A Study of High-Dose Chemoradiation Using Biologically-Based Target Volume Definition in Patients With Glioblastoma

• Sponsor: University of Michigan Rogel Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT02805179
• Collaborator: (none)
• Enrollment: 26
• Location: 1
• Arm: 1
• Actual Duration (Months): 49.9
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

This is a study to determine the safety and effectiveness of high-dose radiation therapy (RT) with concurrent temozolomide in patients with newly diagnosed glioblastoma.

Condition or Disease	Intervention/Treatment	Phase
Glioma	Radiation: High Dose Radiation; Drug: Temozolomide	Phase 2

Detailed Description

After analysis demonstrated the improved prognostic value of identifying both hypercellular tumor (TVHCV) based on high b-value diffusion-weighted magnetic resonance imaging (DW-MRI) and hyperperfused tumor (TVCBV) based on dynamic contrast-enhanced MRI (DCE-MRI), the study was amended and later-enrolled patients boosted to both TVHCV and TVCBV.

Study Design

• Study Type: Interventional
• Actual Enrollment: 26 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of High Dose Radiotherapy and Concurrent Temozolomide Using Biologically-Based Target Volume Definition in Patients With Newly Diagnosed Glioblastoma
• Actual Study Start Date: Sep 22, 2016
• Actual Primary Completion Date: Feb 6, 2020
• Actual Study Completion Date: Nov 18, 2020

Arms and Interventions

Arm

Intervention/Treatment

Experimental: High Dose Chemoradiation Patients will receive high dose radiation based in part on advanced imaging, and concurrent temozolomide. Four weeks after the completion of chemoradiation, patients will receive adjuvant temozolomide.

Radiation: High Dose Radiation; Radiation will be delivered once daily for a total of 30 fractions, five days per week.; Drug: Temozolomide; Patients will receive concurrent temozolomide (75 mg/m^2 daily for 6 weeks). Adjuvant temozolomide will be given at 150-200 mg/m^2, D1-5 every 28 days for a minimum of six cycles and will be started approximately four weeks following completion of radiotherapy.

Outcome Measures

Primary Outcome Measures

1. Overall Survival at 12 Months [12 months after completion of chemoradiation]

   Percentage of patients alive at 12 months after completion of chemoradiation

2. Median Overall Survival [Median follow-up time was 26 months]

   Median overall survival in months

Secondary Outcome Measures

1. Median Progression-free Survival [Median follow-up time was 26 months]

   From start of RT until disease progression or death, or until date of last imaging follow-up, estimated using Kaplan-Meier. Progression is defined by any of the following: >= 25% increase in sum of the products of perpendicular diameters of enhancing lesions (compared with baseline if no decrease) on stable or increasing doses of corticosteroids; a significant increase in T2/FLAIR non-enhancing lesions on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy, not due to comorbid events; appearance of any new lesions; clear progression of non-measurable lesions; or definite clinical deterioration not attributable to causes other than tumor, or to decrease in corticosteroid dose. When pathologic confirmation was unavailable, progression was defined as worsening enhancement based on imaging with or without adjunctive advanced imaging including perfusion MRI or magnetic resonance spectroscopy, when clinically indicated.

2. Median Change in Tumor Volume From Baseline to Mid-radiation Treatment (Week 4) [Baseline to Week 4]

   Tumor volume will be measured by diffusion MRI and perfusion MRI before treatment start and at mid-treatment.

3. Percentage of Patients That Experienced Deterioration in Quality of Life (QOL) [Baseline to 1 and 7 months]

   Percentage of patients that experienced deterioration in QOL per the European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire (EORTC QLQ-C30). EORTC QLQ-C30 is a 30-item questionnaire to assess the overall quality of life in cancer patients. EORTC QLQ-C30 includes functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting), and other (dyspnea, appetite loss, insomnia, constipation/diarrhea, and financial difficulties). Most questions used 4-point scale (1 'Not at All' to 4 'Very Much'); 2 questions used 7-point scale (1 'Very Poor' to 7 'Excellent'). Scores are averaged, and transformed to 0-100 scale; higher score=better level of physical functioning.

