analyzed separately for the Phase-II publication.

Arm/Group Title	Dose 250 mg/m^2 of Gefitinib (Phase II, Brain Stem Gliomas)	Dose 250 mg/m^2 of Gefitinib (Phase I)	Dose 100 mg/m^2 of Gefitinib	Dose 375 mg/m^2 of Gefitinib
Arm/Group Description	Brain Stem Glioma patients treated on the Phase-II trial. Seven patients were treated during Phase-I at the Phase-II dose, and thus eligible for the Phase-II trial, and included in this part of the report. Only 18 patients had samples for the PK evaluation.	This cohort includes all Phase-I patients treated at 250 mg/m^2 of Gefitinib regardless of diagnosis; that is, this group includes both brain stem gliomas and supratentorial malignant gliomas. Only six of 11 patients had adequate PK samples for the PK evaluation.	This cohort includes all Phase-I patients treated at 100 mg/m^2 of Gefitinib regardless of diagnosis; that is, this group includes both brain stem gliomas and supratentorial malignant gliomas. Eight (8) of 10 patients had adequate PK samples for the PK evaluation.	This cohort includes all Phase-I patients treated at 375 mg/m^2 of Gefitinib regardless of diagnosis; that is, this group includes both brain stem gliomas and supratentorial malignant gliomas. Eight of 12 patients had adequate PK samples for the PK evaluation.
Measure Participants	18	6	8	8
Median (Full Range) [mcg/ml]	1.10	0.83	0.44	1.89

11. Secondary Outcome

Title	Elimination Half Life of Gefitinib (t1/2)
Time Frame	Week 2 of course 1

Outcome Measure Data

Analysis Population Description

PK Data was combined at each dose level accross strata (Stratum 1A, Stratum 1B, and Stratum 2); at Dose 250 mg/m^2 of Gefitinib accross strata, PK data from Phase-I patients was analysed earlier for the publication of the Phase-I trial. PK data for the Phase-II patients was analyzed separately for the Phase-II publication.

Arm/Group Title	Dose 250 mg/m^2 of Gefitinib (Phase II, Brain Stem Gliomas)	Dose 250 mg/m^2 of Gefitinib (Phase I)	Dose 100 mg/m^2 of Gefitinib	Dose 375 mg/m^2 of Gefitinib
Arm/Group Description	Brain Stem Glioma patients treated on the Phase-II trial. Seven patients were treated during Phase-I at the Phase-II dose, and thus eligible for the Phase-II trial, and included in this part of the report. Only 18 patients had samples for the PK evaluation.	This cohort includes all Phase-I patients treated at 250 mg/m^2 of Gefitinib regardless of diagnosis; that is, this group includes both brain stem gliomas and supratentorial malignant gliomas. Only six of 11 patients had adequate PK samples for the PK evaluation.	This cohort includes all Phase-I patients treated at 100 mg/m^2 of Gefitinib regardless of diagnosis; that is, this group includes both brain stem gliomas and supratentorial malignant gliomas. Eight (8) of 10 patients had adequate PK samples for the PK evaluation.	This cohort includes all Phase-I patients treated at 375 mg/m^2 of Gefitinib regardless of diagnosis; that is, this group includes both brain stem gliomas and supratentorial malignant gliomas. Eight of 12 patients had adequate PK samples for the PK evaluation.
Measure Participants	18	6	8	8
Median (Full Range) [hour]	15.2	17.6	9.9	10.4

12. Secondary Outcome

Title	Clearance of Gefitinib (Cl)
Time Frame	Week 2 of course 1

Outcome Measure Data

Analysis Population Description

PK Data was combined at each dose level accross strata (Stratum 1A, Stratum 1B, and Stratum 2); at Dose 250 mg/m^2 of Gefitinib accross strata, PK data from Phase-I patients was analysed earlier for the publication of the Phase-I trial. PK data for the Phase-II patients was analyzed separately for the Phase-II publication.

