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Molecularly Determined Treatment of Diffuse Intrinsic Pontine Gliomas (DIPG)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01182350
Recruitment Status : Terminated (Per design: Stop if fewer than 3 cohorts by molecular classification were with 10 participants or only 1 cohort enrolled at least 15 participants of 50.)
First Posted : August 16, 2010
Results First Posted : September 4, 2019
Last Update Posted : September 4, 2019
Sponsor:
Collaborators:
Boston Children’s Hospital
University of California, San Francisco
Ann & Robert H Lurie Children's Hospital of Chicago
Children's Healthcare of Atlanta
Children's Hospital Colorado
Children's Hospital Los Angeles
Children's Hospital of Michigan
Children's Hospitals and Clinics of Minnesota
Cook Children's Medical Center
OHSU Doernbecher Children's Hospital
Duke University
Johns Hopkins University
Nicklaus Children's Hospital f/k/a Miami Children's Hospital
Nemours Children's Clinic
New York University
Milton S. Hershey Medical Center
Seattle Children's Hospital
Lucile Packard Children's Hospital
University of Louisville
Children's National Research Institute
Washington University School of Medicine
Phoenix Children's Hospital
Medical University of South Carolina
Information provided by (Responsible Party):
Karen D. Wright MD, Dana-Farber Cancer Institute

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Diffuse Intrinsic Pontine Glioma
Interventions Drug: Bevacizumab
Drug: Erlotinib
Drug: Temozolomide
Radiation: Radiation
Enrollment 53
Recruitment Details Study screening procedures were conducted at 23 sites in the United States. Eligible participants enrolled between September 2011 and September 2015.
Pre-assignment Details  
Arm/Group Title Cohort 1: MGMT-/EGFR- Cohort 2: MGMT-/EGFR+ Cohort 3 MGMT+/EGFR- Cohort 4. MGMT+/EGFR+ Ineligible for Direct Treatment Assignment
Hide Arm/Group Description

Protocol treatment lasts approximately 52 weeks including a 4-week interim period once radiation therapy is completed and a maintenance phase (cycle duration=28 days).

Radiation therapy: Given in 180 cGy fractions to a total dose of 59.4 + 1.8 Gy/−5.4 Gy for approximately 7 weeks beginning 7–21 days after biopsy Bevacizumab: Administered intravenously at 10 mg/kg beginning no sooner than 21 days from biopsy and every 14 days concurrent with radiation therapy, through the interim period and for up to 10 maintenance cycles

Protocol treatment lasts approximately 52 weeks including a 4-week interim period once radiation therapy is completed and a maintenance phase (cycle duration=28 days).

Radiation therapy: Given in 180 cGy fractions to a total dose of 59.4 + 1.8 Gy/−5.4 Gy for approximately 7 weeks beginning 7–21 days after biopsy Bevacizumab: Administered intravenously at 10 mg/kg beginning no sooner than 21 days from biopsy and every 14 days concurrent with radiation therapy, through the interim period and for up to 10 maintenance cycles

Protocol treatment lasts approximately 52 weeks including a 4-week interim period once radiation therapy is completed and a maintenance phase (cycle duration=28 days).

Radiation therapy: Given in 180 cGy fractions to a total dose of 59.4 + 1.8 Gy/−5.4 Gy for approximately 7 weeks beginning 7–21 days after biopsy Bevacizumab: Administered intravenously at 10 mg/kg beginning no sooner than 21 days from biopsy and every 14 days concurrent with radiation therapy, through the interim period and for up to 10 maintenance cycles Temozolomide: Administered orally at 90 mg/m2/day continuously during radiation therapy, held through the interim period and then 200 mg/m2/day for 5 days for up to 10 maintenance cycles

Protocol treatment lasts approximately 52 weeks including a 4-week interim period once radiation therapy is completed and a maintenance phase (cycle duration=28 days).

Radiation therapy: Given in 180 cGy fractions to a total dose of 59.4 + 1.8 Gy/−5.4 Gy for approximately 7 weeks beginning 7–21 days after biopsy Bevacizumab: Administered intravenously at 10 mg/kg beginning no sooner than 21 days from biopsy and every 14 days concurrent with radiation therapy, through the interim period and for up to 10 maintenance cycles Erlotinib: Administered orally at 85 mg/m2 daily continuously during radiation therapy, through the interim period and for up to 10 maintenance cycles

Temozolomide: Administered orally at 90 mg/m2/day continuously during radiation therapy, held through the interim period and then 200 mg/m2/day for 5 days for up to 10 maintenance cycles

All enrolled participants were to receive surgical biopsy to guide treatment assignment based on molecular results.Participants without an evaluable sample were ineligible for direct treatment assignment.
Period Title: Overall Study
Started 30 14 3 3 3
Underwent Stereotactic Biopsy 30 14 3 3 0
Started Assigned Chemoradiation 27 14 2 2 0
Completed 3 0 0 0 0
Not Completed 27 14 3 3 3
Reason Not Completed
Adverse Event             5             0             0             0             0
Disease Progression             15             12             0             1             0
Death             0             1             1             0             0
Withdrawal by Subject             3             1             0             1             0
Alternative Therapy             2             0             1             0             0
Travel Issue/Prefer Treatment at Home             2             0             1             1             0
Unevaluable for Biopsy             0             0             0             0             3
Arm/Group Title All Biopsied Participants
Hide Arm/Group Description

Protocol treatment lasts approximately 52 weeks including a 4-week interim period once radiation therapy is completed and a maintenance phase (cycle duration=28 days).

Treatment directed based on tumor biopsy results requires classification of patients into 1 of 4 potential cohorts: O^6-methylguanine–DNA methyltransferase (MGMT) promoter methylation status (negative versus positive) and epidermal growth factor receptor (EGFR) overexpression status (negative versus positive).

