Study Evaluating Two Dose Levels of Targretin Capsules in Participants With Refractory Cutaneous T-Cell Lymphoma (CTCL)

Phase IV Randomized Study of Two Dose Levels of Targretin® Capsules in Subjects With Refractory Cutaneous T-Cell Lymphoma

This is a multicenter, randomized, open-label, Phase IV study to assess the efficacy, tolerability, and safety of 2 initial dose levels of bexarotene capsules in participants with refractory CTCL.

Study Overview

• Status: Completed
• Conditions: Refractory Cutaneous T-cell Lymphoma
• Intervention / Treatment: Drug: Bexarotene

• Study Type: Interventional
• Enrollment (Actual): 59
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • Florida
    • Miami, Florida, United States, 33136
      • Florida Academic Dermatology Centers
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota Medical School
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University
  • New York
    • Rochester, New York, United States, 14642
      • University of Rochester
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals-Case Medical Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh
  • Tennessee
    • Nashville, Tennessee, United States, 37206
      • Vanderbilt
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute at The University of Utah

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:

1. A CTCL without central nervous system (CNS) involvement, confirmed by biopsy to be histologically consistent with CTCL diagnosis by a dermatopathologist.
2. Refractory to at least 1 systemic therapy for CTCL. (Refractory is defined as resistance to therapy due either to lack of response of at least 50% improvement or progression of disease while still on therapy after an initial response.)
3. Systemic therapy for CTCL is indicated.
4. A Karnofsky performance score ≥60%.
5. Age ≥18 years.
6. Females of childbearing potential must have a negative serum beta human chorionic gonadotropin (ß-hCG) with a sensitivity of at least 50 milli-international units/liter (mIU/L) within 7 days prior to the initiation of treatment. Females of childbearing potential must have used simultaneously two highly effective methods of contraception (strongly recommended that 1 of the 2 forms of contraception be non-hormonal such as condom plus spermicide, condom plus diaphragm with spermicide, or have a vasectomized partner) or use an intrauterine device or must have been sexually abstinent for at least four weeks prior to or at least 1 menstrual cycle prior to (whichever is longer) the negative pregnancy test through entry in the study. Sexual abstinence or effective contraception must be used for at least 1 month prior to the initiation of therapy, during therapy, and for at least 1 month following discontinuation of therapy. Perimenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential.
7. Male participants with female partners of childbearing potential must agree to sexual abstinence or to practice 2 reliable forms of effective contraception used simultaneously (strongly recommended that 1 of the 2 forms of contraception be non-hormonal such as condom plus spermicide, condom plus diaphragm with spermicide, or partner with tubal ligation) or partner may use an intrauterine device, during the entire period of bexarotene capsule treatment and for at least 1 month after treatment is discontinued. Male participants with female sexual partners who are pregnant, possibly pregnant or who could become pregnant during the study must agree to use condoms during sexual intercourse during the entire period of bexarotene capsule treatment and for at least 1 month after the last dose of bexarotene capsules.
8. Must be willing and able to give informed consent and complete and understand, either oral or written, study procedures and assessments.
9. Participant must be suitable for participation in the study in the Investigator's opinion.
10. Fasting serum triglyceride within normal limits (<150 mg/deciliter [dL]) prior to study entry.
11. Adequate renal function as evidenced by serum creatinine ≤2.0 mg/dL or calculated creatinine clearance ≥40 milliliters (mL)/minute (min) as per the Cockroft and Gault formula.
12. Adequate hepatic function that is characterized by aspartate aminotransferase (SGOT [AST]), alanine aminotransferase (SGPT [ALT]), or serum bilirubin <2.5 times the upper limit of normal.
13. Adequate bone marrow function as evidenced by hemoglobin ≥8 grams (g)/dL, absolute neutrophil count (ANC) ≥1,000/milliliters cubed (mm^3), and platelets ≥50,000/mm^3.

Exclusion Criteria

1. Cutaneous T-cell lymphoma involving the central nervous system.
2. Participants with known Human Immunodeficiency Virus (HIV) infection and active Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection (HBV/HCV or HIV testing is not required for the purpose of this study).
3. Participation in any other investigational drug study within 30 days of entry in this study.
4. Within 5 years after the onset of menopause.
5. Received systemic corticosteroids within 6 months of entry in the study.
6. Known hypersensitivity to bexarotene or other component of bexarotene capsules.
7. Pregnancy, intent to become pregnant, or breast-feeding.
8. Received gemfibrozil within 1 day of starting the study.

9. Prior therapy for the treatment of CTCL:

   1. Psoralens and ultraviolet A light (PUVA) or ultraviolet B light (UVB) therapy within 3 weeks of study entry.
   2. Electron beam radiation therapy (EBT) or photopheresis within 3 weeks of study entry.

