Erlotinib Hydrochloride in Preventing Liver Cancer in Patients With Cirrhosis of the Liver

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02273362
• Collaborator: (none)
• Enrollment: 25
• Locations: 6
• Arm: 1
• Patients Per Site: 4.2

Study Details

Study Description

Brief Summary

This pilot phase I/II trial studies the best dose of erlotinib hydrochloride and to see how well it works in preventing liver cancer in patients with scarring (cirrhosis) of the liver. Erlotinib hydrochloride may help to inhibit the development of fibrous tissue and prevent liver cancer from forming in patients with cirrhosis of the liver.

Condition or Disease	Intervention/Treatment	Phase
Cirrhosis; Hepatocellular Carcinoma	Drug: Erlotinib; Drug: Erlotinib Hydrochloride; Other: Laboratory Biomarker Analysis; Other: Quality-of-Life Assessment	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. Determine the safe and minimum effective dose (MED) of daily erlotinib (erlotinib hydrochloride) that inhibits epidermal growth factor receptor (EGFR) signaling in the target organ (liver) as assessed by phosphorylated (phospho)-EGFR staining.

SECONDARY OBJECTIVES:

1. Determine the relationship between erlotinib dose-schedule and side effects in participants with cirrhosis.

TRANSLATIONAL OBJECTIVES:

1. Determine the relationship between erlotinib dose-schedule and immuno-histochemical staining pattern of phospho-ERK, proliferating cell nuclear antigen (PCNA), epidermal growth factor (EGF), and alpha smooth muscle actin (alphaSMA) in the liver.

2. Determine the relationship between erlotinib dose-schedule and gene expression signature associated with prognosis in cirrhosis participants following hepatocellular carcinoma (HCC) resection.

3. Determine the relationship between erlotinib dose-schedule and viral load in participants with hepatitis C virus (HCV) positive (+).

4. Determine the relationship between erlotinib dose-schedule and erlotinib plasma level on day of liver resection.

OUTLINE: This is a phase I, dose-escalation/de-escalation study followed by a phase II study.

Patients receive erlotinib hydrochloride orally (PO) once daily (QD) for 7 days (depending on the date of surgery, treatment range may be 5-14 days).

Study Design

• Study Type: Interventional
• Actual Enrollment: 25 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: Pilot Study of EGFR Inhibition With Erlotinib in Cirrhosis to Inhibit Fibrogenesis and Prevent Hepatocellular Carcinoma
• Actual Study Start Date: Nov 24, 2014
• Actual Primary Completion Date: Feb 11, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Prevention (erlotinib hydrochloride) Patients receive erlotinib hydrochloride PO QD for 7 days (depending on the date of surgery, treatment range may be 5-14 days).	Drug: Erlotinib; Given PO; Drug: Erlotinib Hydrochloride; Given PO; Other Names: Cp-358,774 OSI-774 Tarceva ; Other: Laboratory Biomarker Analysis; Correlative studies; Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment

Outcome Measures

Primary Outcome Measures

1. Response (at Least a 50% Reduction in Liver Phospho-EGFR Staining) [Up to day 7]

   A response is defined as having at least a 50% reduction in liver phospho-EGFR staining (50% reduction in the percentage of positive pixels).> > For each dose level, we report the number of participants achieving a response (at least 50% reduction in liver phospho-EGFR staining). > > The Minimum effective dose (MED) is defined as the dose which at least a 40% of patients report a response.

Secondary Outcome Measures

1. Adverse Event Profile [Up to day 7]

   Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4. For this endpoint, we are reporting the number of participants with Grade 3 or higher as their worst reported adverse event.

Other Outcome Measures

1. Changes in Phospho-ERK Levels in the Liver [Baseline to day 7]

   The relationship between dose-level and staining of biomarkers in the liver will be assessed. The baseline biomarker expression levels across all the dose levels using analysis of variance (ANOVA) or the nonparametric equivalent will be compared. The changes in these biomarker values will be assessed using the Wilcoxon signed-rank test and compare these changes across dose levels using ANOVA. Graphical methods will be used to assess the differences in these biomarker values across dose levels. All categorical variables will be analyzed using chi-square or Fisher's exact tests.