Overall Number of Baseline Participants 50
Hide Baseline Analysis Population Description
The analysis dataset is comprised of all enrolled participants who underwent stereotactic biopsy.
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 50 participants
6.3
(3.3 to 17.5)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 50 participants
Female
27
  54.0%
Male
23
  46.0%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
United States Number Analyzed 50 participants
50
 100.0%
Molecular Classification   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 50 participants
MGMT-/EGFR-
30
  60.0%
MGMT-/EGFR+
14
  28.0%
MGMT+/EGFR-
3
   6.0%
MGMT+/EGFR+
3
   6.0%
[1]
Measure Description: Treatment directed based on tumor biopsy results requires classification of patients into 1 of 4 potential cohorts: O^6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status (negative versus positive) and epidermal growth factor receptor (EGFR) overexpression status (negative versus positive).
1.Primary Outcome
Title 9-month Overall Survival (OS) Rate
Hide Description 9-month overall survival is the percentage of participants remaining alive 9 months from registration.
Time Frame 9 months
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population is comprised of the subset of participants who underwent biopsy, obtained a molecularly-based treatment assignment and started assigned chemoradiation therapy.
Arm/Group Title All Patients Starting Assigned Chemoradiation
Hide Arm/Group Description:

Protocol treatment lasts approximately 52 weeks including a 4-week interim period once radiation therapy is completed and a maintenance phase (cycle duration=28 days).

Treatment directed based on tumor biopsy results requires classification of patients into 1 of 4 potential cohorts: O^6-methylguanine–DNA methyltransferase (MGMT) promoter methylation status (negative versus positive) and epidermal growth factor receptor (EGFR) overexpression status (negative versus positive).

Overall Number of Participants Analyzed 45
Measure Type: Number
Number (90% Confidence Interval)
Unit of Measure: percentage of participants
64.4
(51.1 to 76.3)
2.Secondary Outcome
Title Rate of Lethal Complications From Surgery
Hide Description The rate of lethal complications from surgery is the percentage of participants dying as a result of surgery.
Time Frame 2 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title All Biopsied Participants
Hide Arm/Group Description:

Protocol treatment lasts approximately 52 weeks including a 4-week interim period once radiation therapy is completed and a maintenance phase (cycle duration=28 days).

Treatment directed based on tumor biopsy results requires classification of patients into 1 of 4 potential cohorts: O6-methylguanine–DNA methyltransferase (MGMT) promoter methylation status (negative versus positive) and epidermal growth factor receptor (EGFR) overexpression status (negative versus positive).

Overall Number of Participants Analyzed 50
Measure Type: Number
Number (90% Confidence Interval)
Unit of Measure: percentage of participants
0.0
(0.0 to 5.8)
3.Secondary Outcome
Title Grade 3-4 Post-Procedural Surgery-Related Toxicity Rate
Hide Description Grade 3-4 post-procedural surgery-related toxicity rate is the percentage of participants experiencing at least one grade 3-4 adverse event (AE) during the post-procedural time frame of 14 days attributable to the surgical procedure based on NCI Common Toxicity Criteria for Adverse Events version 4 (CTCAEv4).
Time Frame 2 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis dataset is comprised of all enrolled participants who underwent stereotactic biopsy.
Arm/Group Title All Biopsied Participants
Hide Arm/Group Description:

Protocol treatment lasts approximately 52 weeks including a 4-week interim period once radiation therapy is completed and a maintenance phase (cycle duration=28 days).

Treatment directed based on tumor biopsy results requires classification of patients into 1 of 4 potential cohorts: O6-methylguanine–DNA methyltransferase (MGMT) promoter methylation status (negative versus positive) and epidermal growth factor receptor (EGFR) overexpression status (negative versus positive).

Overall Number of Participants Analyzed 50
Measure Type: Number
Number (90% Confidence Interval)
Unit of Measure: percentage of participants
10.0
(4.1 to 19.9)
4.Secondary Outcome
Title Delay in Radiation Therapy Start
Hide Description The number of participants delaying the start of radiation therapy by more than 3 weeks due to complications as a result of surgical biopsy to obtain diagnostic tumor sample.
Time Frame 3 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis dataset is comprised of all enrolled participants who underwent stereotactic biopsy.
Arm/Group Title All Biopsied Participants
Hide Arm/Group Description:

Protocol treatment lasts approximately 52 weeks including a 4-week interim period once radiation therapy is completed and a maintenance phase (cycle duration=28 days).

Treatment directed based on tumor biopsy results requires classification of patients into 1 of 4 potential cohorts: O6-methylguanine–DNA methyltransferase (MGMT) promoter methylation status (negative versus positive) and epidermal growth factor receptor (EGFR) overexpression status (negative versus positive).

Overall Number of Participants Analyzed 50
Measure Type: Count of Participants
Unit of Measure: Participants
1
   2.0%
5.Secondary Outcome
Title Feasibility Rate of Molecular Approach to Therapy
Hide Description Feasibility rate of the molecular strategy is based on the percentage of participants either with inadequate tissue from surgical biopsy to confirm DIPG diagnosis and/or with uninterpretable results for identification of EGFR overexpression and MGMT methylation status.
Time Frame 3 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis dataset is comprised of all enrolled participants who underwent stereotactic biopsy.
Arm/Group Title All Biopsied Participants
Hide Arm/Group Description:

Protocol treatment lasts approximately 52 weeks including a 4-week interim period once radiation therapy is completed and a maintenance phase (cycle duration=28 days).

Treatment directed based on tumor biopsy results requires classification of patients into 1 of 4 potential cohorts: O6-methylguanine–DNA methyltransferase (MGMT) promoter methylation status (negative versus positive) and epidermal growth factor receptor (EGFR) overexpression status (negative versus positive).

