Characterization of Baseline Biomarker Variability in Participants With Hepatocellular Carcinoma (MK-0000-215)

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01521780
• Collaborator: (none)
• Enrollment: 12
• Arms: 3
• Duration (Months): 7

Study Details

Study Description

Brief Summary

The purpose of this study is to characterize the baseline variability of a panel of tissue (tumor and adjacent) and blood-based biomarkers obtained from participants with hepatocellular carcinoma (HCC). The primary hypothesis is that the upper bound of the 80% Confidence Interval of log beta-catenin protein or messenger RNA (mRNA) expression from one core needle biopsy (CNB) equivalent is =< 0.65.

Condition or Disease	Intervention/Treatment	Phase
Hepatocellular Carcinoma	Procedure: MRI; Procedure: Pathology; Procedure: Blood Samples; Procedure: Blood Samples	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• Official Title: A Clinical Study to Characterize Baseline Biomarker Variability in Participants With Hepatocellular Carcinoma for Utilization of Target Engagement and Pharmacodynamic Biomarkers in Future Phase I Trials
• Study Start Date: Apr 1, 2012
• Actual Primary Completion Date: Sep 1, 2012
• Actual Study Completion Date: Nov 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Imaging Magnetic resonance imaging (MRI) of HCC tumor.	Procedure: MRI; Participants undergo volumetric & diffusion weighted (DW) MRI. Participants are scanned twice, with an intervening fifteen minute walk between the scans.; Procedure: Blood Samples; Blood is collected from participants during screening Visit 1 - 24.5 ml, and follow up Visit 4 - 5.5 ml.
Experimental: Pathology Pathology samples from surgical resection of HCC tumor and adjacent liver.	Procedure: Pathology; Participants who are undergoing surgical resection of HCC per their standard of care treatment, will submit tumor samples for biomarker analysis.; Procedure: Blood Samples; Blood is collected from participants during screening Visit 1 - 24.5 ml. During Visit 3, blood samples totaling 22 ml, are collected at least 6-18 hours post-resection, and every other day up to a week until discharge. At follow up Visit 4, 5.5 ml of blood is collected.
Experimental: Imaging/Pathology MRI of HCC tumor, followed by pathology samples from surgical resection of HCC tumor and adjacent liver.	Procedure: MRI; Participants undergo volumetric & diffusion weighted (DW) MRI. Participants are scanned twice, with an intervening fifteen minute walk between the scans.; Procedure: Pathology; Participants who are undergoing surgical resection of HCC per their standard of care treatment, will submit tumor samples for biomarker analysis.; Procedure: Blood Samples; Blood is collected from participants during screening Visit 1 - 24.5 ml. During Visit 3, blood samples totaling 22 ml, are collected at least 6-18 hours post-resection, and every other day up to a week until discharge. At follow up Visit 4, 5.5 ml of blood is collected.

Outcome Measures

Primary Outcome Measures

1. Expression Levels of Beta-catenin mRNA From Core Needle Biopsy (CNB) Equivalents of Resected HCC. [Visit 3, approximately 7 days after screening Visit 1.]

   Resected tumors were fixed with formalin in paraffin embedded (FFPE) blocks, which were used to prepare multiple serial slide sections. The sections were to be analyzed for beta-catenin messenger RNA (mRNA) by quantitative reverse transcription polymerase chain reaction (qRT-PCR).

2. Expression Levels of Beta-catenin Protein From Core Needle Biopsy (CNB) Equivalents of Resected HCC. [Visit 3, approximately 7 days after screening Visit 1.]

   Resected tumors were fixed in FFPE blocks, which were used to prepare multiple serial slide sections. The sections were to be analyzed for beta-catenin protein by automated image analysis.

Secondary Outcome Measures

1. Tumor Volumes From Repeated MRI Measurements of HCC. [Visit 2, approximately 7 days after screening Visit 1.]

   Two volumetric MRI and diffusion weighted (DW) MRI scans were performed without contrast on each participant. The two scans were separated by 10 to 15 minutes, and each scan was read by a separate reader to determine the volume of each tumor. The mean of log tumor volume is presented, based on tumors as observation units.

2. Median Apparent Diffusion Coefficient (Median ADC) of Tumors From Repeated MRI Measurements of HCC. [Visit 2, approximately 7 days after screening Visit 1.]

   Two volumetric MRI and diffusion weighted (DW) MRI scans were performed without contrast on each participant. The two scans were separated by 10 to 15 minutes, and each scan was read by a separate reader to derive a Median ADC for each tumor. The mean of the Median ADCs is presented based on tumours as observation units.

3. Expression Levels of Beta-catenin mRNA From CNB Equivalents of Liver Adjacent to HCC. [Visit 3, approximately 7 days after screening Visit 1.]

   Tissues adjacent to resected tumors were fixed in FFPE blocks, which were used to prepare multiple serial slide sections. The sections were to be analyzed for beta-catenin mRNA by qRT-PCR.

4. Expression Levels of Beta-catenin Protein From CNB Equivalents of Liver Adjacent to HCC. [Visit 3, approximately 7 days after screening Visit 1.]