4. Percentage of Patients With Failure; Central or In-field vs. Marginal or Distant [Median 26 months]

   Failures will be classified as central or in-field, marginal or distant based on previously published criteria. 1) "central," in which 95% or more of the recurrent tumor volume (Vrecur) was within D95, the region treated to high dose (95% of the prescription dose); 2) "in-field," in which 80% or more of Vrecur was within the D95 isodose surface; 3) "marginal," when between 20 and 80% of Vrecur was inside the D95 surface; 4) "outside," in which less than 20% of Vrecur was inside the D95 surface.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Newly diagnosed histologically-confirmed supratentorial World Health Organization (WHO) grade IV gliomas including glioblastoma multiforme and gliosarcoma

• Age 18 or older

• Karnofsky performance status (a measure to quantify general well being and activities of daily life; scale ranges from 0 to 100 where 100 is perfect health) of greater than or equal to 70

• Life expectancy of at least 12 weeks

• Adequate bone marrow reserve (hemoglobin greater than or equal to 10, absolute neutrophil count greater than or equal to 1500, platelets greater than or equal to 100,000); acceptable liver function (total bilirubin less than or equal to 2.0 mg/dl, ALT (Alanine Aminotransferase)/AST (Aspartate Aminotransferase) less than or equal to 5 times the normal range); acceptable renal function (serum creatinine less than or equal to 2.0 mg/dl). Eligibility level for hemoglobin may be reached by transfusion.

• Maximal contiguous volume of tumor based on high b-value diffusion MRI < 1/3 volume of brain

• Patients must be registered within 6 weeks of most recent resection.

• Patients must have signed a study-specific informed consent.

Exclusion Criteria:

• Recurrent glioma, or tumor involving the brainstem or cerebellum. Prior low-grade glioma without prior RT, now with malignant progression are eligible.

• Prior use of Gliadel wafers or any other intratumoral or intracavitary treatment is not permitted. Prior chemotherapy for a different cancer is allowable, except for Temozolomide or Bevacizumab.

• Evidence of cerebrospinal fluid dissemination (positive cerebrospinal fluid cytology for malignancy or MRI findings consistent with CSF dissemination)

• Evidence of severe concurrent disease requiring treatment

• Prior invasive malignancy (except non-melanoma skin cancer) unless disease-free for a minimum of 3 years (for example, carcinoma in situ of breast, oral cavity or cervix are all permissible)

• Patients unable to undergo Magnetic Resonance Imaging exams (MRI) (i.e. patients with non-compatible devices such as cardiac pacemakers, other implanted electronic devices, metallic prostheses, or ferromagnetic prostheses (e.g. pins in artificial joints and surgical pins/clips) or unable to receive gadolinium for MRI, as per the standard UM Department of Radiology MRI screening criteria)

• Patients treated with previous cranial or head/neck radiotherapy leading to radiation field overlap

• Females of child-bearing potential must have a negative pregnancy test within 14 days prior to registration. Patients with reproductive potential must agree to use an effective contraceptive method during treatment.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Michigan Hospital	Ann Arbor	Michigan	United States	48109

Sponsors and Collaborators

• University of Michigan Rogel Cancer Center

Investigators

• Principal Investigator: Michelle Kim, M.D., University of Michigan Rogel Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 5, 2017

More Information

Publications

None provided.

• Responsible Party: University of Michigan Rogel Cancer Center
• ClinicalTrials.gov Identifier: NCT02805179
• Other Study ID Numbers: UMCC 2012.006; HUM00113549
• First Posted: Jun 17, 2016
• Last Update Posted: Apr 15, 2021
• Last Verified: Mar 1, 2021