2. Changes in PCNA Levels in the Liver [Baseline to day 7]

   The relationship between dose-level and staining of biomarkers in the liver will be assessed. The baseline biomarker expression levels across all the dose levels using ANOVA or the nonparametric equivalent will be compared. The changes in these biomarker values will be assessed using the Wilcoxon signed-rank test and compare these changes across dose levels using ANOVA. Graphical methods will be used to assess the differences in these biomarker values across dose levels. All categorical variables will be analyzed using chi-square or Fisher's exact tests.

3. Changes in EGF Levels in the Liver [Baseline to day 7]

   The relationship between dose-level and staining of biomarkers in the liver will be assessed. The baseline biomarker expression levels across all the dose levels using ANOVA or the nonparametric equivalent will be compared. The changes in these biomarker values will be assessed using the Wilcoxon signed-rank test and compare these changes across dose levels using ANOVA. Graphical methods will be used to assess the differences in these biomarker values across dose levels. All categorical variables will be analyzed using chi-square or Fisher's exact tests.

4. Changes in alphaSMA Levels in the Liver [Baseline to day 7]

   The relationship between dose-level and staining of biomarkers in the liver will be assessed. The baseline biomarker expression levels across all the dose levels using ANOVA or the nonparametric equivalent will be compared. The changes in these biomarker values will be assessed using the Wilcoxon signed-rank test and compare these changes across dose levels using ANOVA. Graphical methods will be used to assess the differences in these biomarker values across dose levels. All categorical variables will be analyzed using chi-square or Fisher's exact tests.

5. Modulation of Gene Expression Signatures Associated With Prognosis in Cirrhosis [Baseline to day 7]

   The relationship between dose and modulation of a gene expression signature associated with prognosis in cirrhosis will be assessed. The baseline biomarker expression levels across all the dose levels using ANOVA or the nonparametric equivalent will be compared. The changes in these biomarker values will be assessed using the Wilcoxon signed-rank test and compare these changes across dose levels using ANOVA. Graphical methods will be used to assess the differences in these biomarker values across dose levels. All categorical variables will be analyzed using chi-square or Fisher's exact tests.

6. Change in Viral Load in Participants With Hepatitis C Virus (HCV)+ [Baseline to 7 days]

   Whether erlotinib hydrochloride is associated with a measurable reduction in viral load in participants with HCV+ will be determined. The baseline biomarker expression levels across all the dose levels using ANOVA or the nonparametric equivalent will be compared. The changes in these biomarker values will be assessed using the Wilcoxon signed-rank test and compare these changes across dose levels using ANOVA. Graphical methods will be used to assess the differences in these biomarker values across dose levels. All categorical variables will be analyzed using chi-square or Fisher's exact tests.

7. Erlotinib Hydrochloride Plasma Level [Day of liver resection]

   The relationship between erlotinib hydrochloride dose-schedule and erlotinib hydrochloride plasma level on the day of liver resection will be determined.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• PRE-REGISTRATION INCLUSION:

• Individuals with a clinical diagnosis fibrosis or cirrhosis of the liver (no more than

Child-Pugh classification A; Child-Pugh-Turcotte score of 6 or less) who have:

• An indication for surgical liver resection, OR

• A clinical liver biopsy (with research tissue specimens available for analysis) =< 3 months prior to pre-registration

• Willingness to discontinue smoking during the study two weeks prior to beginning the study and willingness to not smoke while taking study medication

• Not pregnant or breast feeding. Note: The effects of erlotinib (Tarceva) on the developing human fetus at the recommended therapeutic dose are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately.