Overall Number of Participants Analyzed 50
Measure Type: Number
Number (90% Confidence Interval)
Unit of Measure: percentage of participants
92.0
(82.6 to 97.2)
6.Secondary Outcome
Title Number of Participants With Grade 3-4 Treatment-Related Toxicity Over Chemoradiation Therapy
Hide Description Counts any participant experiencing at least one treatment-related grade 3 or 4 adverse event (AE) with treatment attribution of possibly, probably or definite based on NCI Common Toxicity Criteria for Adverse Events version 4 (CTCAEv4) over chemoradiation therapy as reported on case report forms.
Time Frame Adverse events were routinely throughout treatment. Treatment duration was a median of 6.4 months (range 0.4-13.4 months) in this study cohort.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population is comprised of the subset of participants who underwent surgical biopsy, obtained a molecularly-based treatment assignment and started assigned chemoradiation therapy.
Arm/Group Title Cohort 1 MGMT-/EGFR- Cohort 2 MGMT-/EGFR+ Cohort 3: MGMT+/EGFR- Cohort 4. MGMT+/EGFR+
Hide Arm/Group Description:

Protocol treatment lasts approximately 52 weeks including a 4-week interim period once radiation therapy is completed and a maintenance phase (cycle duration=28 days).

Radiation therapy: Given in 180 cGy fractions to a total dose of 59.4 + 1.8 Gy/−5.4 Gy for approximately 7 weeks beginning 7–21 days after biopsy Bevacizumab: Administered intravenously at 10 mg/kg beginning no sooner than 21 days from biopsy and every 14 days concurrent with radiation therapy, through the interim period and for up to 10 maintenance cycles

Protocol treatment lasts approximately 52 weeks including a 4-week interim period once radiation therapy is completed and a maintenance phase (cycle duration=28 days).

Radiation therapy: Given in 180 cGy fractions to a total dose of 59.4 + 1.8 Gy/−5.4 Gy for approximately 7 weeks beginning 7–21 days after biopsy Bevacizumab: Administered intravenously at 10 mg/kg beginning no sooner than 21 days from biopsy and every 14 days concurrent with radiation therapy, through the interim period and for up to 10 maintenance cycles Erlotinib: Administered orally at 85 mg/m2 daily continuously during radiation therapy, through the interim period and for up to 10 maintenance cycles

Protocol treatment lasts approximately 52 weeks including a 4-week interim period once radiation therapy is completed and a maintenance phase (cycle duration=28 days).

Radiation therapy: Given in 180 cGy fractions to a total dose of 59.4 + 1.8 Gy/−5.4 Gy for approximately 7 weeks beginning 7–21 days after biopsy Bevacizumab: Administered intravenously at 10 mg/kg beginning no sooner than 21 days from biopsy and every 14 days concurrent with radiation therapy, through the interim period and for up to 10 maintenance cycles Temozolomide: Administered orally at 90 mg/m2/day continuously during radiation therapy, held through the interim period and then 200 mg/m2/day for 5 days for up to 10 maintenance cycles

Protocol treatment lasts approximately 52 weeks including a 4-week interim period once radiation therapy is completed and a maintenance phase (cycle duration=28 days).

Radiation therapy: Given in 180 cGy fractions to a total dose of 59.4 + 1.8 Gy/−5.4 Gy for approximately 7 weeks beginning 7–21 days after biopsy Bevacizumab: Administered intravenously at 10 mg/kg beginning no sooner than 21 days from biopsy and every 14 days concurrent with radiation therapy, through the interim period and for up to 10 maintenance cycles Erlotinib: Administered orally at 85 mg/m2 daily continuously during radiation therapy, through the interim period and for up to 10 maintenance cycles Temozolomide: Administered orally at 90 mg/m2/day continuously during radiation therapy, held through the interim period and then 200 mg/m2/day for 5 days for up to 10 maintenance cycles

Overall Number of Participants Analyzed 27 14 2 2
Measure Type: Count of Participants
Unit of Measure: Participants
5
  18.5%
5
  35.7%
0
   0.0%
0
   0.0%
7.Secondary Outcome
Title Median Progression Free Survival (PFS)
Hide Description PFS based on the Kaplan-Meier method is defined as the duration of time [months (m)] from study entry to documented disease progression (PD) or death. Participants alive without PD are censored at the date of last disease assessment. For intrinsic pontine brainstem gliomas, only one lesion/mass is present at diagnosis. Comparisons of maximal 2-dimensional measurements, TxW (product of the longest diameter [width (W)] and its longest perpendicular diameter [transverse (T)]) are used to assess response for this target lesion. PD is 25% or more increase, taking as reference the smallest product observed since the start of treatment, or the appearance of one or more new lesions.
Time Frame Disease assessments using a standard CNS imaging protocol occurred chemoradiation cycles 1 and 2, every other maintenance cycle, every 3 months post-treatment year 1 then annually until PD or therapy change; In this study cohort, follow-up was up to 34m.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population is comprised of the subset of participants who underwent surgical biopsy, obtained a molecularly-based treatment assignment and started assigned chemoradiation therapy. The PFS was aggregated across cohorts per statistical analysis plan to evaluate the effect of the "molecular strategy".
Arm/Group Title All Patients Starting Assigned Chemoradiation
Hide Arm/Group Description:

Protocol treatment lasts approximately 52 weeks including a 4-week interim period once radiation therapy is completed and a maintenance phase (cycle duration=28 days).

Treatment directed based on tumor biopsy results requires classification of patients into 1 of 4 potential cohorts: O^6-methylguanine–DNA methyltransferase (MGMT) promoter methylation status (negative versus positive) and epidermal growth factor receptor (EGFR) overexpression status (negative versus positive).

Overall Number of Participants Analyzed 45
Median (Full Range)
Unit of Measure: months
8
(1 to 16)
8.Post-Hoc Outcome
Title 9-month Overall Survival (OS) Rate by Molecular Cohort
Hide Description 9-month OS rate is the percentage of participants alive at 9 months from registration.
Time Frame 9 months
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population is comprised of the subset of participants who underwent surgical biopsy, obtained a molecularly-based treatment assignment and started assigned chemoradiation therapy.
Arm/Group Title Cohort 1: MGMT-/EGFR- Cohort 2: MGMT-/EGFR+ Cohort 3. MGMT+/EGFR- Cohort 4. MGMT+/EGFR+
Hide Arm/Group Description:

Protocol treatment lasts approximately 52 weeks including a 4-week interim period once radiation therapy is completed and a maintenance phase (cycle duration=28 days).

