Proof of Principle Trial to Determine if Nutritional Supplement Conjugated Linoleic Acid (CLA) Can Modulate the Lipogenic Pathway in Breast Cancer Tissue

An in Vivo Proof of Principle Trial to Determine Whether the Nutritional Supplement Conjugated Linoleic Acid (CLA, Clarinol™) Can Modulate the Lipogenic Pathway in Breast Cancer Tissue

Status

Completed

Phases

Early Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00908791

Enrollment

Registered

2009-05-27

Start date

2009-06-30

Completion date

2013-03-31

Last updated

2019-04-01

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Breast Cancer

Keywords

Conjugated Linoleic Acid, Proof of Principle, Lipogenic Pathway, Clarinol

Brief summary

Conjugated Linoleic Acid (CLA) is obtained in the human diet by consumption of foods containing ruminant fat. Milk and dairy products have shown the highest amounts of CLA. Clarinol (CLA), is considered a natural supplement and is not regulated by the Food and Drug Administration (FDA). CLA is known to inhibit proliferation of human breast cancer cells and tumors in rodent breast cancer models and reduced Spot 14 (THRSP, S14) and Fatty Acid Synthase (FASN) gene expression in breast cancer cells and tht the two major CLA isomers used in nutritional supplements (C9, t11 and t10, c12) were equipotent in reducing breast cancer cell growth. This study looks at the hypothesis that S14 expression is decreased by CLA and will characterize the major pharmacodynamic (PD) effects of CLA in newly diagnosed Breast cancer patients on Tumor tissue lipogenic pathway. FASN, S14 and Lipoprotein Lipase (LPL), Ki67 and apoptotic index expression will be assessed by quantitative immunohistochemistry (IHC) in initial breast cancer biopsies and compared to that in resected breast tumor tissue after the study subject has been taking CLA for ten to twenty-eight days. Tissue from adjacent breast adipocytes will also be analyzed to determine whether adipose tissue effects can serve as a surrogate marker for those in tumor tissue. A sample of the original biopsy will be compared to the tumor resection sample to determine the levels of CLA in the breast cancer cells.

Interventions

DRUGConjugated Linoleic Acid (CLA)

Conjugated linoleic acid (CLA, Clarinol™) oral soft gel capsules will be administered in an open-labeled, manner to all subjects enrolled in the study. Subjects will be treated with 7.5 grams of oral CLA daily, taken in divided dose, twice daily between 8 am and 12 noon and between 8 pm and 12 midnight. CLA will be taken for a minimum of ten days prior to surgical resection of their breast malignancy. In the event that the subject's surgical resection date is delayed, subjects may take CLA for up to 28 days. The last dose of CLA prior to the surgical resection will be taken at 12 midnight or as close as possible to that time and the patient will record the time of the last dosing.

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

BASIC_SCIENCE

Masking

NONE

Eligibility

Sex/Gender

FEMALE

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* All study patients must have histologically confirmed invasive adenocarcinoma of the breast. Their breast cancer must be resectable clinical stage I or II breast cancer as defined by the current AJCC TNM Staging System (Greene FL, Page DL, Fleming ID, et al.: editors. AJCC cancer staging manual, 6th edition. New York: Springer; 2002). * All patients must be able to and give informed consent indicating they are aware of the investigational nature of this treatment, prior to entry into the study. * All subjects must be Age \>18 years. * All subject must have adequate hepatic and renal function documented prior to study entry to include: hepatic transaminases (AST or ALT) ≤ 1.5 times the upper limits of normal, total bilirubin ≤ 1.5 times the upper limits of normal, serum creatinine ≤ 1.5 times the upper limit of normal or eCRCl ≥ 60 mL/min.

Exclusion criteria

* Patients who have received prior or be receiving radiation therapy for their breast cancer will be excluded. * Patients who have received prior chemotherapy or receiving chemotherapy or hormonal therapy for their breast cancer will not be included. * Women must be surgically sterilized or post-menopausal or women of childbearing potential must be using an adequate method of contraception. Women of childbearing potential must be using at least one of the following: oral, implanted, injectable contraceptive hormones, or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or have a partner that is sterile (e.g., vasectomy). Women of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to start of study therapy. Women who are pregnant or breast-feeding and women of childbearing potential not using an adequate method of birth control will be excluded. * Patients with gastrointestinal abnormalities including: inability to take oral medication, requirement for intravenous alimentation, or prior surgical procedures affecting nutrient /drug absorption will be excluded. * A serious uncontrolled medical disorder or active infection which would impair their ability to receive study treatment will be excluded. Significant cardiac disease, including uncontrolled high blood pressure, unstable angina, and congestive heart failure, myocardial infarction within the previous 3 months or serious cardiac arrhythmias will be excluded. Dementia or significantly altered mental status that would prohibit the understanding or rendering of informed consent and compliance with the requirements of this protocol will be excluded.

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Spot 14 Expression Pre and Post CLA as Assessed by Quantitative Immunohistochemistry and Staining Intensities Scored at 0, 1, or 2	Up to 28 days	To determine whether ≥ 10 days of CLA consumption suppresses Spot 14 expression in breast cancer tissue in vivo. The staining intensities scoring system used is: no immuostaining (0), weak staining (1), and strong staining (2). The scoring system used objectively and quantitatively assesses the expression of Spot 14, fatty acid synthase, and lipoprotein lipase using the image processing and analysis software Image-Pro Plus™ (MediaCybernetics).