• Additional relevant MeSH terms: Glioblastoma; Temozolomide

Study Results

Participant Flow

Arm/Group Title	All Participants
Arm/Group Description	Patients will receive high dose radiation based in part on advanced imaging, and concurrent temozolomide. Four weeks after the completion of chemoradiation, patients will receive adjuvant temozolomide. High Dose Radiation: Radiation will be delivered once daily for a total of 30 fractions, five days per week. Temozolomide: Patients will receive concurrent temozolomide (75 mg/m^2 daily for 6 weeks). Adjuvant temozolomide will be given at 150-200 mg/m^2, D1-5 every 28 days for a minimum of six cycles and will be started approximately four weeks following completion of radiotherapy.
Period Title: Overall Study
STARTED	26
Eligible Patients That Started Dose-intensified Chemo-radiation	23
Subset of Participants, Boosted to Both High B-value Diffusion and Perfusion	13
COMPLETED	23
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	High Dose Chemoradiation
Arm/Group Description	Patients will receive high dose radiation based in part on advanced imaging, and concurrent temozolomide. Four weeks after the completion of chemoradiation, patients will receive adjuvant temozolomide. High Dose Radiation: Radiation will be delivered once daily for a total of 30 fractions, five days per week. Temozolomide: Patients will receive concurrent temozolomide (75 mg/m^2 daily for 6 weeks). Adjuvant temozolomide will be given at 150-200 mg/m^2, D1-5 every 28 days for a minimum of six cycles and will be started approximately four weeks following completion of radiotherapy.
Overall Participants	26
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	62
Sex: Female, Male (Count of Participants)
Female	10 38.5%
Male	16 61.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	26 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 3.8%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 3.8%
White	24 92.3%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Overall Survival at 12 Months
Description	Percentage of patients alive at 12 months after completion of chemoradiation
Time Frame	12 months after completion of chemoradiation

Outcome Measure Data

Analysis Population Description

all eligible patients who completed dose-intensified chemo-radiation

Arm/Group Title	High Dose Chemoradiation
Arm/Group Description	Patients will receive high dose radiation based in part on advanced imaging, and concurrent temozolomide. Four weeks after the completion of chemoradiation, patients will receive adjuvant temozolomide. High Dose Radiation: Radiation will be delivered once daily for a total of 30 fractions, five days per week. Temozolomide: Patients will receive concurrent temozolomide (75 mg/m^2 daily for 6 weeks). Adjuvant temozolomide will be given at 150-200 mg/m^2, D1-5 every 28 days for a minimum of six cycles and will be started approximately four weeks following completion of radiotherapy.
Measure Participants	23
all eligible patients who completed dose-intensified chemo-radiation	74 284.6%
only patients who were boosted to both diffusion and perfusion	92 353.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose Chemoradiation
	Comments
	Type of Statistical Test	Superiority
	Comments	Compared to historical controls
Statistical Test of Hypothesis	p-Value	0.03
	Comments
	Method	1-sided binomial test
	Comments

2. Primary Outcome

Title	Median Overall Survival
Description	Median overall survival in months
Time Frame	Median follow-up time was 26 months

Outcome Measure Data

Analysis Population Description

all eligible patients who completed dose-intensified chemo-radiation

Arm/Group Title	High Dose Chemoradiation
Arm/Group Description	Patients will receive high dose radiation based in part on advanced imaging, and concurrent temozolomide. Four weeks after the completion of chemoradiation, patients will receive adjuvant temozolomide. High Dose Radiation: Radiation will be delivered once daily for a total of 30 fractions, five days per week. Temozolomide: Patients will receive concurrent temozolomide (75 mg/m^2 daily for 6 weeks). Adjuvant temozolomide will be given at 150-200 mg/m^2, D1-5 every 28 days for a minimum of six cycles and will be started approximately four weeks following completion of radiotherapy.
Measure Participants	23
all eligible patients who completed dose-intensified chemo-radiation	20
only patients who were boosted to both diffusion and perfusion	20

3. Secondary Outcome

Title	Median Progression-free Survival
Description	From start of RT until disease progression or death, or until date of last imaging follow-up, estimated using Kaplan-Meier. Progression is defined by any of the following: >= 25% increase in sum of the products of perpendicular diameters of enhancing lesions (compared with baseline if no decrease) on stable or increasing doses of corticosteroids; a significant increase in T2/FLAIR non-enhancing lesions on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy, not due to comorbid events; appearance of any new lesions; clear progression of non-measurable lesions; or definite clinical deterioration not attributable to causes other than tumor, or to decrease in corticosteroid dose. When pathologic confirmation was unavailable, progression was defined as worsening enhancement based on imaging with or without adjunctive advanced imaging including perfusion MRI or magnetic resonance spectroscopy, when clinically indicated.
Time Frame	Median follow-up time was 26 months