Radiation therapy: Given in 180 cGy fractions to a total dose of 59.4 + 1.8 Gy/−5.4 Gy for approximately 7 weeks beginning 7–21 days after biopsy

Bevacizumab: Administered intravenously at 10 mg/kg beginning no sooner than 21 days from biopsy and every 14 days concurrent with radiation therapy, through the interim period and for up to 10 maintenance cycles

Protocol treatment lasts approximately 52 weeks including a 4-week interim period once radiation therapy is completed and a maintenance phase (cycle duration=28 days).

Radiation therapy: Given in 180 cGy fractions to a total dose of 59.4 + 1.8 Gy/−5.4 Gy for approximately 7 weeks beginning 7–21 days after biopsy

Bevacizumab: Administered intravenously at 10 mg/kg beginning no sooner than 21 days from biopsy and every 14 days concurrent with radiation therapy, through the interim period and for up to 10 maintenance cycles

Erlotinib: Administered orally at 85 mg/m2 daily continuously during radiation therapy, through the interim period and for up to 10 maintenance cycles

Protocol treatment lasts approximately 52 weeks including a 4-week interim period once radiation therapy is completed and a maintenance phase (cycle duration=28 days).

Radiation therapy: Given in 180 cGy fractions to a total dose of 59.4 + 1.8 Gy/−5.4 Gy for approximately 7 weeks beginning 7–21 days after biopsy

Bevacizumab: Administered intravenously at 10 mg/kg beginning no sooner than 21 days from biopsy and every 14 days concurrent with radiation therapy, through the interim period and for up to 10 maintenance cycles

Temozolomide: Administered orally at 90 mg/m2/day continuously during radiation therapy, held through the interim period and then 200 mg/m2/day for 5 days for up to 10 maintenance cycles

Protocol treatment lasts approximately 52 weeks including a 4-week interim period once radiation therapy is completed and a maintenance phase (cycle duration=28 days).

Radiation therapy: Given in 180 cGy fractions to a total dose of 59.4 + 1.8 Gy/−5.4 Gy for approximately 7 weeks beginning 7–21 days after biopsy

Bevacizumab: Administered intravenously at 10 mg/kg beginning no sooner than 21 days from biopsy and every 14 days concurrent with radiation therapy, through the interim period and for up to 10 maintenance cycles

Erlotinib: Administered orally at 85 mg/m2 daily continuously during radiation therapy, through the interim period and for up to 10 maintenance cycles

Overall Number of Participants Analyzed 27 14 2 2
Measure Type: Number
Number (90% Confidence Interval)
Unit of Measure: percentage of participants
66.7
(49.1 to 81.4)
57.1
(32.5 to 79.4)
50.0
(2.6 to 97.5)
100
(22.4 to 100)
Time Frame Adverse events were routinely throughout treatment. Treatment duration was a median of 6.4 months (range 0.4-13.4 months) in this study cohort.
Adverse Event Reporting Description Maximum grade toxicity by type was first calculated within each arm. Serious AEs were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv4. All remaining events regardless of treatment attribution were classified as Other AEs. No further data is available to specify classification of other beyond the general term. The analysis population is comprised of the subset of participants who underwent surgical biopsy.
 
Arm/Group Title Cohort 1 MGMT-/EGFR- Cohort 2 MGMT-/EGFR+ Cohort 3: MGMT+/EGFR- Cohort 4. MGMT+/EGFR+
Hide Arm/Group Description

Protocol treatment lasts approximately 52 weeks including a 4-week interim period once radiation therapy is completed and a maintenance phase (cycle duration=28 days).

Radiation therapy: Given in 180 cGy fractions to a total dose of 59.4 + 1.8 Gy/−5.4 Gy for approximately 7 weeks beginning 7–21 days after biopsy Bevacizumab: Administered intravenously at 10 mg/kg beginning no sooner than 21 days from biopsy and every 14 days concurrent with radiation therapy, through the interim period and for up to 10 maintenance cycles

Protocol treatment lasts approximately 52 weeks including a 4-week interim period once radiation therapy is completed and a maintenance phase (cycle duration=28 days).

Radiation therapy: Given in 180 cGy fractions to a total dose of 59.4 + 1.8 Gy/−5.4 Gy for approximately 7 weeks beginning 7–21 days after biopsy Bevacizumab: Administered intravenously at 10 mg/kg beginning no sooner than 21 days from biopsy and every 14 days concurrent with radiation therapy, through the interim period and for up to 10 maintenance cycles Erlotinib: Administered orally at 85 mg/m2 daily continuously during radiation therapy, through the interim period and for up to 10 maintenance cycles

Protocol treatment lasts approximately 52 weeks including a 4-week interim period once radiation therapy is completed and a maintenance phase (cycle duration=28 days).

Radiation therapy: Given in 180 cGy fractions to a total dose of 59.4 + 1.8 Gy/−5.4 Gy for approximately 7 weeks beginning 7–21 days after biopsy Bevacizumab: Administered intravenously at 10 mg/kg beginning no sooner than 21 days from biopsy and every 14 days concurrent with radiation therapy, through the interim period and for up to 10 maintenance cycles Temozolomide: Administered orally at 90 mg/m2/day continuously during radiation therapy, held through the interim period and then 200 mg/m2/day for 5 days for up to 10 maintenance cycles

Protocol treatment lasts approximately 52 weeks including a 4-week interim period once radiation therapy is completed and a maintenance phase (cycle duration=28 days).