Arm/Group Title	Dose 250 mg/m^2 of Gefitinib (Phase II, Brain Stem Gliomas)	Dose 250 mg/m^2 of Gefitinib (Phase I)	Dose 100 mg/m^2 of Gefitinib	Dose 375 mg/m^2 of Gefitinib
Arm/Group Description	Brain Stem Glioma patients treated on the Phase-II trial. Seven patients were treated during Phase-I at the Phase-II dose, and thus eligible for the Phase-II trial, and included in this part of the report. Only 18 patients had samples for the PK evaluation.	This cohort includes all Phase-I patients treated at 250 mg/m^2 of Gefitinib regardless of diagnosis; that is, this group includes both brain stem gliomas and supratentorial malignant gliomas. Only six of 11 patients had adequate PK samples for the PK evaluation.	This cohort includes all Phase-I patients treated at 100 mg/m^2 of Gefitinib regardless of diagnosis; that is, this group includes both brain stem gliomas and supratentorial malignant gliomas. Eight (8) of 10 patients had adequate PK samples for the PK evaluation.	This cohort includes all Phase-I patients treated at 375 mg/m^2 of Gefitinib regardless of diagnosis; that is, this group includes both brain stem gliomas and supratentorial malignant gliomas. Eight of 12 patients had adequate PK samples for the PK evaluation.
Measure Participants	18	6	8	8
Median (Full Range) [L/hr/m2]	15.2	20.9	12.8	15.0

13. Secondary Outcome

Title	Time of Maximum Clearance of Gefitinib (Tmax)
Time Frame	Week 2 of course 1

Outcome Measure Data

Analysis Population Description

PK Data was combined at each dose level accross strata (Stratum 1A, Stratum 1B, and Stratum 2); at Dose 250 mg/m^2 of Gefitinib accross strata, PK data from Phase-I patients was analysed earlier for the publication of the Phase-I trial. PK data for the Phase-II patients was analyzed separately for the Phase-II publication.

Arm/Group Title	Dose 250 mg/m^2 of Gefitinib (Phase II, Brain Stem Gliomas)	Dose 250 mg/m^2 of Gefitinib (Phase I)	Dose 100 mg/m^2 of Gefitinib	Dose 375 mg/m^2 of Gefitinib
Arm/Group Description	Brain Stem Glioma patients treated on the Phase-II trial. Seven patients were treated during Phase-I at the Phase-II dose, and thus eligible for the Phase-II trial, and included in this part of the report. Only 18 patients had samples for the PK evaluation.	This cohort includes all Phase-I patients treated at 250 mg/m^2 of Gefitinib regardless of diagnosis; that is, this group includes both brain stem gliomas and supratentorial malignant gliomas. Only six of 11 patients had adequate PK samples for the PK evaluation.	This cohort includes all Phase-I patients treated at 100 mg/m^2 of Gefitinib regardless of diagnosis; that is, this group includes both brain stem gliomas and supratentorial malignant gliomas. Eight (8) of 10 patients had adequate PK samples for the PK evaluation.	This cohort includes all Phase-I patients treated at 375 mg/m^2 of Gefitinib regardless of diagnosis; that is, this group includes both brain stem gliomas and supratentorial malignant gliomas. Eight of 12 patients had adequate PK samples for the PK evaluation.
Measure Participants	18	6	8	8
Median (Full Range) [Hour]	3.2	4.2	4.9	4.2

14. Secondary Outcome

Title	Gefitinib Area Under the Concentration Curve From 0-24 Hours (AUC)
Time Frame	Week 2 of course 1

Outcome Measure Data

Analysis Population Description

PK Data was combined at each dose level accross strata (Stratum 1A, Stratum 1B, and Stratum 2); at Dose 250 mg/m^2 of Gefitinib accross strata, PK data from Phase-I patients was analysed earlier for the publication of the Phase-I trial. PK data for the Phase-II patients was analyzed separately for the Phase-II publication.