   Tissues adjacent to resected tumors were fixed in FFPE blocks, which were used to prepare multiple serial slide sections. The sections were to be analyzed for beta-catenin protein by automated image analysis.

5. Expression Levels of Low Density Lipoprotein Receptor (LDL-R) in Resected HCC and Adjacent Liver From Whole Tissue Sections. [Visit 3, approximately 7 days after screening Visit 1.]

   Resected tumors and adjacent tissues were fixed in FFPE blocks, which were used to prepare multiple serial slide sections. The sections were to be analyzed for LDL-R protein by automated image analysis.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Diagnosed with HCC.

• Candidate for surgical resection or has no contraindications to MRI procedures.

Exclusion Criteria:

• Prior loco-regional treatment of tumor, unless there is untreated tumor present representing a distinct untreated nodule.

• Confirmed or suspected diagnosis of fibrolamellar HCC, mixed HCC/cholangiocarcinoma or metastatic tumor.

• Had a liver transplant.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Merck Sharp & Dohme LLC

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT01521780
• Other Study ID Numbers: 0000-215
• First Posted: Jan 31, 2012
• Last Update Posted: Nov 1, 2015
• Last Verified: Oct 1, 2015

• Keywords provided by Merck Sharp & Dohme LLC: hepatocellular carcinoma; MRI; pharmacogenomics; beta-catenin
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Hepatocellular

Study Results

Participant Flow

Arm/Group Title	Imaging	Pathology	Imaging/Pathology
Arm/Group Description	Magnetic resonance imaging (MRI) of Hepatocellular carcinoma (HCC) tumor.	Pathology samples from surgical resection of HCC tumor and adjacent liver.	MRI of HCC tumor, followed by pathology samples from surgical resection of HCC tumor and adjacent liver.
Period Title: Overall Study
STARTED	9	1	2
COMPLETED	9	1	2
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	All Participants
Arm/Group Description	Participants who enrolled in the study
Overall Participants	12
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	61.4 (14.43)
Sex: Female, Male (Count of Participants)
Female	1 8.3%
Male	11 91.7%

Outcome Measures

1. Primary Outcome

Title	Expression Levels of Beta-catenin mRNA From Core Needle Biopsy (CNB) Equivalents of Resected HCC.
Description	Resected tumors were fixed with formalin in paraffin embedded (FFPE) blocks, which were used to prepare multiple serial slide sections. The sections were to be analyzed for beta-catenin messenger RNA (mRNA) by quantitative reverse transcription polymerase chain reaction (qRT-PCR).
Time Frame	Visit 3, approximately 7 days after screening Visit 1.

Outcome Measure Data

Analysis Population Description

Due to early termination of the study, the low number of samples were not assayed and efficacy analyses were not performed.

Arm/Group Title	Imaging	Pathology	Imaging/Pathology
Arm/Group Description	Magnetic resonance imaging (MRI) of HCC tumor.	Pathology samples from surgical resection of HCC tumor and adjacent liver.	MRI of HCC tumor, followed by pathology samples from surgical resection of HCC tumor and adjacent liver.
Measure Participants	0	0	0

2. Primary Outcome

Title	Expression Levels of Beta-catenin Protein From Core Needle Biopsy (CNB) Equivalents of Resected HCC.
Description	Resected tumors were fixed in FFPE blocks, which were used to prepare multiple serial slide sections. The sections were to be analyzed for beta-catenin protein by automated image analysis.
Time Frame	Visit 3, approximately 7 days after screening Visit 1.

Outcome Measure Data

Analysis Population Description

Due to early termination of the study, the low number of samples were not assayed and efficacy analyses were not performed.

Arm/Group Title	Imaging	Pathology	Imaging/Pathology
Arm/Group Description	Magnetic resonance imaging (MRI) of HCC tumor.	Pathology samples from surgical resection of HCC tumor and adjacent liver.	MRI of HCC tumor, followed by pathology samples from surgical resection of HCC tumor and adjacent liver.
Measure Participants	0	0	0

3. Secondary Outcome

Title	Tumor Volumes From Repeated MRI Measurements of HCC.
Description	Two volumetric MRI and diffusion weighted (DW) MRI scans were performed without contrast on each participant. The two scans were separated by 10 to 15 minutes, and each scan was read by a separate reader to determine the volume of each tumor. The mean of log tumor volume is presented, based on tumors as observation units.
Time Frame	Visit 2, approximately 7 days after screening Visit 1.

Outcome Measure Data

Analysis Population Description

Eleven participants underwent MRI and DW MRI scans and only ten of their tumors were deemed measurable by both readers for analysis. Participants in both the Imaging and Imaging/Pathology treatment groups were combined for this analysis, whereas participants in the Pathology only treatment group were not analyzed for this outcome measure.