Radiation therapy: Given in 180 cGy fractions to a total dose of 59.4 + 1.8 Gy/−5.4 Gy for approximately 7 weeks beginning 7–21 days after biopsy Bevacizumab: Administered intravenously at 10 mg/kg beginning no sooner than 21 days from biopsy and every 14 days concurrent with radiation therapy, through the interim period and for up to 10 maintenance cycles Erlotinib: Administered orally at 85 mg/m2 daily continuously during radiation therapy, through the interim period and for up to 10 maintenance cycles Temozolomide: Administered orally at 90 mg/m2/day continuously during radiation therapy, held through the interim period and then 200 mg/m2/day for 5 days for up to 10 maintenance cycles

All-Cause Mortality
Cohort 1 MGMT-/EGFR- Cohort 2 MGMT-/EGFR+ Cohort 3: MGMT+/EGFR- Cohort 4. MGMT+/EGFR+
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   29/30 (96.67%)   14/14 (100.00%)   3/3 (100.00%)   2/3 (66.67%) 
Hide Serious Adverse Events
Cohort 1 MGMT-/EGFR- Cohort 2 MGMT-/EGFR+ Cohort 3: MGMT+/EGFR- Cohort 4. MGMT+/EGFR+
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   8/30 (26.67%)   9/14 (64.29%)   1/3 (33.33%)   2/3 (66.67%) 
Blood and lymphatic system disorders         
Anemia  1  0/30 (0.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Gastrointestinal disorders         
Dysphagia  1  0/30 (0.00%)  2/14 (14.29%)  0/3 (0.00%)  0/3 (0.00%) 
Vomiting  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Infections and infestations         
Rash pustular  1  0/30 (0.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Wound infection  1  0/30 (0.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Injury, poisoning and procedural complications         
Wound complication  1  0/30 (0.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Investigations         
CD4 lymphocytes decreased  1  0/30 (0.00%)  0/14 (0.00%)  1/3 (33.33%)  0/3 (0.00%) 
Lymphocyte count decreased  1  2/30 (6.67%)  2/14 (14.29%)  0/3 (0.00%)  0/3 (0.00%) 
Neutrophil count decreased  1  0/30 (0.00%)  0/14 (0.00%)  0/3 (0.00%)  1/3 (33.33%) 
Platelet count decreased  1  0/30 (0.00%)  0/14 (0.00%)  0/3 (0.00%)  1/3 (33.33%) 
White blood cell decreased  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  1/3 (33.33%) 
Metabolism and nutrition disorders         
Anorexia  1  0/30 (0.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Dehydration  1  0/30 (0.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Hypokalemia  1  0/30 (0.00%)  0/14 (0.00%)  0/3 (0.00%)  1/3 (33.33%) 
Hyponatremia  1  0/30 (0.00%)  0/14 (0.00%)  0/3 (0.00%)  1/3 (33.33%) 
Musculoskeletal and connective tissue disorders         
Muscle weakness left-sided  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Muscle weakness right-sided  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Pain in extremity  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Nervous system disorders         
Ataxia  1  2/30 (6.67%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Depressed level of consciousness  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Dysarthria  1  0/30 (0.00%)  2/14 (14.29%)  0/3 (0.00%)  0/3 (0.00%) 
Dysphasia  1  1/30 (3.33%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Headache  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Hydrocephalus  1  0/30 (0.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Somnolence  1  0/30 (0.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Spasticity  1  0/30 (0.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Skin and subcutaneous tissue disorders         
Palmar-plantar erythrodysesthesia syndrome  1  0/30 (0.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Rash maculo-papular  1  0/30 (0.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Skin and subcutaneous tissue disorders-Other  1  0/30 (0.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Vascular disorders         
Hematoma  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Hypertension  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  1/3 (33.33%) 
1
Term from vocabulary, CTCAE (4.0)
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Cohort 1 MGMT-/EGFR- Cohort 2 MGMT-/EGFR+ Cohort 3: MGMT+/EGFR- Cohort 4. MGMT+/EGFR+
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   30/30 (100.00%)   14/14 (100.00%)   3/3 (100.00%)   3/3 (100.00%) 
Blood and lymphatic system disorders         
Anemia  1  7/30 (23.33%)  4/14 (28.57%)  2/3 (66.67%)  1/3 (33.33%) 
Blood and lymphatic system disorders - Other  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Cardiac disorders         
Cardiac disorders - Other  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Sinus bradycardia  1  6/30 (20.00%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Sinus bradycardia  1  0/30 (0.00%)  2/14 (14.29%)  2/3 (66.67%)  1/3 (33.33%) 
Sinus tachycardia  1  5/30 (16.67%)  1/14 (7.14%)  1/3 (33.33%)  0/3 (0.00%) 
Ear and labyrinth disorders         
Ear and labyrinth disorders - Other  1  0/30 (0.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Ear pain  1  1/30 (3.33%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
External ear inflammation  1  0/30 (0.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
External ear pain  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Middle ear inflammation  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Tinnitus  1  2/30 (6.67%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Vertigo  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Endocrine disorders         