   3. Topical retinoids, nitrogen mustard, carmustine (BCNU), imiquimod, or other antipruritic medication within 2 weeks of study entry.

      If antipruritic medication cannot be avoided, antihistamine or antipruritic agents must be administered using a stable dose regimen for at least 1 week prior to initiation of study drug treatment and throughout the study, unless it is determined that a discontinuation or reduction in dose is indicated. Prior to the enrollment of any participant who will be taking systemic or dermatologically-applied antihistamine or anti-pruritic agent, the investigator must contact Eisai to discuss the need for such agent. Mineral oil, baby oil, and simple moisturizing lotions may be used as emollients. Low- to mid- potency topical corticosteroids are allowed only for participants with erythroderma (Stage III/IV CTCL) using a stable dose regimen for at least 4 weeks prior to study entry. High potency topical corticosteroids and tar baths are NOT permitted.

      NOTE: Prior to the enrollment of any participant who will be taking systemic or dermatologically-applied antihistamine or anti-pruritic agent, the Investigator must contact the Sponsor to discuss the need for such agent.

   4. Anticancer therapy of any kind (for example, methotrexate, cyclophosphamide, vorinostat, romidepsin, and interferon) within 30 days of entry to the study. Participant must recover from all signs of toxicity prior to entry in the study.
   5. Oral retinoid therapy for any indication within 3 months of study entry.
   6. Systemic therapy with Vitamin A in doses of greater than 15,000 International Units (IU) (5,000 microgram [mcg]) per day (equivalent to approximately 3 times Recommended Daily Allowance [RDA]) within 30 days of entry in this study.
10. Systemic antibiotic therapy within 2 weeks of entry in the study. (Participants with infections requiring antibiotics or likely to require antibiotics should be appropriately treated with a course of antibiotics terminating at least two weeks prior to entry, or if indicated, a chronic suppressive or prophylactic dose of antibiotics stabilized at least 2 weeks prior to entry. Participants who require initiation of or changes in antibiotic therapy during the study will not be considered a violation of the study protocol).
11. History of pancreatitis or significant risk factors for developing pancreatitis (for example, prior pancreatitis, uncontrolled hyperlipidemia, excessive alcohol consumption, uncontrolled diabetes mellitus, biliary tract disease, and medications known to increase triglyceride levels or to be associated with pancreatic toxicity).
12. Unwillingness or inability to minimize exposure to sunlight and artificial ultraviolet light while receiving bexarotene capsules.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Bexarotene 150 milligrams (mg)/square meter (m^2)/day; Participants will receive bexarotene 150 mg/m^2/day once daily for 24 weeks.	Drug: Bexarotene; Soft gelatin capsules to be taken orally with at least 6 ounces of water or other fluid either with or immediately following the evening meal (a moderate or full meal) or a nutritionally defined liquid food.; Other Names: Targretin®
Experimental: Bexarotene 300 mg/m^2/day; Participants will receive bexarotene 300 mg/m^2/day once daily for 24 weeks.	Drug: Bexarotene; Soft gelatin capsules to be taken orally with at least 6 ounces of water or other fluid either with or immediately following the evening meal (a moderate or full meal) or a nutritionally defined liquid food.; Other Names: Targretin®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Tumor Response (Complete Response [CR], Clinical Complete Response [CCR], and Partial Response [PR]) in up to 5 Index Lesions as Determined by Investigator's Composite Assessment (CA) of Index Lesion Disease Severity	Index lesion symptoms/grade include: erythema=0 (no evidence)-8 (very severe); scaling=0 (no evidence)-8 (very severe); plaque elevation=0 (no evidence)-8 (extreme elevation); hypopigmentation/hyperpigmentation=0 (no evidence of change)-8 (very severe change); area of involvement=0 (0 centimeters [cm]^2)-18 (>300 cm^2). CA generated by sum of grades of signs/symptoms for each index lesion. Index lesion CA grade at baseline was divided into CA grade at each subsequent study visit to determine participant's response to treatment. Ratio of CA <1.0=improvement in disease; ratio >1.0=worsening of disease. Tumor response as determined by CA=percentage of participants achieving CR (CA ratio=0, no clinically abnormal lymph nodes, and absence of histologic signs of CTCL); CCR (CA ratio=0 and no clinically abnormal lymph nodes); and PR (CA ratio=≤0.5, <25% increase in number/aggregate area of abnormal lymph nodes/tumors, and no new abnormal lymph nodes in documented area of absence of disease).	Baseline up to Week 24