Outcome Measure Data

Analysis Population Description

all eligible patients who completed dose-intensified chemo-radiation

Arm/Group Title	High Dose Chemoradiation
Arm/Group Description	Patients will receive high dose radiation based in part on advanced imaging, and concurrent temozolomide. Four weeks after the completion of chemoradiation, patients will receive adjuvant temozolomide. High Dose Radiation: Radiation will be delivered once daily for a total of 30 fractions, five days per week. Temozolomide: Patients will receive concurrent temozolomide (75 mg/m^2 daily for 6 weeks). Adjuvant temozolomide will be given at 150-200 mg/m^2, D1-5 every 28 days for a minimum of six cycles and will be started approximately four weeks following completion of radiotherapy.
Measure Participants	23
all eligible patients who completed dose-intensified chemo-radiation	10
only patients who were boosted to both diffusion and perfusion	12

4. Secondary Outcome

Title	Median Change in Tumor Volume From Baseline to Mid-radiation Treatment (Week 4)
Description	Tumor volume will be measured by diffusion MRI and perfusion MRI before treatment start and at mid-treatment.
Time Frame	Baseline to Week 4

Outcome Measure Data

Analysis Population Description

All enrolled patients had available imaging were included in this analysis

Arm/Group Title	High Dose Chemoradiation
Arm/Group Description	Patients will receive high dose radiation based in part on advanced imaging, and concurrent temozolomide. Four weeks after the completion of chemoradiation, patients will receive adjuvant temozolomide. High Dose Radiation: Radiation will be delivered once daily for a total of 30 fractions, five days per week. Temozolomide: Patients will receive concurrent temozolomide (75 mg/m^2 daily for 6 weeks). Adjuvant temozolomide will be given at 150-200 mg/m^2, D1-5 every 28 days for a minimum of six cycles and will be started approximately four weeks following completion of radiotherapy.
Measure Participants	26
Median (Inter-Quartile Range) [cubic centimeters]	-2.9

5. Secondary Outcome

Title	Percentage of Patients That Experienced Deterioration in Quality of Life (QOL)
Description	Percentage of patients that experienced deterioration in QOL per the European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire (EORTC QLQ-C30). EORTC QLQ-C30 is a 30-item questionnaire to assess the overall quality of life in cancer patients. EORTC QLQ-C30 includes functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting), and other (dyspnea, appetite loss, insomnia, constipation/diarrhea, and financial difficulties). Most questions used 4-point scale (1 'Not at All' to 4 'Very Much'); 2 questions used 7-point scale (1 'Very Poor' to 7 'Excellent'). Scores are averaged, and transformed to 0-100 scale; higher score=better level of physical functioning.
Time Frame	Baseline to 1 and 7 months

Outcome Measure Data

Analysis Population Description

all eligible patients who completed dose-intensified chemo-radiation

Arm/Group Title	High Dose Chemoradiation
Arm/Group Description	Patients will receive high dose radiation based in part on advanced imaging, and concurrent temozolomide. Four weeks after the completion of chemoradiation, patients will receive adjuvant temozolomide. High Dose Radiation: Radiation will be delivered once daily for a total of 30 fractions, five days per week. Temozolomide: Patients will receive concurrent temozolomide (75 mg/m^2 daily for 6 weeks). Adjuvant temozolomide will be given at 150-200 mg/m^2, D1-5 every 28 days for a minimum of six cycles and will be started approximately four weeks following completion of radiotherapy.
Measure Participants	23
at 1 month	26 100%
at 7 months	33 126.9%