Adrenal insufficiency  1  0/30 (0.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Cushingoid  1  5/30 (16.67%)  3/14 (21.43%)  0/3 (0.00%)  0/3 (0.00%) 
Eye disorders         
Conjunctivitis  1  1/30 (3.33%)  0/14 (0.00%)  1/3 (33.33%)  0/3 (0.00%) 
Eye disorders - Other  1  7/30 (23.33%)  2/14 (14.29%)  0/3 (0.00%)  0/3 (0.00%) 
Eyelid function disorder  1  0/30 (0.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Optic nerve disorder  1  0/30 (0.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Gastrointestinal disorders         
Abdominal distension  1  3/30 (10.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Abdominal pain  1  7/30 (23.33%)  2/14 (14.29%)  1/3 (33.33%)  0/3 (0.00%) 
Anal hemorrhage  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Bloating  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Cheilitis  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Constipation  1  11/30 (36.67%)  5/14 (35.71%)  3/3 (100.00%)  0/3 (0.00%) 
Dental caries  1  0/30 (0.00%)  2/14 (14.29%)  0/3 (0.00%)  0/3 (0.00%) 
Diarrhea  1  3/30 (10.00%)  6/14 (42.86%)  0/3 (0.00%)  1/3 (33.33%) 
Dry mouth  1  2/30 (6.67%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Dyspepsia  1  3/30 (10.00%)  1/14 (7.14%)  1/3 (33.33%)  0/3 (0.00%) 
Dysphagia  1  4/30 (13.33%)  4/14 (28.57%)  0/3 (0.00%)  0/3 (0.00%) 
Esophageal obstruction  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Gastritis  1  0/30 (0.00%)  2/14 (14.29%)  0/3 (0.00%)  0/3 (0.00%) 
Gastrointestinal disorders - Other  1  2/30 (6.67%)  0/14 (0.00%)  0/3 (0.00%)  1/3 (33.33%) 
Gastrointestinal pain  1  0/30 (0.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Mucositis oral  1  2/30 (6.67%)  2/14 (14.29%)  0/3 (0.00%)  1/3 (33.33%) 
Nausea  1  12/30 (40.00%)  4/14 (28.57%)  2/3 (66.67%)  3/3 (100.00%) 
Oral pain  1  1/30 (3.33%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Rectal pain  1  2/30 (6.67%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Salivary gland fistula  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Stomach pain  1  0/30 (0.00%)  0/14 (0.00%)  0/3 (0.00%)  1/3 (33.33%) 
Toothache  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Vomiting  1  16/30 (53.33%)  9/14 (64.29%)  1/3 (33.33%)  3/3 (100.00%) 
General disorders         
Death NOS  1  2/30 (6.67%)  1/14 (7.14%)  1/3 (33.33%)  2/3 (66.67%) 
Edema face  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Edema limbs  1  1/30 (3.33%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Fatigue  1  14/30 (46.67%)  4/14 (28.57%)  1/3 (33.33%)  1/3 (33.33%) 
Fever  1  4/30 (13.33%)  4/14 (28.57%)  1/3 (33.33%)  1/3 (33.33%) 
Gait disturbance  1  4/30 (13.33%)  3/14 (21.43%)  0/3 (0.00%)  0/3 (0.00%) 
General disorders and administration site conditions - Other  1  0/30 (0.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Irritability  1  4/30 (13.33%)  2/14 (14.29%)  0/3 (0.00%)  0/3 (0.00%) 
Malaise  1  1/30 (3.33%)  2/14 (14.29%)  0/3 (0.00%)  0/3 (0.00%) 
Neck edema  1  0/30 (0.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Non-cardiac chest pain  1  1/30 (3.33%)  0/14 (0.00%)  1/3 (33.33%)  0/3 (0.00%) 
Pain  1  5/30 (16.67%)  3/14 (21.43%)  1/3 (33.33%)  0/3 (0.00%) 
Immune system disorders         
Allergic reaction  1  1/30 (3.33%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Infections and infestations         
Abdominal infection  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Conjunctivitis infective  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Device related infection  1  0/30 (0.00%)  2/14 (14.29%)  0/3 (0.00%)  0/3 (0.00%) 
Encephalitis infection  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Infections and infestations - Other  1  3/30 (10.00%)  0/14 (0.00%)  1/3 (33.33%)  0/3 (0.00%) 
Lung infection  1  2/30 (6.67%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Mediastinal infection  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Mucosal infection  1  5/30 (16.67%)  3/14 (21.43%)  1/3 (33.33%)  0/3 (0.00%) 
Otitis externa  1  0/30 (0.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Otitis media  1  0/30 (0.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Paronychia  1  0/30 (0.00%)  0/14 (0.00%)  0/3 (0.00%)  1/3 (33.33%) 
Rash pustular  1  0/30 (0.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Rhinitis infective  1  1/30 (3.33%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Sinusitis  1  2/30 (6.67%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Skin infection  1  3/30 (10.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Upper respiratory infection  1  7/30 (23.33%)  4/14 (28.57%)  0/3 (0.00%)  0/3 (0.00%) 
Urinary tract infection  1  2/30 (6.67%)  5/14 (35.71%)  1/3 (33.33%)  0/3 (0.00%) 
Wound infection  1  0/30 (0.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Injury, poisoning and procedural complications         
Bruising  1  1/30 (3.33%)  1/14 (7.14%)  0/3 (0.00%)  1/3 (33.33%) 
Dermatitis radiation  1  1/30 (3.33%)  0/14 (0.00%)  1/3 (33.33%)  0/3 (0.00%) 
Fall  1  3/30 (10.00%)  0/14 (0.00%)  0/3 (0.00%)  1/3 (33.33%) 
Postoperative hemorrhage  1  0/30 (0.00%)  0/14 (0.00%)  1/3 (33.33%)  0/3 (0.00%) 
Wound complication  1  1/30 (3.33%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Investigations         
Alanine aminotransferase increased  1  10/30 (33.33%)  6/14 (42.86%)  1/3 (33.33%)  1/3 (33.33%) 
Alkaline phosphatase increased  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Aspartate aminotransferase increased  1  4/30 (13.33%)  5/14 (35.71%)  1/3 (33.33%)  1/3 (33.33%) 