Arm/Group Title	Dose 250 mg/m^2 of Gefitinib (Phase II, Brain Stem Gliomas)	Dose 250 mg/m^2 of Gefitinib (Phase I)	Dose 100 mg/m^2 of Gefitinib	Dose 375 mg/m^2 of Gefitinib
Arm/Group Description	Brain Stem Glioma patients treated on the Phase-II trial. Seven patients were treated during Phase-I at the Phase-II dose, and thus eligible for the Phase-II trial, and included in this part of the report. Only 18 patients had samples for the PK evaluation.	This cohort includes all Phase-I patients treated at 250 mg/m^2 of Gefitinib regardless of diagnosis; that is, this group includes both brain stem gliomas and supratentorial malignant gliomas. Only six of 11 patients had adequate PK samples for the PK evaluation.	This cohort includes all Phase-I patients treated at 100 mg/m^2 of Gefitinib regardless of diagnosis; that is, this group includes both brain stem gliomas and supratentorial malignant gliomas. Eight (8) of 10 patients had adequate PK samples for the PK evaluation.	This cohort includes all Phase-I patients treated at 375 mg/m^2 of Gefitinib regardless of diagnosis; that is, this group includes both brain stem gliomas and supratentorial malignant gliomas. Eight of 12 patients had adequate PK samples for the PK evaluation.
Measure Participants	18	6	8	8
Median (Full Range) [mcg/L*hr]	16.4	11.8	5.3	25.3

15. Secondary Outcome

Title	Number of Patients With Epidermal Growth Factor Receptor (EGFR) Amplification
Description	Epidermal growth factor receptor (EFGR) is a protein found on the surface of cells to which epidermal growth factor (EGF) binds. When EGF attaches to EGFR, it activates the enzyme tyrosine kinase, triggering reactions that cause the cells to grow and multiply.
Time Frame	Pre-treatment

Outcome Measure Data

Analysis Population Description

Epidermal growth factor receptor is only possible with tumor sample, which is only potentially available from supratentorial malignant glioma patients treated on Stratum-1B and Stratum-2. Of 10 Stratum-1B and 3 Stratum-2 patients (n=13), tumor material was available from 11 patients (8 in Stratum-1A and 3 in Stratum-2).

Arm/Group Title	Stratum IB and Stratum II
Arm/Group Description	Activation and mutations of EGFR have been associated with many cancers. In this secondary objective, we identify how many patients have activated EGFR and this requires a tumor sample from patients, which is only available from supratentorial malignant glioma patients treated on Stratum IB and Stratum II.
Measure Participants	11
Number [Participants]	5 83.3%