• Willingness to use adequate contraception to avoid pregnancy or impregnation until 2 weeks after discontinuing study agent

• Willingness to provide mandatory blood specimens

• Able to undergo:

• Percutaneous or transjugular biopsy of cirrhotic liver at least 7 days prior to liver resection (surgical cohort), OR

• A biopsy of the cirrhotic liver (non-surgical cohort)

• Willingness to authorize collection of tissue from surgically-resected liver or clinical liver biopsy for analyses

• Ability to understand and the willingness to sign a written informed consent document

• REGISTRATION INCLUSION:

• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

• International normalized ratio (INR) =< 1.5

• Platelets >= 50 B/L (10^9/L)

• Total bilirubin =< 3 x institutional upper limit of normal (ULN)

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 x institutional ULN

• Creatinine =< 1.5 x institutional ULN

• Non-surgical cohort only: positive phospho-EGFR assessment (>= 100 stained pixels) from tissue obtained from previous clinical liver biopsy

• Pre-intervention biopsy sample collected

Exclusion Criteria:

• PRE-REGISTRATION EXCLUSION:

• Any prior treatment with erlotinib or other agent whose primary mechanism of action is known to inhibit EGFR

• Participants with a known diagnosis of human immunodeficiency virus (HIV); Note: an HIV screening test does not have to be performed to evaluate this criterion

• Participants who regularly (>= 2 times per week) use drugs that alter the pH of the gastrointestinal (GI) tract, such as proton pump inhibitors (PPI) and antacids; exceptions: individuals who use prescription PPIs and have approval from their primary health care provider to discontinue for the duration of clinical trial participation may be enrolled; an alternate drug to control gastroesophageal reflux disease (GERD)/peptic ulcer disease (PUD) symptoms will be suggested

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or psychiatric illness/social situations that would limit compliance with study requirements

• Use of potent CYP3A4 inhibitors, such as ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole, and grapefruit or grapefruit juice

• Use of CYP3A4 inducers such as rifampicin, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital, and St. John's wort

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to erlotinib (Tarceva)

• Participants who cannot have their warfarin, Lovenox, Plavix, or other comparable medications held for percutaneous or transjugular liver biopsy and surgery if so indicated

• Non-surgical cohort only: pathology report from clinical liver biopsy (=< 3 months prior to pre-registration) demonstrates no histologic abnormalities associated with chronic hepatitis, steatohepatitis, fibrosis, or cirrhosis

• REGISTRATION EXCLUSION:

• Receiving any other investigational agents =< 6 months prior to registration

• Surgical cohort (cohort A only): percutaneous or transjugular biopsy incomplete or not performed

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic in Florida	Jacksonville	Florida	United States	32224-9980
2	Massachusetts General Hospital Cancer Center	Boston	Massachusetts	United States	02114
3	Mayo Clinic in Rochester	Rochester	Minnesota	United States	55905
4	Mount Sinai Hospital	New York	New York	United States	10029
5	Case Western Reserve University	Cleveland	Ohio	United States	44106
6	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Kenneth K Tanabe, Mayo Clinic

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 10, 2019

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT02273362
• Other Study ID Numbers: NCI-2014-02170; NCI-2014-02170; HHSN261201200042I; N01-CN-2012-00042; MAY2013-02-02; MAY2013-02-02; N01CN00042; P30CA015083
• First Posted: Oct 24, 2014
• Last Update Posted: Feb 25, 2022
• Last Verified: Feb 1, 2022

• Additional relevant MeSH terms: Carcinoma; Carcinoma, Hepatocellular; Liver Cirrhosis; Fibrosis; Erlotinib Hydrochloride