6. Secondary Outcome

Title	Percentage of Patients With Failure; Central or In-field vs. Marginal or Distant
Description	Failures will be classified as central or in-field, marginal or distant based on previously published criteria. 1) "central," in which 95% or more of the recurrent tumor volume (Vrecur) was within D95, the region treated to high dose (95% of the prescription dose); 2) "in-field," in which 80% or more of Vrecur was within the D95 isodose surface; 3) "marginal," when between 20 and 80% of Vrecur was inside the D95 surface; 4) "outside," in which less than 20% of Vrecur was inside the D95 surface.
Time Frame	Median 26 months

Outcome Measure Data

Analysis Population Description

all eligible patients who completed dose-intensified chemo-radiation

Arm/Group Title	High Dose Chemoradiation
Arm/Group Description	Patients will receive high dose radiation based in part on advanced imaging, and concurrent temozolomide. Four weeks after the completion of chemoradiation, patients will receive adjuvant temozolomide. High Dose Radiation: Radiation will be delivered once daily for a total of 30 fractions, five days per week. Temozolomide: Patients will receive concurrent temozolomide (75 mg/m^2 daily for 6 weeks). Adjuvant temozolomide will be given at 150-200 mg/m^2, D1-5 every 28 days for a minimum of six cycles and will be started approximately four weeks following completion of radiotherapy.
Measure Participants	23
central or in-field	31 119.2%
non-central/non-in-field (marginal or distant)	69 265.4%