Adverse Events

Arm/Group Title	Stratum IA at Dose 100 mg/m^2		Stratum IA at Dose 250 mg/m^2		Stratum IA at Dose 375 mg/m^2		Stratum IB at Dose 100 mg/m^2		Stratum IB at Dose 250 mg/m^2		Stratum IB at Dose 375 mg/m^2		Stratum II at Dose 100 mg/m^2
Arm/Group Description	Brain Stem Glioma patients treated at 100 mg/m2		Brain Stem Glioma patients treated at 250 mg/m2		Brain Stem Glioma patients treated at 375 mg/m2		Patients with STMG treated at 100 mg/m2		Patients with STMG treated at 250 mg/m2		Patients with STMG treated at 375 mg/m2		Patients with STMG treated at 100 mg/m2 who are receiving EIACD
All Cause Mortality
	Stratum IA at Dose 100 mg/m^2		Stratum IA at Dose 250 mg/m^2		Stratum IA at Dose 375 mg/m^2		Stratum IB at Dose 100 mg/m^2		Stratum IB at Dose 250 mg/m^2		Stratum IB at Dose 375 mg/m^2		Stratum II at Dose 100 mg/m^2
	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)
Serious Adverse Events
	Stratum IA at Dose 100 mg/m^2		Stratum IA at Dose 250 mg/m^2		Stratum IA at Dose 375 mg/m^2		Stratum IB at Dose 100 mg/m^2		Stratum IB at Dose 250 mg/m^2		Stratum IB at Dose 375 mg/m^2		Stratum II at Dose 100 mg/m^2
	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	2/6 (33.3%)		15/43 (34.9%)		5/7 (71.4%)		1/2 (50%)		1/3 (33.3%)		5/5 (100%)		1/3 (33.3%)
Blood and lymphatic system disorders
Hemoglobin (Hgb)	0/6 (0%)		0/43 (0%)		1/7 (14.3%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Lymphopenia	1/6 (16.7%)		3/43 (7%)		1/7 (14.3%)		0/2 (0%)		1/3 (33.3%)		2/5 (40%)		0/3 (0%)
Gastrointestinal disorders
Anorexia	0/6 (0%)		2/43 (4.7%)		1/7 (14.3%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Dehydration	0/6 (0%)		0/43 (0%)		1/7 (14.3%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Diarrhea patients without colostomy	0/6 (0%)		0/43 (0%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		1/5 (20%)		0/3 (0%)
Nausea	0/6 (0%)		0/43 (0%)		1/7 (14.3%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Vomiting	0/6 (0%)		0/43 (0%)		1/7 (14.3%)		1/2 (50%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
General disorders
Death not associated with CTCAE term (Disease progression NOS )	0/6 (0%)		4/43 (9.3%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Fatigue (lethargy, malaise, asthenia)	0/6 (0%)		1/43 (2.3%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Weight loss	0/6 (0%)		2/43 (4.7%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Infections and infestations
Infection with normal ANC or Grade 1 or 2 neutrophils (Bladder (urinary) )	0/6 (0%)		1/43 (2.3%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Infection with normal ANC or Grade 1 or 2 neutrophils (Conjunctiva )	0/6 (0%)		1/43 (2.3%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Infection with normal ANC or Grade 1 or 2 neutrophils (Skin (cellulitis) )	0/6 (0%)		1/43 (2.3%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Infection with unknown ANC (Brain (encephalitis, infectious) )	0/6 (0%)		1/43 (2.3%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Infection without neutropenia	0/6 (0%)		0/43 (0%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		1/5 (20%)		0/3 (0%)
Investigations