Study Results

Participant Flow

Arm/Group Title	Dose Level 0 ( 75 mg Erlotinib Hydrochloride Daily)	Dose Level -1 (50 mg Erlotinib Daily)	Dose Level -2 (25 mg Erlotinib Daily)
Arm/Group Description	Patients receive 75 mg erlotinib hydrochloride PO QD for 7 days.	Patients receive 50 mg erlotinib hydrochloride PO QD for 7 days.	Patients receive 25 mg erlotinib hydrochloride PO QD for 7 days.
Period Title: Overall Study
STARTED	5	6	14
COMPLETED	5	6	14
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Dose Level 0 ( 75 mg Erlotinib Hydrochloride Daily)	Dose Level -1 (50 mg Erlotinib Daily)	Dose Level -2 (25 mg Erlotinib Daily)	Total
Arm/Group Description	Patients receive 75 mg erlotinib hydrochloride PO QD for 7 days.	Patients receive 50 mg erlotinib hydrochloride PO QD for 7 days.	Patients receive 25 mg erlotinib hydrochloride PO QD for 7 days.	Total of all reporting groups
Overall Participants	5	6	14	25
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	61	58.5	66	64
Sex: Female, Male (Count of Participants)
Female	2 40%	2 33.3%	4 28.6%	8 32%
Male	3 60%	4 66.7%	10 71.4%	17 68%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 20%	0 0%	1 7.1%	2 8%
Not Hispanic or Latino	3 60%	4 66.7%	11 78.6%	18 72%
Unknown or Not Reported	1 20%	2 33.3%	2 14.3%	5 20%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	1 7.1%	1 4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	1 20%	0 0%	1 7.1%	2 8%
White	2 40%	6 100%	12 85.7%	20 80%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	2 40%	0 0%	0 0%	2 8%
Region of Enrollment (participants) [Number]
United States	5 100%	6 100%	14 100%	25 100%

Outcome Measures

1. Primary Outcome

Title	Response (at Least a 50% Reduction in Liver Phospho-EGFR Staining)
Description	A response is defined as having at least a 50% reduction in liver phospho-EGFR staining (50% reduction in the percentage of positive pixels).> > For each dose level, we report the number of participants achieving a response (at least 50% reduction in liver phospho-EGFR staining). > > The Minimum effective dose (MED) is defined as the dose which at least a 40% of patients report a response.
Time Frame	Up to day 7

Outcome Measure Data

Analysis Population Description

In Dose Level 0, 1 participant terminated intervention early due to physician decision and 1 participant lost pre-intervention tissue specimens. 1 participant in dose level -1 terminated intervention early due to adverse event. In Dose Level -2, 3 participants did not have additional pre-intervention tissue specimens available beyond eligibility and 1 participant was not evaluable for phospho-EGFR staining at post-intervention due to no benign liver tissue.

Arm/Group Title	Dose Level 0 ( 75 mg Erlotinib Hydrochloride Daily)	Dose Level -1 (50 mg Erlotinib Daily)	Dose Level -2 (25 mg Erlotinib Daily)
Arm/Group Description	Patients receive 75 mg erlotinib hydrochloride PO QD for 7 days.	Patients receive 50 mg erlotinib hydrochloride PO QD for 7 days.	Patients receive 25 mg erlotinib hydrochloride PO QD for 7 days.
Measure Participants	3	5	10
Count of Participants [Participants]	3 60%	3 50%	6 42.9%

2. Secondary Outcome

Title	Adverse Event Profile
Description	Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4. For this endpoint, we are reporting the number of participants with Grade 3 or higher as their worst reported adverse event.
Time Frame	Up to day 7

Outcome Measure Data

Analysis Population Description

All patients that began protocol treatment are included in this analysis.

Arm/Group Title	Dose Level 0 ( 75 mg Erlotinib Hydrochloride Daily)	Dose Level -1 (50 mg Erlotinib Daily)	Dose Level -2 (25 mg Erlotinib Daily)
Arm/Group Description	Patients receive 75 mg erlotinib hydrochloride PO QD for 7 days.	Patients receive 50 mg erlotinib hydrochloride PO QD for 7 days.	Patients receive 25 mg erlotinib hydrochloride PO QD for 7 days.
Measure Participants	5	6	14
Count of Participants [Participants]	0 0%	1 16.7%	2 14.3%

3. Other Pre-specified Outcome

Title	Changes in Phospho-ERK Levels in the Liver
Description	The relationship between dose-level and staining of biomarkers in the liver will be assessed. The baseline biomarker expression levels across all the dose levels using analysis of variance (ANOVA) or the nonparametric equivalent will be compared. The changes in these biomarker values will be assessed using the Wilcoxon signed-rank test and compare these changes across dose levels using ANOVA. Graphical methods will be used to assess the differences in these biomarker values across dose levels. All categorical variables will be analyzed using chi-square or Fisher's exact tests.
Time Frame	Baseline to day 7