Number of Participants With Tumor Response of CR, CCR, PR, SD, and PD as Determined by Physician's Global Assessment (PGA) of Clinical Condition	The PGA was an assessment of the overall extent of improvement/worsening from Baseline of the participant's overall disease compared with the condition every 4 weeks thereafter during treatment. CR=PGA grade of 0 (completely clear of disease since Baseline) and absence of histologic signs of CTCL. CCR=PGA grade of 0. PR=PGA grade of 1 (almost clear [≥90%-<100%] of disease since Baseline), 2 (marked improvement [≥75%-<90%] of disease since Baseline), 3 (moderate improvement [≥50%-<70%] of disease since Baseline). Stable Disease (SD)=PGA grade of 4 (slight improvement [<25%-<50%] of disease since Baseline) or 5 (no change in disease [+/-<25% change since Baseline]). Progressive Disease (PD)=PGA grade of 6 (worse disease [≥25%] than at baseline). If visceral disease or an abnormal lymph node was located in a documented area of absence of disease, then PD would be reported for the participant.	Baseline up to Week 24
Number of Participants With Tumor Response of CR, CCR, PR, SD, and PD as Determined Percent Body Surface Area (BSA) Involvement	To determine BSA involvement, the area of the participant's palm was defined as 1% of the participant's BSA. The extent of involvement of disease was determined as multiples of the participant's palm area and expressed as a percentage of the participant's total BSA at Baseline (Day 1) and every 4 weeks thereafter during treatment. CR=percent BSA 0% and documented absence of histologic signs of CTCL. CCR=Percent BSA 0%. PR=a decrease from Baseline in percent BSA of at least 50%. SD=none of the response classifications (that is, CR, CCR, PR, or PD) accurately describe the disease status. PD=an increase from Baseline in percent BSA of at least 25%.	Baseline up to Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Tumor Response (CR, CCR, or PR) as Determined by Investigator's CA of Index Lesion Disease Severity	Defined as time interval from onset of response to time participant relapses or last date of data collected with an assessment of participant still meeting response criteria. Index lesion symptoms/grade: erythema/scaling=0 (no evidence)-8 (very severe); plaque elevation=0 (no evidence)-8 (extreme elevation); hypopigmentation/hyperpigmentation=0 (no evidence)-8 (very severe change); area of involvement=0 (0 cm^2)-18 (>300 cm^2). CA: sum of signs/symptoms grades for index lesion. Index lesion CA grade at baseline divided into CA grade at study visit to determine treatment response. CA Ratio <1.0=improvement and >1.0=worsening of disease. Tumor response=percentage of participants with CR (CA ratio=0, no clinically abnormal lymph nodes, absence of CTCL histologic signs); CCR (CA ratio=0; no clinically abnormal lymph nodes); PR (CA ratio=≤0.5, <25% increase in number/aggregate area of abnormal lymph nodes/tumors, no new abnormal lymph nodes in documented area of absence of disease).	Baseline up to Week 24
Duration of Tumor Response (CR, CCR, or PR) as Determined by PGA of Clinical Condition	Defined as time interval from onset of response to time participant relapses or last date of data collected with an assessment of participant still meeting response criteria. PGA was an assessment of the overall extent of improvement/worsening from Baseline of the participant's overall disease compared with the condition every 4 weeks thereafter during treatment. CR=PGA grade of 0 (completely clear of disease since Baseline) and absence of histologic signs of CTCL. CCR=PGA grade of 0. PR=PGA grade of 1 (almost clear [≥90%-<100%] of disease since Baseline), 2 (marked improvement [≥75%-<90%] of disease since Baseline), 3 (moderate improvement [≥50%-<70%] of disease since Baseline).	Baseline up to Week 24
Duration of Tumor Response (CR, CCR, or PR) as Determined by Percent BSA Involvement	Defined as time interval from onset of response to time participant relapses or last date of data collected with an assessment of participant still meeting response criteria. To determine BSA, the area of the participant's palm was defined as 1% of the participant's BSA. The extent of involvement of disease was determined as multiples of the participant's palm area and expressed as a percentage of the participant's total BSA at Baseline (Day 1) and every 4 weeks thereafter during treatment. CR=percent BSA 0% and documented absence of histologic signs of CTCL. CCR=Percent BSA 0%. PR=a decrease from Baseline in percent BSA of at least 50%.	Baseline up to Week 24
Time to Tumor Response (CR, CCR, or PR) as Determined by CA of Index Lesion Disease Severity	Defined as time interval from first day of bexarotene treatment to time of first observation when participant met the criteria of CR, CCR, or PR. Index lesion symptoms/grade: erythema/scaling=0 (no evidence)-8 (very severe); plaque elevation=0 (no evidence)-8 (extreme elevation); hypopigmentation/hyperpigmentation=0 (no evidence)-8 (very severe change); and area of involvement=0 (0 cm^2)-18 (>300 cm^2). CA: sum of signs/symptoms grades for index lesion. Index lesion CA grade at baseline divided into CA grade at study visit to determine treatment response. CA Ratio <1.0=improvement and >1.0=worsening of disease. Tumor response=percentage of participants with CR (CA ratio=0, no clinically abnormal lymph nodes, and absence of CTCL histologic signs); CCR (CA ratio=0 and no clinically abnormal lymph nodes); and PR (CA ratio=≤0.5, <25% increase in number/aggregate area of abnormal lymph nodes/tumors, and no new abnormal lymph nodes in documented area of absence of disease).	Baseline up to Week 24