Bilirubin	0/6 (0%)		0/43 (0%)		1/7 (14.3%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Neutrophils/granulocytes (ANC/AGC)	0/6 (0%)		0/43 (0%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		1/5 (20%)		0/3 (0%)
Fibrinogen	1/6 (16.7%)		0/43 (0%)		1/7 (14.3%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Metabolism and nutrition disorders
Hyperkalemia	0/6 (0%)		0/43 (0%)		1/7 (14.3%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Potassium, serum-low (hypokalemia)	0/6 (0%)		1/43 (2.3%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Uric acid, serum-high (hyperuricemia)	0/6 (0%)		1/43 (2.3%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Nervous system disorders
CNS hemorrhage/bleeding	0/6 (0%)		3/43 (7%)		1/7 (14.3%)		0/2 (0%)		1/3 (33.3%)		2/5 (40%)		0/3 (0%)
Depressed level of consciousness	0/6 (0%)		0/43 (0%)		1/7 (14.3%)		0/2 (0%)		0/3 (0%)		1/5 (20%)		0/3 (0%)
Headache	0/6 (0%)		1/43 (2.3%)		2/7 (28.6%)		1/2 (50%)		0/3 (0%)		3/5 (60%)		0/3 (0%)
Hydrocephalus	0/6 (0%)		1/43 (2.3%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Neurology - Other	0/6 (0%)		0/43 (0%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		1/3 (33.3%)
Neuropathy - cranial	0/6 (0%)		1/43 (2.3%)		1/7 (14.3%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Neuropathy - sensory	0/6 (0%)		1/43 (2.3%)		1/7 (14.3%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Neuropathy: cranial (CN IX Motor-pharynx; Sensory-ear, pharynx, tongue )	0/6 (0%)		1/43 (2.3%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Nystagmus	0/6 (0%)		0/43 (0%)		1/7 (14.3%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Seizure	0/6 (0%)		1/43 (2.3%)		0/7 (0%)		1/2 (50%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Somnolence/depressed level of consciousness	0/6 (0%)		1/43 (2.3%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Speech impairment (e.g., dysphasis or aphasia)	0/6 (0%)		0/43 (0%)		1/7 (14.3%)		1/2 (50%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Neuropathy: motor	0/6 (0%)		1/43 (2.3%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Psychiatric disorders
Confusion	0/6 (0%)		0/43 (0%)		0/7 (0%)		1/2 (50%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/6 (0%)		0/43 (0%)		1/7 (14.3%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Hypoxia	0/6 (0%)		2/43 (4.7%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Skin and subcutaneous tissue disorders
Nail changes	0/6 (0%)		1/43 (2.3%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Other (Not Including Serious) Adverse Events
	Stratum IA at Dose 100 mg/m^2		Stratum IA at Dose 250 mg/m^2		Stratum IA at Dose 375 mg/m^2		Stratum IB at Dose 100 mg/m^2		Stratum IB at Dose 250 mg/m^2		Stratum IB at Dose 375 mg/m^2		Stratum II at Dose 100 mg/m^2
	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	6/6 (100%)		43/43 (100%)		7/7 (100%)		2/2 (100%)		3/3 (100%)		5/5 (100%)		3/3 (100%)
Blood and lymphatic system disorders
Hemoglobin	4/6 (66.7%)		12/43 (27.9%)		4/7 (57.1%)		0/2 (0%)		0/3 (0%)		1/5 (20%)		1/3 (33.3%)
Cardiac disorders
Palpitations	0/6 (0%)		0/43 (0%)		1/7 (14.3%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Ear and labyrinth disorders