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Other Pre-specified Outcome

Title	Changes in PCNA Levels in the Liver
Description	The relationship between dose-level and staining of biomarkers in the liver will be assessed. The baseline biomarker expression levels across all the dose levels using ANOVA or the nonparametric equivalent will be compared. The changes in these biomarker values will be assessed using the Wilcoxon signed-rank test and compare these changes across dose levels using ANOVA. Graphical methods will be used to assess the differences in these biomarker values across dose levels. All categorical variables will be analyzed using chi-square or Fisher's exact tests.
Time Frame	Baseline to day 7

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Other Pre-specified Outcome

Title	Changes in EGF Levels in the Liver
Description	The relationship between dose-level and staining of biomarkers in the liver will be assessed. The baseline biomarker expression levels across all the dose levels using ANOVA or the nonparametric equivalent will be compared. The changes in these biomarker values will be assessed using the Wilcoxon signed-rank test and compare these changes across dose levels using ANOVA. Graphical methods will be used to assess the differences in these biomarker values across dose levels. All categorical variables will be analyzed using chi-square or Fisher's exact tests.
Time Frame	Baseline to day 7

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Other Pre-specified Outcome

Title	Changes in alphaSMA Levels in the Liver
Description	The relationship between dose-level and staining of biomarkers in the liver will be assessed. The baseline biomarker expression levels across all the dose levels using ANOVA or the nonparametric equivalent will be compared. The changes in these biomarker values will be assessed using the Wilcoxon signed-rank test and compare these changes across dose levels using ANOVA. Graphical methods will be used to assess the differences in these biomarker values across dose levels. All categorical variables will be analyzed using chi-square or Fisher's exact tests.
Time Frame	Baseline to day 7

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Other Pre-specified Outcome

Title	Modulation of Gene Expression Signatures Associated With Prognosis in Cirrhosis
Description	The relationship between dose and modulation of a gene expression signature associated with prognosis in cirrhosis will be assessed. The baseline biomarker expression levels across all the dose levels using ANOVA or the nonparametric equivalent will be compared. The changes in these biomarker values will be assessed using the Wilcoxon signed-rank test and compare these changes across dose levels using ANOVA. Graphical methods will be used to assess the differences in these biomarker values across dose levels. All categorical variables will be analyzed using chi-square or Fisher's exact tests.
Time Frame	Baseline to day 7

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Other Pre-specified Outcome

Title	Change in Viral Load in Participants With Hepatitis C Virus (HCV)+
Description	Whether erlotinib hydrochloride is associated with a measurable reduction in viral load in participants with HCV+ will be determined. The baseline biomarker expression levels across all the dose levels using ANOVA or the nonparametric equivalent will be compared. The changes in these biomarker values will be assessed using the Wilcoxon signed-rank test and compare these changes across dose levels using ANOVA. Graphical methods will be used to assess the differences in these biomarker values across dose levels. All categorical variables will be analyzed using chi-square or Fisher's exact tests.
Time Frame	Baseline to 7 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Other Pre-specified Outcome

Title	Erlotinib Hydrochloride Plasma Level
Description	The relationship between erlotinib hydrochloride dose-schedule and erlotinib hydrochloride plasma level on the day of liver resection will be determined.
Time Frame	Day of liver resection