Time to Tumor Response (CR, CCR, or PR) as Determined by PGA of Clinical Condition	Defined as time interval from first day of bexarotene treatment to time of first observation when participant met the criteria of CR, CCR, or PR. PGA was an assessment of the overall extent of improvement/worsening from Baseline of the participant's overall disease compared with the condition every 4 weeks thereafter during treatment. CR=PGA grade of 0 (completely clear of disease since Baseline) and absence of histologic signs of CTCL. CCR=PGA grade of 0. PR=PGA grade of 1 (almost clear [≥90%-<100%] of disease since Baseline), 2 (marked improvement [≥75%-<90%] of disease since Baseline), 3 (moderate improvement [≥50%-<70%] of disease since Baseline).	Baseline up to Week 24
Time to Tumor Response (CR, CCR, or PR) as Determined by Percent BSA Involvement	Defined as time interval from first day of bexarotene treatment to time of first observation when participant met the criteria of CR, CCR, or PR. To determine BSA, the area of the participant's palm was defined as 1% of the participant's BSA. The extent of involvement of disease was determined as multiples of the participant's palm area and expressed as a percentage of the participant's total BSA at Baseline (Day 1) and every 4 weeks thereafter during treatment. CR=percent BSA 0% and documented absence of histologic signs of CTCL. CCR=Percent BSA 0%. PR=a decrease from Baseline in percent BSA of at least 50%.	Baseline up to Week 24
Time to Tumor Progression as Determined by CA of Index Lesion Disease Severity	Defined as time interval from first day of bexarotene treatment to time of first observation when participant met criteria for PD. Index lesion symptoms/grade: erythema/scaling=0 (no evidence)-8 (very severe); plaque elevation=0 (no evidence)-8 (extreme elevation); hypopigmentation/hyperpigmentation=0 (no evidence)-8 (very severe change); and area of involvement=0 (0 cm^2)-18 (>300 cm^2). CA: sum of signs/symptoms grades for index lesion. Index lesion CA grade at baseline divided into CA grade at study visit to determine treatment response. CA Ratio <1.0=improvement and >1.0=worsening of disease. Criteria for PD requires at least 1 component of the following: CA ratio=≥1.25, ≥25% increase in number/aggregate area of abnormal lymph nodes/tumors, or no new abnormal lymph nodes in documented area of absence of disease.	Baseline up to Week 24
Time to Tumor Progression as Determined by PGA of Clinical Condition	Defined as time interval from first day of bexarotene treatment to time of first observation when participant met criteria for PD. PGA was an assessment of the overall extent of improvement/worsening from Baseline of the participant's overall disease compared with the condition every 4 weeks thereafter during treatment. PD=PGA grade of 6 (worse disease [≥25%] than at baseline). If visceral disease or an abnormal lymph node was located in a documented area of absence of disease, then PD would be reported for the participant.	Baseline up to Week 24
Time to Tumor Progression as Determined by Percent BSA Involvement	Defined as time interval from first day of bexarotene treatment to time of first observation when participant met criteria for PD. To determine BSA involvement, the area of the participant's palm was defined as 1% of the participant's BSA. The extent of involvement of disease was determined as multiples of the participant's palm area and expressed as a percentage of the participant's total BSA at Baseline (Day 1) and every 4 weeks thereafter during treatment. PD=an increase from Baseline in percent BSA of at least 25%.	Baseline up to Week 24

Collaborators and Investigators

• Sponsor: Bausch Health Americas, Inc.
• Investigators: Study Director: Mandeep Kaur, MD, Valeant Pharmaceutical NA

Study record dates

Study Major Dates

• Study Start (Actual): January 6, 2010
• Primary Completion (Actual): February 20, 2014
• Study Completion (Actual): February 20, 2014

Study Registration Dates

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

Study Record Updates

• Last Update Posted (Actual): November 12, 2019
• Last Update Submitted That Met QC Criteria: November 8, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: MF; CTCL; bexarotene; Targretin; Refractory Cutaneous T-cell Lymphoma; cutaneous T-cell Lymphoma; Mycoses fungoides
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, T-Cell; Lymphoma, T-Cell, Peripheral; Lymphoma, T-Cell, Cutaneous; Antineoplastic Agents; Bexarotene
• Other Study ID Numbers: E7273-G000-401