Auditory/Ear - Other (Specify, __)	1/6 (16.7%)		0/43 (0%)		1/7 (14.3%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Endocrine disorders
Cushingoid appearance (e.g., moon face, buffalo hump, centripetal obesity, cutaneous striae)	4/6 (66.7%)		14/43 (32.6%)		1/7 (14.3%)		0/2 (0%)		1/3 (33.3%)		2/5 (40%)		0/3 (0%)
Eye disorders
Dry eye syndrome	0/6 (0%)		0/43 (0%)		0/7 (0%)		0/2 (0%)		1/3 (33.3%)		0/5 (0%)		0/3 (0%)
Keratitis (corneal inflammation/corneal ulceration)	1/6 (16.7%)		0/43 (0%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Ocular surface disease	1/6 (16.7%)		0/43 (0%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Ocular/Visual - Other (Specify, __)	1/6 (16.7%)		3/43 (7%)		0/7 (0%)		1/2 (50%)		1/3 (33.3%)		0/5 (0%)		0/3 (0%)
Ophthalmoplegia/diplopia (double vision)	0/6 (0%)		6/43 (14%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Gastrointestinal disorders
Cheilitis	0/6 (0%)		3/43 (7%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Constipation	2/6 (33.3%)		18/43 (41.9%)		2/7 (28.6%)		0/2 (0%)		1/3 (33.3%)		1/5 (20%)		0/3 (0%)
Diarrhea	2/6 (33.3%)		26/43 (60.5%)		2/7 (28.6%)		0/2 (0%)		2/3 (66.7%)		0/5 (0%)		1/3 (33.3%)
Dry mouth/salivary gland (xerostomia)	1/6 (16.7%)		0/43 (0%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Dysphagia (difficulty swallowing)	0/6 (0%)		5/43 (11.6%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Esophagitis	0/6 (0%)		0/43 (0%)		1/7 (14.3%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Flatulence	0/6 (0%)		0/43 (0%)		1/7 (14.3%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Gastritis (including bile reflux gastritis)	1/6 (16.7%)		0/43 (0%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Gastrointestinal - Other (Specify, __)	0/6 (0%)		0/43 (0%)		1/7 (14.3%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Heartburn/dyspepsia	1/6 (16.7%)		4/43 (9.3%)		1/7 (14.3%)		0/2 (0%)		0/3 (0%)		1/5 (20%)		0/3 (0%)
Nausea	1/6 (16.7%)		17/43 (39.5%)		3/7 (42.9%)		1/2 (50%)		1/3 (33.3%)		3/5 (60%)		0/3 (0%)
Vomiting	4/6 (66.7%)		32/43 (74.4%)		4/7 (57.1%)		2/2 (100%)		2/3 (66.7%)		3/5 (60%)		0/3 (0%)
General disorders
Constitutional Symptoms - Other (Specify, __)	5/6 (83.3%)		4/43 (9.3%)		7/7 (100%)		2/2 (100%)		3/3 (100%)		3/5 (60%)		2/3 (66.7%)
Fatigue (asthenia, lethargy, malaise)	0/6 (0%)		22/43 (51.2%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L)	1/6 (16.7%)		13/43 (30.2%)		1/7 (14.3%)		0/2 (0%)		0/3 (0%)		1/5 (20%)		0/3 (0%)
Infections and infestations
Infection - Other (Specify, __)	5/6 (83.3%)		7/43 (16.3%)		2/7 (28.6%)		0/2 (0%)		3/3 (100%)		3/5 (60%)		1/3 (33.3%)
Investigations
ALT, SGPT (serum glutamic pyruvic transaminase)	2/6 (33.3%)		22/43 (51.2%)		2/7 (28.6%)		0/2 (0%)		1/3 (33.3%)		1/5 (20%)		1/3 (33.3%)
AST, SGOT(serum glutamic oxaloacetic transaminase)	2/6 (33.3%)		13/43 (30.2%)		1/7 (14.3%)		0/2 (0%)		1/3 (33.3%)		1/5 (20%)		1/3 (33.3%)
Alkaline phosphatase	0/6 (0%)		4/43 (9.3%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		1/3 (33.3%)