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	7 days
Arm/Group Title	Dose Level 0 ( 75 mg Erlotinib Hydrochloride Daily)		Dose Level -1 (50 mg Erlotinib Daily)		Dose Level -2 (25 mg Erlotinib Daily)
Arm/Group Description	Patients receive 75 mg erlotinib hydrochloride PO QD for 7 days.		Patients receive 50 mg erlotinib hydrochloride PO QD for 7 days.		Patients receive 25 mg erlotinib hydrochloride PO QD for 7 days.
All Cause Mortality
	Dose Level 0 ( 75 mg Erlotinib Hydrochloride Daily)		Dose Level -1 (50 mg Erlotinib Daily)		Dose Level -2 (25 mg Erlotinib Daily)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/6 (0%)		0/14 (0%)
Serious Adverse Events
	Dose Level 0 ( 75 mg Erlotinib Hydrochloride Daily)		Dose Level -1 (50 mg Erlotinib Daily)		Dose Level -2 (25 mg Erlotinib Daily)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/6 (0%)		1/14 (7.1%)
Blood and lymphatic system disorders
Anemia	0/5 (0%)	0	0/6 (0%)	0	1/14 (7.1%)	1
Other (Not Including Serious) Adverse Events
	Dose Level 0 ( 75 mg Erlotinib Hydrochloride Daily)		Dose Level -1 (50 mg Erlotinib Daily)		Dose Level -2 (25 mg Erlotinib Daily)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/5 (40%)		4/6 (66.7%)		7/14 (50%)
Cardiac disorders
Acute coronary syndrome	0/5 (0%)	0	1/6 (16.7%)	1	0/14 (0%)	0
Chest pain - cardiac	0/5 (0%)	0	1/6 (16.7%)	1	0/14 (0%)	0
Gastrointestinal disorders
Abdominal pain	0/5 (0%)	0	0/6 (0%)	0	1/14 (7.1%)	2
Constipation	0/5 (0%)	0	1/6 (16.7%)	1	0/14 (0%)	0
Diarrhea	0/5 (0%)	0	0/6 (0%)	0	1/14 (7.1%)	1
Dyspepsia	0/5 (0%)	0	1/6 (16.7%)	1	0/14 (0%)	0
Gastroesophageal reflux disease	0/5 (0%)	0	0/6 (0%)	0	2/14 (14.3%)	2
Gastrointestinal disorders - Oth spec	0/5 (0%)	0	0/6 (0%)	0	1/14 (7.1%)	1
Mucositis oral	0/5 (0%)	0	1/6 (16.7%)	1	0/14 (0%)	0
Nausea	0/5 (0%)	0	1/6 (16.7%)	1	2/14 (14.3%)	2
Stomach pain	0/5 (0%)	0	1/6 (16.7%)	1	0/14 (0%)	0
General disorders
Fatigue	0/5 (0%)	0	1/6 (16.7%)	1	1/14 (7.1%)	1
Flu like symptoms	0/5 (0%)	0	0/6 (0%)	0	1/14 (7.1%)	1
Infections and infestations
Infections and infestations - Oth spec	0/5 (0%)	0	1/6 (16.7%)	1	0/14 (0%)	0
Injury, poisoning and procedural complications
Fall	0/5 (0%)	0	1/6 (16.7%)	1	0/14 (0%)	0
Wound dehiscence	0/5 (0%)	0	0/6 (0%)	0	1/14 (7.1%)	1
Investigations
Blood bilirubin increased	1/5 (20%)	1	0/6 (0%)	0	0/14 (0%)	0
Metabolism and nutrition disorders
Metabolism, nutrition disord - Oth spec	0/5 (0%)	0	0/6 (0%)	0	1/14 (7.1%)	1
Musculoskeletal and connective tissue disorders
Buttock pain	0/5 (0%)	0	1/6 (16.7%)	1	0/14 (0%)	0
Musculoskeletal, conn tissue - Oth spec	0/5 (0%)	0	1/6 (16.7%)	1	0/14 (0%)	0
Nervous system disorders
Headache	1/5 (20%)	1	1/6 (16.7%)	1	0/14 (0%)	0
Renal and urinary disorders
Urinary urgency	1/5 (20%)	1	0/6 (0%)	0	0/14 (0%)	0
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	0/5 (0%)	0	1/6 (16.7%)	1	0/14 (0%)	0
Dyspnea	0/5 (0%)	0	1/6 (16.7%)	1	0/14 (0%)	0
Epistaxis	0/5 (0%)	0	0/6 (0%)	0	1/14 (7.1%)	1
Sinus pain	0/5 (0%)	0	0/6 (0%)	0	1/14 (7.1%)	1
Skin and subcutaneous tissue disorders
Pruritus	0/5 (0%)	0	1/6 (16.7%)	1	0/14 (0%)	0
Rash acneiform	1/5 (20%)	1	1/6 (16.7%)	1	1/14 (7.1%)	1
Skin and subcut tissue disord - Oth spec	0/5 (0%)	0	0/6 (0%)	0	1/14 (7.1%)	1

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.