Secondary

Measure	Time frame	Description
Number of Participants With LPL Expression Pre and Post CLA as Assessed by Quantitative Immunohistochemistry and Staining Intensities Scored at 0, 1, or 2	Pre-CLA treatment and up to 2 years Post-CLA treatment	To determine whether ≥ 10 days of CLA consumption suppresses LPL expression in brest cancer tissue in vivo. The staining intensities scoring system used is: no immuostaining (0), weak staining (1), and strong staining (2). The scoring system used objectively and quantitatively assesses the expression of Spot 14, fatty acid synthase, and lipoprotein lipase using the image processing and analysis software Image-Pro Plus™ (MediaCybernetics).
Number of Participants With Ki67 Expression Pre and Post CLA as Assessed by Quantitative Immunohistochemistry	Pre-CLA treatment and up to 2 years Post-CLA treatment	To determine whether ≥ 10 days of CLA consumption impacts the status of tumor proliferation by calculating the percentage of cells expressing Ki67.
Assess Tumor Cell Apoptosis by Immunostaining for Cleaved Caspase 3 Pre and Post CLA	Pre-CLA treatment and up to 2 years Post-CLA treatment	To determine whether ≥ 10 days of CLA consumption impacts the status of tumor cell apoptosis by measuring the presence of immunostaining for cleaved caspase 3.
Number of Participants With FASN Expression Pre and Post CLA as Assessed by Quantitative Immunohistochemistry and Staining Intensities Scored at 0, 1, or 2	Pre-CLA treatment and up to 2 years Post-CLA treatment	To determine whether ≥ 10 days of CLA consumption suppresses FASN expression in breast cancer tissue in vivo. The staining intensities scoring system used is: no immuostaining (0), weak staining (1), and strong staining (2). The scoring system used objectively and quantitatively assesses the expression of Spot 14, fatty acid synthase, and lipoprotein lipase using the image processing and analysis software Image-Pro Plus™ (MediaCybernetics).
Number of Participants With Measurable Concentration of the Circulating Plasma Free CLA Isomers c9t11 and t10c12 Matched to Ki-67 Expression	Pre-CLA treatment and up to 2 years Post-CLA treatment	—
Safety of Short Term Treatment With 7.5 Gram CLA Per Day.	2 months	—
Number of Participants With Measurable Concentration of the Circulating Plasma Free CLA Isomers c9,t11 and t10,c12 Matched to Spot 14 Expression.	Pre-CLA treatment and up to 2 years Post-CLA treatment	—

Countries

United States

Participant flow

Recruitment details

Women with invasive breast cancer were recruited from the Breast Oncology Clinic at the Norris Cotton Cancer Center at the Geisel School of Medicine at Dartmouth from June 2009 to March 2011. All patients gave written informed consent before entry into the study.

Pre-assignment details

Participants must have been able to take the study drug for a minimum of 10 days prior to tumor resection. For some potential participants the surgery date was scheduled earlier than 10 days and the study drug was not dispensed.

Participants by arm

Arm	Count
Single Arm Study Women with histologically proven invasive non-metastatic breast cancer.	24
Total	24

Baseline characteristics

Characteristic	Single Arm Study
Age, Categorical <=18 years	0 Participants
Age, Categorical >=65 years	9 Participants
Age, Categorical Between 18 and 65 years	15 Participants
Age, Continuous	57.36 years STANDARD_DEVIATION 11.14
Region of Enrollment United States	24 participants
Sex: Female, Male Female	24 Participants
Sex: Female, Male Male	0 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	14 / 24
serious Total, serious adverse events	0 / 24

Outcome results

Primary

Number of Participants With Spot 14 Expression Pre and Post CLA as Assessed by Quantitative Immunohistochemistry and Staining Intensities Scored at 0, 1, or 2

To determine whether ≥ 10 days of CLA consumption suppresses Spot 14 expression in breast cancer tissue in vivo. The staining intensities scoring system used is: no immuostaining (0), weak staining (1), and strong staining (2). The scoring system used objectively and quantitatively assesses the expression of Spot 14, fatty acid synthase, and lipoprotein lipase using the image processing and analysis software Image-Pro Plus™ (MediaCybernetics).

Time frame: Up to 28 days

Arm	Measure	Group	Value (NUMBER)
Pre CLA	Number of Participants With Spot 14 Expression Pre and Post CLA as Assessed by Quantitative Immunohistochemistry and Staining Intensities Scored at 0, 1, or 2	Spot 14 Expression Grade 0	0 participants
Pre CLA	Number of Participants With Spot 14 Expression Pre and Post CLA as Assessed by Quantitative Immunohistochemistry and Staining Intensities Scored at 0, 1, or 2	Spot 14 Expression Grade 1	10 participants
Pre CLA	Number of Participants With Spot 14 Expression Pre and Post CLA as Assessed by Quantitative Immunohistochemistry and Staining Intensities Scored at 0, 1, or 2	Spot 14 Expression Grade 2	14 participants
Post CLA	Number of Participants With Spot 14 Expression Pre and Post CLA as Assessed by Quantitative Immunohistochemistry and Staining Intensities Scored at 0, 1, or 2	Spot 14 Expression Grade 0	0 participants
Post CLA	Number of Participants With Spot 14 Expression Pre and Post CLA as Assessed by Quantitative Immunohistochemistry and Staining Intensities Scored at 0, 1, or 2	Spot 14 Expression Grade 1	22 participants
Post CLA	Number of Participants With Spot 14 Expression Pre and Post CLA as Assessed by Quantitative Immunohistochemistry and Staining Intensities Scored at 0, 1, or 2	Spot 14 Expression Grade 2	2 participants

p-value: 0.003McNemar

Secondary

Assess Tumor Cell Apoptosis by Immunostaining for Cleaved Caspase 3 Pre and Post CLA

To determine whether ≥ 10 days of CLA consumption impacts the status of tumor cell apoptosis by measuring the presence of immunostaining for cleaved caspase 3.