Blood bilirubin increased  1  1/30 (3.33%)  2/14 (14.29%)  1/3 (33.33%)  0/3 (0.00%) 
CD4 lymphocytes decreased  1  0/30 (0.00%)  0/14 (0.00%)  1/3 (33.33%)  0/3 (0.00%) 
Creatinine increased  1  1/30 (3.33%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Hemoglobin increased  1  2/30 (6.67%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Investigations - Other  1  0/30 (0.00%)  2/14 (14.29%)  0/3 (0.00%)  1/3 (33.33%) 
Lymphocyte count decreased  1  16/30 (53.33%)  5/14 (35.71%)  1/3 (33.33%)  1/3 (33.33%) 
Neutrophil count decreased  1  5/30 (16.67%)  2/14 (14.29%)  0/3 (0.00%)  0/3 (0.00%) 
Platelet count decreased  1  10/30 (33.33%)  2/14 (14.29%)  1/3 (33.33%)  0/3 (0.00%) 
Weight gain  1  6/30 (20.00%)  4/14 (28.57%)  1/3 (33.33%)  0/3 (0.00%) 
Weight loss  1  3/30 (10.00%)  3/14 (21.43%)  0/3 (0.00%)  0/3 (0.00%) 
White blood cell decreased  1  13/30 (43.33%)  3/14 (21.43%)  1/3 (33.33%)  1/3 (33.33%) 
Metabolism and nutrition disorders         
Alkalosis  1  0/30 (0.00%)  0/14 (0.00%)  1/3 (33.33%)  0/3 (0.00%) 
Anorexia  1  4/30 (13.33%)  5/14 (35.71%)  0/3 (0.00%)  1/3 (33.33%) 
Dehydration  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  1/3 (33.33%) 
Hypercalcemia  1  2/30 (6.67%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Hyperglycemia  1  8/30 (26.67%)  5/14 (35.71%)  0/3 (0.00%)  2/3 (66.67%) 
Hyperkalemia  1  2/30 (6.67%)  0/14 (0.00%)  0/3 (0.00%)  1/3 (33.33%) 
Hypernatremia  1  0/30 (0.00%)  0/14 (0.00%)  1/3 (33.33%)  0/3 (0.00%) 
Hypoalbuminemia  1  2/30 (6.67%)  5/14 (35.71%)  0/3 (0.00%)  1/3 (33.33%) 
Hypocalcemia  1  3/30 (10.00%)  4/14 (28.57%)  1/3 (33.33%)  0/3 (0.00%) 
Hypoglycemia  1  3/30 (10.00%)  2/14 (14.29%)  0/3 (0.00%)  0/3 (0.00%) 
Hypokalemia  1  5/30 (16.67%)  3/14 (21.43%)  1/3 (33.33%)  3/3 (100.00%) 
Hypomagnesemia  1  0/30 (0.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Hyponatremia  1  5/30 (16.67%)  1/14 (7.14%)  2/3 (66.67%)  2/3 (66.67%) 
Hypophosphatemia  1  4/30 (13.33%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Metabolism and nutrition disorders - Other  1  2/30 (6.67%)  1/14 (7.14%)  0/3 (0.00%)  1/3 (33.33%) 
Musculoskeletal and connective tissue disorders         
Generalized muscle weakness  1  2/30 (6.67%)  1/14 (7.14%)  1/3 (33.33%)  0/3 (0.00%) 
Joint range of motion decreased  1  0/30 (0.00%)  0/14 (0.00%)  0/3 (0.00%)  1/3 (33.33%) 
Joint range of motion decreased cervical spine  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Muscle weakness left-sided  1  3/30 (10.00%)  2/14 (14.29%)  1/3 (33.33%)  0/3 (0.00%) 
Muscle weakness lower limb  1  2/30 (6.67%)  1/14 (7.14%)  1/3 (33.33%)  0/3 (0.00%) 
Muscle weakness right-sided  1  3/30 (10.00%)  2/14 (14.29%)  0/3 (0.00%)  0/3 (0.00%) 
Muscle weakness upper limb  1  1/30 (3.33%)  1/14 (7.14%)  0/3 (0.00%)  1/3 (33.33%) 
Musculoskeletal and connective tissue disorder - Other, specify  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Pain in extremity  1  4/30 (13.33%)  0/14 (0.00%)  0/3 (0.00%)  1/3 (33.33%) 
Nervous system disorders         
Abducens nerve disorder  1  6/30 (20.00%)  4/14 (28.57%)  1/3 (33.33%)  0/3 (0.00%) 
Ataxia  1  7/30 (23.33%)  4/14 (28.57%)  0/3 (0.00%)  0/3 (0.00%) 
Depressed level of consciousness  1  3/30 (10.00%)  1/14 (7.14%)  1/3 (33.33%)  0/3 (0.00%) 
Dizziness  1  3/30 (10.00%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Dysarthria  1  3/30 (10.00%)  3/14 (21.43%)  1/3 (33.33%)  0/3 (0.00%) 
Dysesthesia  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Dysgeusia  1  1/30 (3.33%)  1/14 (7.14%)  1/3 (33.33%)  0/3 (0.00%) 
Dysphasia  1  2/30 (6.67%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Encephalopathy  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Facial muscle weakness  1  0/30 (0.00%)  0/14 (0.00%)  1/3 (33.33%)  0/3 (0.00%) 
Facial nerve disorder  1  6/30 (20.00%)  3/14 (21.43%)  1/3 (33.33%)  0/3 (0.00%) 
Glossopharyngeal nerve disorder  1  2/30 (6.67%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Headache  1  20/30 (66.67%)  7/14 (50.00%)  2/3 (66.67%)  0/3 (0.00%) 
Hydrocephalus  1  3/30 (10.00%)  0/14 (0.00%)  2/3 (66.67%)  0/3 (0.00%) 
Hypoglossal nerve disorder  1  2/30 (6.67%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Intracranial hemorrhage  1  5/30 (16.67%)  0/14 (0.00%)  2/3 (66.67%)  1/3 (33.33%) 
IVth nerve disorder  1  2/30 (6.67%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Lethargy  1  1/30 (3.33%)  0/14 (0.00%)  1/3 (33.33%)  1/3 (33.33%) 
Movements involuntary  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Nervous system disorders - Other  1  4/30 (13.33%)  3/14 (21.43%)  1/3 (33.33%)  1/3 (33.33%) 
Nystagmus  1  3/30 (10.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Oculomotor nerve disorder  1  3/30 (10.00%)  1/14 (7.14%)  1/3 (33.33%)  0/3 (0.00%) 
Paresthesia  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Peripheral motor neuropathy  1  3/30 (10.00%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Peripheral sensory neuropathy  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  1/3 (33.33%) 
Pyramidal tract syndrome  1  0/30 (0.00%)  2/14 (14.29%)  1/3 (33.33%)  0/3 (0.00%) 
Somnolence  1  4/30 (13.33%)  0/14 (0.00%)  1/3 (33.33%)  0/3 (0.00%) 
Spasticity  1  2/30 (6.67%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Tremor  1  0/30 (0.00%)  2/14 (14.29%)  1/3 (33.33%)  0/3 (0.00%) 
Trigeminal nerve disorder  1  0/30 (0.00%)  2/14 (14.29%)  0/3 (0.00%)  0/3 (0.00%) 
Vagus nerve disorder  1  2/30 (6.67%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Psychiatric disorders         