Arm/Group Title	Imaging and Imaging/Pathology
Arm/Group Description	Magnetic resonance imaging (MRI) of HCC tumor.
Measure Participants	11
Measure Tumors	10
Mean (Standard Deviation) [log cm^3]	3.38 (0.235)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Imaging
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Within subject coefficient of variation
	Estimated Value	0.0803
	Confidence Interval	(1-Sided) 90%; to 0.1163
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Median Apparent Diffusion Coefficient (Median ADC) of Tumors From Repeated MRI Measurements of HCC.
Description	Two volumetric MRI and diffusion weighted (DW) MRI scans were performed without contrast on each participant. The two scans were separated by 10 to 15 minutes, and each scan was read by a separate reader to derive a Median ADC for each tumor. The mean of the Median ADCs is presented based on tumours as observation units.
Time Frame	Visit 2, approximately 7 days after screening Visit 1.

Outcome Measure Data

Analysis Population Description

Eleven participants underwent MRI and DW MRI scans and only eight of their tumors were deemed measurable by both readers for analysis. Participants in both the Imaging and Imaging/Pathology treatment groups were combined for this analysis, whereas participants in the Pathology only treatment group were not analyzed for this outcome measure.

Arm/Group Title	Imaging and Imaging/Pathology
Arm/Group Description	Magnetic resonance imaging (MRI) of HCC tumor.
Measure Participants	11
Measure Tumors	8
Mean (Standard Deviation) [um^2/s]	1340.56 (64.45)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Imaging
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Within subject coefficient of variation
	Estimated Value	0.0555
	Confidence Interval	(1-Sided) 90%; to 0.0733
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Expression Levels of Beta-catenin mRNA From CNB Equivalents of Liver Adjacent to HCC.
Description	Tissues adjacent to resected tumors were fixed in FFPE blocks, which were used to prepare multiple serial slide sections. The sections were to be analyzed for beta-catenin mRNA by qRT-PCR.
Time Frame	Visit 3, approximately 7 days after screening Visit 1.

Outcome Measure Data

Analysis Population Description

Due to early termination of the study, the low number of samples were not assayed and efficacy analyses were not performed.

Arm/Group Title	Imaging	Pathology	Imaging/Pathology
Arm/Group Description	Magnetic resonance imaging (MRI) of HCC tumor.	Pathology samples from surgical resection of HCC tumor and adjacent liver.	MRI of HCC tumor, followed by pathology samples from surgical resection of HCC tumor and adjacent liver.
Measure Participants	0	0	0

6. Secondary Outcome

Title	Expression Levels of Beta-catenin Protein From CNB Equivalents of Liver Adjacent to HCC.
Description	Tissues adjacent to resected tumors were fixed in FFPE blocks, which were used to prepare multiple serial slide sections. The sections were to be analyzed for beta-catenin protein by automated image analysis.
Time Frame	Visit 3, approximately 7 days after screening Visit 1.

Outcome Measure Data

Analysis Population Description

Due to early termination of the study, the low number of samples were not assayed and efficacy analyses were not performed.

Arm/Group Title	Imaging	Pathology	Imaging/Pathology
Arm/Group Description	Magnetic resonance imaging (MRI) of HCC tumor.	Pathology samples from surgical resection of HCC tumor and adjacent liver.	MRI of HCC tumor, followed by pathology samples from surgical resection of HCC tumor and adjacent liver.
Measure Participants	0	0	0

7. Secondary Outcome

Title	Expression Levels of Low Density Lipoprotein Receptor (LDL-R) in Resected HCC and Adjacent Liver From Whole Tissue Sections.
Description	Resected tumors and adjacent tissues were fixed in FFPE blocks, which were used to prepare multiple serial slide sections. The sections were to be analyzed for LDL-R protein by automated image analysis.
Time Frame	Visit 3, approximately 7 days after screening Visit 1.

Outcome Measure Data

Analysis Population Description

Due to early termination of the study, the low number of samples were not assayed and efficacy analyses were not performed.

Arm/Group Title	Imaging	Pathology	Imaging/Pathology
Arm/Group Description	Magnetic resonance imaging (MRI) of HCC tumor.	Pathology samples from surgical resection of HCC tumor and adjacent liver.	MRI of HCC tumor, followed by pathology samples from surgical resection of HCC tumor and adjacent liver.
Measure Participants	0	0	0

Adverse Events

Arm/Group Title	Imaging		Pathology		Imaging/Pathology
Arm/Group Description	Magnetic resonance imaging (MRI) of HCC tumor.		Pathology samples from surgical resection of HCC tumor and adjacent liver.		MRI of HCC tumor, followed by pathology samples from surgical resection of HCC tumor and adjacent liver.
All Cause Mortality
	Imaging		Pathology		Imaging/Pathology
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Imaging		Pathology		Imaging/Pathology
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/1 (0%)		0/2 (0%)
Other (Not Including Serious) Adverse Events
	Imaging		Pathology		Imaging/Pathology
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/1 (0%)		0/2 (0%)

Limitations/Caveats

The study was terminated early.

More Information

Certain Agreements

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

The SPONSOR must have the opportunity to review all proposed abstracts, manuscripts or presentations regarding this study 60 days prior to submission for publication/presentation. Any information identified by the SPONSOR as confidential must be deleted prior to submission.