Adverse Events

Time Frame	Time frame for toxicity was from the time of the initial intervention through 30 days following the completion of radiation therapy. Subacute and late neurologic toxicity beyond 30 days was assessed every 2 to 3 months, and all patients were monitored for late neurologic toxicity until last follow-up or death. The median follow-up time was 26 months.
Arm/Group Title	All Enrolled Patients
Arm/Group Description	Patients will receive high dose radiation based in part on advanced imaging, and concurrent temozolomide. Four weeks after the completion of chemoradiation, patients will receive adjuvant temozolomide. High Dose Radiation: Radiation will be delivered once daily for a total of 30 fractions, five days per week. Temozolomide: Patients will receive concurrent temozolomide (75 mg/m^2 daily for 6 weeks). Adjuvant temozolomide will be given at 150-200 mg/m^2, D1-5 every 28 days for a minimum of six cycles and will be started approximately four weeks following completion of radiotherapy.
All Cause Mortality
	All Enrolled Patients
	Affected / at Risk (%)	# Events
Total	21/26 (80.8%)
Serious Adverse Events
	All Enrolled Patients
	Affected / at Risk (%)	# Events
Total	8/26 (30.8%)
Gastrointestinal disorders
Nausea	1/26 (3.8%)	1
General disorders
Localized edema	1/26 (3.8%)	1
Infections and infestations
Urinary tract infection	1/26 (3.8%)	1
Wound infection	1/26 (3.8%)	1
Musculoskeletal and connective tissue disorders
Muscle weakness left-sided	1/26 (3.8%)	1
Muscle weakness right-sided	1/26 (3.8%)	1
Nervous system disorders
Headache	1/26 (3.8%)	1
Nervous system disorders - Other	2/26 (7.7%)	3
Psychiatric disorders
Confusion	2/26 (7.7%)	2
Vascular disorders
Thromboembolic event	2/26 (7.7%)	3
Other (Not Including Serious) Adverse Events
	All Enrolled Patients
	Affected / at Risk (%)	# Events
Total	25/26 (96.2%)
Blood and lymphatic system disorders
Anemia	2/26 (7.7%)	2
Cardiac disorders
Ventricular tachycardia	1/26 (3.8%)	1
Ear and labyrinth disorders
Ear and labyrinth disorders - Other	1/26 (3.8%)	1
Hearing impaired	2/26 (7.7%)	2
Vertigo	1/26 (3.8%)	1
Eye disorders
Blurred vision	2/26 (7.7%)	2
Eye disorders - Other	3/26 (11.5%)	3
Gastrointestinal disorders
Abdominal pain	1/26 (3.8%)	1
Constipation	9/26 (34.6%)	9
Diarrhea	2/26 (7.7%)	2
Dry mouth	1/26 (3.8%)	1
Dyspepsia	1/26 (3.8%)	1
Gastroesophageal reflux disease	1/26 (3.8%)	1
Nausea	11/26 (42.3%)	15
Salivary duct inflammation	1/26 (3.8%)	1
Stomach pain	1/26 (3.8%)	1
General disorders
Edema face	2/26 (7.7%)	2
Edema limbs	1/26 (3.8%)	1
Fatigue	20/26 (76.9%)	26
Gait disturbance	1/26 (3.8%)	1
General disorders and administration site conditions - Other	5/26 (19.2%)	7
Localized edema	1/26 (3.8%)	1
Non-cardiac chest pain	1/26 (3.8%)	1
Pain	5/26 (19.2%)	6
Immune system disorders
Allergic reaction	3/26 (11.5%)	4
Infections and infestations
Infections and infestations - Other	1/26 (3.8%)	1
Papulopustular rash	1/26 (3.8%)	1
Sinusitis	1/26 (3.8%)	1
Injury, poisoning and procedural complications
Dermatitis radiation	1/26 (3.8%)	1
Fall	2/26 (7.7%)	2
Wound complication	1/26 (3.8%)	1
Investigations
Creatinine increased	1/26 (3.8%)	1
Investigations - Other	2/26 (7.7%)	2
Lymphocyte count decreased	2/26 (7.7%)	2
Platelet count decreased	7/26 (26.9%)	16
Weight gain	2/26 (7.7%)	2
Weight loss	1/26 (3.8%)	1
Metabolism and nutrition disorders
Anorexia	2/26 (7.7%)	2
Hyponatremia	1/26 (3.8%)	1
Musculoskeletal and connective tissue disorders
Back pain	2/26 (7.7%)	2
Generalized muscle weakness	2/26 (7.7%)	2
Muscle weakness left-sided	1/26 (3.8%)	1
Muscle weakness lower limb	2/26 (7.7%)	2
Muscle weakness right-sided	4/26 (15.4%)	5
Muscle weakness upper limb	3/26 (11.5%)	3
Myalgia	1/26 (3.8%)	1
Neck pain	1/26 (3.8%)	1
Pain in extremity	3/26 (11.5%)	3
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other	2/26 (7.7%)	2
Nervous system disorders
Ataxia	1/26 (3.8%)	1
Concentration impairment	1/26 (3.8%)	1
Dizziness	7/26 (26.9%)	7
Dysarthria	3/26 (11.5%)	4
Dysgeusia	1/26 (3.8%)	1
Dysphasia	2/26 (7.7%)	2
Headache	8/26 (30.8%)	8
Hypersomnia	1/26 (3.8%)	1
Nervous system disorders - Other	1/26 (3.8%)	1
Paresthesia	4/26 (15.4%)	6
Seizure	3/26 (11.5%)	4
Somnolence	1/26 (3.8%)	1
Tremor	1/26 (3.8%)	1
Psychiatric disorders
Anxiety	3/26 (11.5%)	3
Confusion	2/26 (7.7%)	2
Depression	4/26 (15.4%)	4
Insomnia	7/26 (26.9%)	9
Psychiatric disorders - Other	1/26 (3.8%)	1
Renal and urinary disorders
Cystitis noninfective	1/26 (3.8%)	1
Renal and urinary disorders - Other	1/26 (3.8%)	1
Urinary frequency	2/26 (7.7%)	2
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	1/26 (3.8%)	1
Apnea	1/26 (3.8%)	1
Cough	1/26 (3.8%)	1
Dyspnea	1/26 (3.8%)	1
Nasal congestion	1/26 (3.8%)	1
Skin and subcutaneous tissue disorders
Alopecia	6/26 (23.1%)	6
Erythema multiforme	1/26 (3.8%)	1
Pruritus	3/26 (11.5%)	3
Skin hyperpigmentation	1/26 (3.8%)	1
Urticaria	1/26 (3.8%)	1
Vascular disorders
Flushing	1/26 (3.8%)	1
Hypertension	1/26 (3.8%)	1
Lymphedema	1/26 (3.8%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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