Agitation  1  2/30 (6.67%)  1/14 (7.14%)  1/3 (33.33%)  0/3 (0.00%) 
Anxiety  1  3/30 (10.00%)  0/14 (0.00%)  1/3 (33.33%)  0/3 (0.00%) 
Confusion  1  1/30 (3.33%)  0/14 (0.00%)  1/3 (33.33%)  0/3 (0.00%) 
Depression  1  2/30 (6.67%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Insomnia  1  6/30 (20.00%)  3/14 (21.43%)  2/3 (66.67%)  1/3 (33.33%) 
Personality change  1  1/30 (3.33%)  2/14 (14.29%)  0/3 (0.00%)  0/3 (0.00%) 
Renal and urinary disorders         
Bladder spasm  1  0/30 (0.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Cystitis noninfective  1  0/30 (0.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Proteinuria  1  4/30 (13.33%)  4/14 (28.57%)  0/3 (0.00%)  0/3 (0.00%) 
Renal and urinary disorders - Other  1  0/30 (0.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Renal calculi  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Urinary frequency  1  0/30 (0.00%)  0/14 (0.00%)  0/3 (0.00%)  1/3 (33.33%) 
Urinary incontinence  1  4/30 (13.33%)  1/14 (7.14%)  1/3 (33.33%)  0/3 (0.00%) 
Urinary retention  1  2/30 (6.67%)  1/14 (7.14%)  1/3 (33.33%)  0/3 (0.00%) 
Urinary tract obstruction  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Urinary tract pain  1  0/30 (0.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Urinary urgency  1  0/30 (0.00%)  0/14 (0.00%)  1/3 (33.33%)  0/3 (0.00%) 
Urine discoloration  1  0/30 (0.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Reproductive system and breast disorders         
Penile pain  1  0/30 (0.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Perineal pain  1  0/30 (0.00%)  0/14 (0.00%)  1/3 (33.33%)  0/3 (0.00%) 
Vaginal discharge  1  2/30 (6.67%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Respiratory, thoracic and mediastinal disorders         
Allergic rhinitis  1  1/30 (3.33%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Apnea  1  2/30 (6.67%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Aspiration  1  1/30 (3.33%)  0/14 (0.00%)  1/3 (33.33%)  0/3 (0.00%) 
Atelectasis  1  0/30 (0.00%)  0/14 (0.00%)  1/3 (33.33%)  0/3 (0.00%) 
Bronchospasm  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Cough  1  12/30 (40.00%)  5/14 (35.71%)  2/3 (66.67%)  1/3 (33.33%) 
Dyspnea  1  5/30 (16.67%)  2/14 (14.29%)  1/3 (33.33%)  0/3 (0.00%) 
Epistaxis  1  4/30 (13.33%)  2/14 (14.29%)  0/3 (0.00%)  0/3 (0.00%) 
Hypoxia  1  1/30 (3.33%)  1/14 (7.14%)  1/3 (33.33%)  0/3 (0.00%) 
Laryngeal inflammation  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Nasal congestion  1  6/30 (20.00%)  5/14 (35.71%)  0/3 (0.00%)  1/3 (33.33%) 
Pneumothorax  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Productive cough  1  0/30 (0.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Pulmonary edema  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Respiratory failure  1  0/30 (0.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Respiratory, thoracic and mediastinal disorders - Other  1  4/30 (13.33%)  1/14 (7.14%)  1/3 (33.33%)  0/3 (0.00%) 
Sneezing  1  0/30 (0.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Sore throat  1  1/30 (3.33%)  2/14 (14.29%)  0/3 (0.00%)  0/3 (0.00%) 
Wheezing  1  2/30 (6.67%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Skin and subcutaneous tissue disorders         
Alopecia  1  4/30 (13.33%)  3/14 (21.43%)  0/3 (0.00%)  1/3 (33.33%) 
Bullous dermatitis  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Dry skin  1  4/30 (13.33%)  8/14 (57.14%)  0/3 (0.00%)  1/3 (33.33%) 
Hirsutism  1  0/30 (0.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Palmar-plantar erythrodysesthesia syndrome  1  0/30 (0.00%)  2/14 (14.29%)  0/3 (0.00%)  0/3 (0.00%) 
Pruritus  1  0/30 (0.00%)  4/14 (28.57%)  0/3 (0.00%)  0/3 (0.00%) 
Purpura  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Rash acneiform  1  2/30 (6.67%)  4/14 (28.57%)  0/3 (0.00%)  0/3 (0.00%) 
Rash maculo-papular  1  3/30 (10.00%)  5/14 (35.71%)  1/3 (33.33%)  2/3 (66.67%) 
Skin and subcutaneous tissue disorders - Other  1  1/30 (3.33%)  5/14 (35.71%)  0/3 (0.00%)  0/3 (0.00%) 
Skin atrophy  1  0/30 (0.00%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Skin hyperpigmentation  1  1/30 (3.33%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Skin hypopigmentation  1  2/30 (6.67%)  1/14 (7.14%)  0/3 (0.00%)  0/3 (0.00%) 
Skin induration  1  1/30 (3.33%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Skin ulceration  1  1/30 (3.33%)  2/14 (14.29%)  0/3 (0.00%)  0/3 (0.00%) 
Vascular disorders         
Flushing  1  2/30 (6.67%)  0/14 (0.00%)  0/3 (0.00%)  0/3 (0.00%) 
Hypertension  1  16/30 (53.33%)  6/14 (42.86%)  2/3 (66.67%)  1/3 (33.33%) 
Hypotension  1  4/30 (13.33%)  4/14 (28.57%)  2/3 (66.67%)  0/3 (0.00%) 
1
Term from vocabulary, CTCAE (4.0)
Indicates events were collected by systematic assessment
The study was terminated early having met the pre-specified stopping rule which required 3 or more cohorts with at least 10 patients each or 2 cohorts with at least 15 patients each in the first 50 patients with informative biopsies.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Karen Wright
Organization: Dana-Farber Cancer Institute
Phone: 617.632.6740
EMail: KarenD_Wright@dfci.harvard.edu
Layout table for additonal information
Responsible Party: Karen D. Wright MD, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier: NCT01182350    
Other Study ID Numbers: DFCI 10-321
First Submitted: August 12, 2010
First Posted: August 16, 2010
Results First Submitted: June 27, 2019
Results First Posted: September 4, 2019
Last Update Posted: September 4, 2019