Amylase	0/6 (0%)		0/43 (0%)		1/7 (14.3%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Creatinine	0/6 (0%)		3/43 (7%)		1/7 (14.3%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Fibrinogen	1/6 (16.7%)		3/43 (7%)		2/7 (28.6%)		0/2 (0%)		0/3 (0%)		1/5 (20%)		0/3 (0%)
GGT (gamma-Glutamyl transpeptidase)	0/6 (0%)		0/43 (0%)		1/7 (14.3%)		0/2 (0%)		0/3 (0%)		1/5 (20%)		0/3 (0%)
Leukocytes (total WBC)	4/6 (66.7%)		19/43 (44.2%)		3/7 (42.9%)		2/2 (100%)		1/3 (33.3%)		2/5 (40%)		1/3 (33.3%)
Lymphopenia	5/6 (83.3%)		25/43 (58.1%)		4/7 (57.1%)		0/2 (0%)		1/3 (33.3%)		3/5 (60%)		0/3 (0%)
Metabolic/Laboratory - Other (Specify, __)	2/6 (33.3%)		0/43 (0%)		1/7 (14.3%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Neutrophils/granulocytes (ANC/AGC)	4/6 (66.7%)		8/43 (18.6%)		2/7 (28.6%)		1/2 (50%)		1/3 (33.3%)		1/5 (20%)		1/3 (33.3%)
Platelets	2/6 (33.3%)		6/43 (14%)		1/7 (14.3%)		0/2 (0%)		0/3 (0%)		2/5 (40%)		0/3 (0%)
Weight gain	0/6 (0%)		3/43 (7%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Metabolism and nutrition disorders
Albumin, serum-low (hypoalbuminemia)	1/6 (16.7%)		15/43 (34.9%)		2/7 (28.6%)		1/2 (50%)		1/3 (33.3%)		3/5 (60%)		0/3 (0%)
Anorexia	3/6 (50%)		11/43 (25.6%)		1/7 (14.3%)		1/2 (50%)		1/3 (33.3%)		0/5 (0%)		1/3 (33.3%)
Bicarbonate, serum-low	0/6 (0%)		5/43 (11.6%)		2/7 (28.6%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Calcium, serum-high (hypercalcemia)	0/6 (0%)		3/43 (7%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Calcium, serum-low (hypocalcemia)	2/6 (33.3%)		20/43 (46.5%)		3/7 (42.9%)		0/2 (0%)		2/3 (66.7%)		2/5 (40%)		1/3 (33.3%)
Dehydration	0/6 (0%)		0/43 (0%)		1/7 (14.3%)		0/2 (0%)		0/3 (0%)		1/5 (20%)		0/3 (0%)
Glucose, serum-high (hyperglycemia)	4/6 (66.7%)		16/43 (37.2%)		4/7 (57.1%)		1/2 (50%)		1/3 (33.3%)		4/5 (80%)		1/3 (33.3%)
Glucose, serum-low (hypoglycemia)	4/6 (66.7%)		8/43 (18.6%)		2/7 (28.6%)		0/2 (0%)		0/3 (0%)		1/5 (20%)		0/3 (0%)
Magnesium, serum-high (hypermagnesemia)	2/6 (33.3%)		10/43 (23.3%)		1/7 (14.3%)		0/2 (0%)		1/3 (33.3%)		0/5 (0%)		0/3 (0%)
Magnesium, serum-low (hypomagnesemia)	0/6 (0%)		0/43 (0%)		1/7 (14.3%)		0/2 (0%)		1/3 (33.3%)		0/5 (0%)		0/3 (0%)
Phosphate, serum-low (hypophosphatemia)	1/6 (16.7%)		21/43 (48.8%)		4/7 (57.1%)		1/2 (50%)		1/3 (33.3%)		0/5 (0%)		1/3 (33.3%)
Potassium, serum-high (hyperkalemia)	1/6 (16.7%)		6/43 (14%)		1/7 (14.3%)		1/2 (50%)		0/3 (0%)		1/5 (20%)		0/3 (0%)
Potassium, serum-low (hypokalemia)	1/6 (16.7%)		20/43 (46.5%)		2/7 (28.6%)		1/2 (50%)		0/3 (0%)		2/5 (40%)		1/3 (33.3%)
Sodium, serum-high (hypernatremia)	0/6 (0%)		10/43 (23.3%)		4/7 (57.1%)		0/2 (0%)		1/3 (33.3%)		1/5 (20%)		0/3 (0%)
Sodium, serum-low (hyponatremia)	0/6 (0%)		10/43 (23.3%)		4/7 (57.1%)		0/2 (0%)		1/3 (33.3%)		1/5 (20%)		0/3 (0%)
Triglyceride, serum-high (hypertriglyceridemia)	0/6 (0%)		0/43 (0%)		0/7 (0%)		1/2 (50%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Uric acid, serum-high (hyperuricemia)	1/6 (16.7%)		6/43 (14%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Nervous system disorders
Ataxia (incoordination)	3/6 (50%)		10/43 (23.3%)		2/7 (28.6%)		1/2 (50%)		0/3 (0%)		0/5 (0%)		1/3 (33.3%)
Cognitive disturbance	0/6 (0%)		0/43 (0%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		1/3 (33.3%)
