A Molecular Pharmacodynamic Dose-titration Trial of Conjugated Linoleic Acid (CLA; Clarinol®) in Patients With Advanced Solid Tumors

It has become apparent that many cancers depend on specific fats (lipids) for their continued growth. Conjugated linoleic acid (CLA) is a safe, popular, and well-tolerated dietary supplement that promotes weight loss and loss of fat. CLA was recently shown to block the metabolism (uptake and production) of lipids required for growth of some cancers, resulting in killing of cancer cells. The investigators will conduct a clinical trial to test whether oral CLA blocks metabolism of lipids in patients with advanced cancers. Since the dose of CLA that may do this is not yet known, the investigators will start at a dose of CLA known to be tolerable and effective for weight loss. If this dose does not block lipid metabolism, the investigators will test higher doses in successive groups of patients until the investigators identify an effective dose, unless the investigators find that these higher doses cannot be tolerated. In order to verify that CLA is absorbed, it is necessary to measure CLA levels in blood before and after doses are given. Likewise, in order to verify that CLA blocks lipid metabolism, the investigators will need to obtain small samples of abdominal fat (and, in some patients, samples of tumors).

Study Overview

• Status: Terminated
• Conditions: Advanced Solid Tumors
• Intervention / Treatment: Dietary supplement: Conjugated Linoleic Acid; Drug: Conjugated Linoleic Acid

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth-Hitchcock Medical Center, Norris Cotton Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

A subject is eligible for inclusion in this study only if all of the following criteria apply:

1. Written informed consent.
2. Age 18 years or more.
3. Performance status of 0, 1, or 2 on the Eastern Co-operative Oncology Group (ECOG) Scale.
4. A predicted life expectancy of at least 3 months, in the estimation of the investigator.
5. Subjects with histologically or cytologically confirmed advanced solid tumors, who have failed conventional therapy for their tumor type or have a tumor type for which no standard effective therapy exists.
6. At least 4 weeks since last chemotherapy, radiotherapy, biologic therapy or surgery. Subjects must be free of post-treatment side effects. No concurrent chemotherapy, biologic therapy or radiotherapy is allowed.

7. Hematological/clinical chemistry criteria of:

   Hemoglobin ≥ 9.0 g/dL WBC ≥ 3,500/mm3 [≥ 3.5 x 109/L] Neutrophils ≥ 1,500/mm3 [≥ 1.5 x 109/L] Platelets ≥ 100,000/mm3 [≥ 100.0 x 109/L] Calculated creatinine clearance ≥60 mL/min using the Cockcroft-Gault Formula.

8. Serum bilirubin < 2.0 mg/dL (34 µmol/L)
9. SGOT/AST, SGPT/ALT and alkaline phosphatase < 2 times the upper limit of normal if liver metastases cannot be visualized by abdominal computed tomography (CT) or magnetic resonance imaging (MRI scan). If liver metastases are present, subjects with < 5 times the upper limit of normal are eligible to participate.
10. Once the RP2D is established, additional patients enrolled at the expanded dose cohort must have tumor that is accessible to two serial biopsies and that is documented (by IHC or RT-PCR) to express S14.

Exclusion Criteria

A subject is ineligible if any of the following criteria apply:

1. Cancer cachexia, defined by the combination of: unintentional weight loss ≥10%, low

   caloric intake (≤ 1500 kcal/day), and systemic inflammation (C-reactive protein ≥ 10mg/L).[52]

2. Type II diabetes mellitus
3. Women who are pregnant or lactating, or women subjects of childbearing potential who refuse to practice adequate contraception. (oral contraceptives or IUD; double barrier such as diaphragm plus spermicide; vasectomized partner who is sterile prior to the female subject's entry and is the sole sexual partner of that female). Childbearing potential is defined as women who are not surgically sterilized (i.e. have not had a hysterectomy, bilateral oophorectomy [ovariectomy], or bilateral tubal ligation) or post-menopausal (i.e., documented absence of menses for one year prior to entry into the study).
4. Men unwilling to abstain from sex or use effective contraception during the study.
5. Subjects with uncontrolled emesis, regardless of etiology.
6. Active infection, or seropositivity for HIV or Hepatitis B/C.
7. Subjects with clinical evidence of any gastrointestinal (GI) conditions (i.e., removal of a portion of the stomach, recent GI obstruction or GI neuropathy) or subjects taking drugs that would alter GI absorption or motility (e.g., cisapride).
8. Intercurrent severe medical problems, which would significantly limit full compliance with the study or expose the subject to unnecessary risk.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: CLA; Open-label dose-titration trial of CLA in patients with advanced, refractory malignancies. oral dose 7.5 g/day 28 day cycle

Dietary supplement: Conjugated Linoleic Acid; This is a open-label dose-titration trial of CLA in patients with advanced, refractory malignancies. The dose a participant receives is dependent upon the cohort to with the patient is assigned. CLA will be given as oral soft gels, once daily, with pharmacokinetic sampling and biopsies (pretreatment and on day 15). Doses will be escalated by patient cohorts, using an accelerated titration design (single-patient cohorts) with expansion to conventional cohort sizes (3-6 patients) once either inhibition of S14 expression or clinical toxicity is observed. Subjects with stable or responsive disease and who tolerate treatment may continue on CLA until the time of disease progression.; Other Names: Clarinol; CLA; Drug: Conjugated Linoleic Acid; Phase I Dose Escalation Study; Other Names: Clarinol, CLA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
To define a tolerable dose of oral CLA, given on a daily schedule, that maximally inhibits S14 expression in adipocytes of patients with advanced solid tumors.	2 years

Secondary Outcome Measures

Outcome Measure	Time Frame
To quantify the effects of CLA on S14 expression in tumor tissue, at its recommended phase II dose	2 years
To quantify effects of CLA on expression of lipogenic enzymes regulated by S14, lipoprotein lipase, and phospho-akt in adipocytes (and tumor tissue).	2 years
To quantify effects of CLA on expression of biomarkers for cellular proliferation, S/G2 phases of cell cycle, and apoptosis in tumor tissue.	2 years
To define the plasma pharmacokinetics of CLA in patients with advanced cancer.	2 years
To obtain data on the safety and tolerability of CLA given orally, on a daily schedule to patients with advanced cancer.	2 years
To document ant tumor activity of CLA, if observed, in this population.	2 years

Collaborators and Investigators

• Sponsor: Dartmouth-Hitchcock Medical Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Raymond P Perez, MD, University of Kansas Medical Center

Study record dates

Study Major Dates

• Study Start: March 1, 2010
• Primary Completion (Actual): December 1, 2012
• Study Completion (Actual): June 1, 2013

Study Registration Dates

• First Submitted: August 3, 2009
• First Submitted That Met QC Criteria: August 3, 2009
• First Posted (Estimate): August 4, 2009

Study Record Updates

• Last Update Posted (Estimate): May 12, 2015
• Last Update Submitted That Met QC Criteria: May 11, 2015
• Last Verified: March 1, 2012

More Information

Terms related to this study

• Keywords: Conjugated Linoleic Acid; Clarinol; S14 Expression
• Additional Relevant MeSH Terms: Neoplasms
• Other Study ID Numbers: D0914; R21CA131820-01A2 (U.S. NIH Grant/Contract)