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

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01007448

Enrollment

Registered

2009-11-04

Start date

2010-01-06

Completion date

2014-02-20

Last updated

2019-11-12

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

Conditions

Refractory Cutaneous T-cell Lymphoma

Keywords

CTCL, bexarotene, Targretin, Refractory Cutaneous T-cell Lymphoma, cutaneous T-cell Lymphoma, MF, Mycoses fungoides

Brief summary

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.

Interventions

DRUGBexarotene

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.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
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	Baseline up to Week 24	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).
Number of Participants With Tumor Response of CR, CCR, PR, SD, and PD as Determined by Physician's Global Assessment (PGA) of Clinical Condition	Baseline up to Week 24	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.
Number of Participants With Tumor Response of CR, CCR, PR, SD, and PD as Determined Percent Body Surface Area (BSA) Involvement	Baseline up to Week 24	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%.

Secondary

Measure	Time frame	Description
Time to Tumor Response (CR, CCR, or PR) as Determined by CA of Index Lesion Disease Severity	Baseline up to Week 24	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).
Time to Tumor Response (CR, CCR, or PR) as Determined by PGA of Clinical Condition	Baseline up to Week 24	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).
Time to Tumor Response (CR, CCR, or PR) as Determined by Percent BSA Involvement	Baseline up to Week 24	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%.
Duration of Tumor Response (CR, CCR, or PR) as Determined by Investigator's CA of Index Lesion Disease Severity	Baseline up to Week 24	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).
Time to Tumor Progression as Determined by PGA of Clinical Condition	Baseline up to Week 24	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.
Time to Tumor Progression as Determined by Percent BSA Involvement	Baseline up to Week 24	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%.
Time to Tumor Progression as Determined by CA of Index Lesion Disease Severity	Baseline up to Week 24	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.
Duration of Tumor Response (CR, CCR, or PR) as Determined by PGA of Clinical Condition	Baseline up to Week 24	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).
Duration of Tumor Response (CR, CCR, or PR) as Determined by Percent BSA Involvement	Baseline up to Week 24	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%.

Countries

United States

Participant flow

Pre-assignment details

Participants were randomized in a 1:1 ratio to bexarotene 150 milligrams (mg)/square meter (m\^2)/day or 300 mg/m\^2/day.

Participants by arm

Arm	Count
Bexarotene 150 mg/m^2/Day Participants received bexarotene 150 mg/m\^2/day once daily for 24 weeks.	30
Bexarotene 300 mg/m^2/Day Participants received bexarotene 300 mg/m\^2/day once daily for 24 weeks.	29
Total	59

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	1	4
Overall Study	Continuing Prohibited Systemic Drugs	1	0
Overall Study	Lack of Efficacy	2	0
Overall Study	Participant Given Prohibited Medication	1	0
Overall Study	Participant Leaving the Country	1	0
Overall Study	Progressive Disease	1	2
Overall Study	Staph Skin Infection Flare	1	0
Overall Study	Withdrawal by Subject	2	3

Baseline characteristics

Characteristic	Bexarotene 150 mg/m^2/Day	Bexarotene 300 mg/m^2/Day	Total
Age, Continuous	60.2 years STANDARD_DEVIATION 14.8	61.0 years STANDARD_DEVIATION 13.94	60.6 years STANDARD_DEVIATION 14.26
Sex: Female, Male Female	13 Participants	13 Participants	26 Participants
Sex: Female, Male Male	17 Participants	16 Participants	33 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	21 / 30	21 / 29
serious Total, serious adverse events	11 / 30	13 / 29

Outcome results

Primary

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).