Dizziness	1/6 (16.7%)		3/43 (7%)		1/7 (14.3%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Memory impairment	0/6 (0%)		0/43 (0%)		1/7 (14.3%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		1/3 (33.3%)
Neurology - Other (Specify, __)	1/6 (16.7%)		5/43 (11.6%)		2/7 (28.6%)		0/2 (0%)		1/3 (33.3%)		2/5 (40%)		1/3 (33.3%)
Neuropathy: motor	3/6 (50%)		12/43 (27.9%)		4/7 (57.1%)		0/2 (0%)		1/3 (33.3%)		0/5 (0%)		1/3 (33.3%)
Neuropathy: sensory	2/6 (33.3%)		3/43 (7%)		0/7 (0%)		1/2 (50%)		0/3 (0%)		2/5 (40%)		0/3 (0%)
Nystagmus	2/6 (33.3%)		0/43 (0%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Seizure	0/6 (0%)		0/43 (0%)		0/7 (0%)		1/2 (50%)		2/3 (66.7%)		0/5 (0%)		1/3 (33.3%)
Somnolence/depressed level of consciousness	1/6 (16.7%)		0/43 (0%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		1/5 (20%)		1/3 (33.3%)
Speech impairment (e.g., dysphasia or aphasia)	0/6 (0%)		5/43 (11.6%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Taste alteration (dysgeusia)	0/6 (0%)		5/43 (11.6%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Psychiatric disorders
Confusion	0/6 (0%)		0/43 (0%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		2/5 (40%)		0/3 (0%)
Insomnia	0/6 (0%)		4/43 (9.3%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Renal and urinary disorders
Incontinence, urinary	0/6 (0%)		3/43 (7%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Renal/Genitourinary - Other (Specify, __)	2/6 (33.3%)		5/43 (11.6%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		1/5 (20%)		1/3 (33.3%)
Urinary frequency/urgency	0/6 (0%)		6/43 (14%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Urinary retention (including neurogenic bladder)	1/6 (16.7%)		0/43 (0%)		1/7 (14.3%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis (including sneezing, nasal stuffiness, postnasal drip)	4/6 (66.7%)		9/43 (20.9%)		1/7 (14.3%)		0/2 (0%)		0/3 (0%)		2/5 (40%)		0/3 (0%)
Cough	1/6 (16.7%)		14/43 (32.6%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		2/5 (40%)		0/3 (0%)
Dyspnea (shortness of breath)	2/6 (33.3%)		5/43 (11.6%)		2/7 (28.6%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Pulmonary/Upper Respiratory - Other (Specify, __)	0/6 (0%)		0/43 (0%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		1/3 (33.3%)
Skin and subcutaneous tissue disorders
Dermatology/Skin - Other (Specify, __)	0/6 (0%)		5/43 (11.6%)		1/7 (14.3%)		0/2 (0%)		1/3 (33.3%)		2/5 (40%)		0/3 (0%)
Dry skin	2/6 (33.3%)		17/43 (39.5%)		3/7 (42.9%)		0/2 (0%)		0/3 (0%)		1/5 (20%)		0/3 (0%)
Hair loss/alopecia (scalp or body)	1/6 (16.7%)		15/43 (34.9%)		0/7 (0%)		0/2 (0%)		1/3 (33.3%)		2/5 (40%)		0/3 (0%)
Nail changes	0/6 (0%)		5/43 (11.6%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Rash/desquamation	4/6 (66.7%)		29/43 (67.4%)		5/7 (71.4%)		0/2 (0%)		2/3 (66.7%)		2/5 (40%)		1/3 (33.3%)
Rash: acne/acneiform	0/6 (0%)		7/43 (16.3%)		0/7 (0%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Vascular disorders
Flushing	1/6 (16.7%)		0/43 (0%)		1/7 (14.3%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)
Hot flashes/flushes	0/6 (0%)		0/43 (0%)		1/7 (14.3%)		0/2 (0%)		0/3 (0%)		0/5 (0%)		0/3 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.