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Phase 1 and 2 Trial of Bexarotene Gel for Skin-Directed Treatment of Patients With Cutaneous T-Cell Lymphoma
Debra Breneman, PhD;
Madeleine Duvic, MD;
Timothy Kuzel, MD;
Richard Yocum, MD;
Joseph Truglia, MD;
Victor J. Stevens, MD
Arch Dermatol. 2002;138:325-332.
ABSTRACT
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Objective To evaluate the safety, dose tolerance, and efficacy of topical bexarotene
gel in patients with early-stage cutaneous T-cell lymphoma (CTCL).
Design Phase 1 and 2, open-label, dose-escalation clinical trial of bexarotene
gel.
Setting Three university-based clinics.
Participants Sixty-seven adults with early-stage (TNM stages IA-IIA) CTCL.
Interventions Bexarotene gel, 0.1%, 0.5%, and 1.0%, applied in incremental dose adjustments
from 0.1% gel every day to 1.0% gel 4 times daily or the maximal tolerated
dose.
Main Outcome Measures Patients were followed for efficacy and safety, and treatment continued
as long as they benefited. Response ( 50% improvement) was evaluated by
the Physician's Global Assessment of cutaneous disease and by an overall severity
assessment of cutaneous disease, including signs of CTCL and area involved.
Results Most patients tolerated topical bexarotene at 1% gel twice daily for
routine use. Adverse events were generally mild to moderate in severity and
were confined to treatment sites. Treatment-limiting toxic effects were associated
with skin irritation and increased with gel exposure. Patients achieved an
overall response rate of 63% and a clinical complete response rate of 21%.
Median projected time to onset of response was 20.1 weeks (range, 4.0-86.0
weeks), and the estimated median response duration from the start of therapy
was 99 weeks. Patients with no previous therapy for mycosis fungoides responded
at a higher rate (75%) than those who previously underwent topical therapies
(67%).
Conclusions Bexarotene gel was well tolerated, was easily self-applied, and had
a substantial response rate in treating patients with early-stage CTCL.
INTRODUCTION
CUTANEOUS T-cell lymphoma (CTCL) is a heterogeneous group of low-grade
non-Hodgkin lymphomas that manifest primarily in the skin.1
Mean age at onset of disease is 50 to 56 years, and it is more common in men
than in women (2.2:1.0) and in blacks than in whites (2:1).2-3
Approximately 1000 or more new cases of CTCL are diagnosed each year in the
United States. The cause is unknown.3
Cutaneous T-cell lymphoma is characterized by the accumulation of a
clonal population of helper (CD4+) T cells with hyperchromatic,
irregularly shaped (cerebriform) nuclei in the epidermis and papillary dermis.4 The most common type of CTCL is mycosis fungoides
(MF), which can progress through patch, plaque, and tumor phases and sometimes
presents as erythroderma. The initial clinical presentation in early-stage
MF is flat, erythematous, hyperpigmented or hypopigmented patches typically
found on sun-protected areas of the body.3
These skin patches may wax and wane for several years before being diagnosed.
Confounding the diagnosis is the fact that MF lesions often respond to corticosteroids
or treatments directed at psoriasis and other dermatoses. After the exclusion
of other skin disorders, such as eczema, tinea, and psoriasis, a diagnosis
of early-stage MF is derived from clinical and histological findings, but
it is often difficult.
The clinical course of MF and other types of CTCL is variable. The stage
at presentation is important in determining the patient's prognosis and the
therapeutic choices.2, 5 A retrospective
review6 at Stanford University found that most
patients (90%) who are treated for MF with stage IA disease never progress
to a more advanced stage of disease, and the overall survival rate of patients
with stage IA disease did not differ from that of control subjects matched
for age, sex, and race. Early-stage MF is treated locally because most patients
respond to skin-directed therapy adequately and because more aggressive therapy
has not been shown to improve survival in this disease.7-9
There are a limited number of skin-directed therapies that have efficacy
in MF or CTCL. Topical corticosteroids applied to CTCL lesions may be of benefit
in patients with limited patch-phase disease, but often they have a limited
duration of effective disease control and are succeeded by other treatments.
Topical mechlorethamine hydrochloride (nitrogen mustard), topical carmustine
(BCNU), electron-beam irradiation, psoralen–UV-A (PUVA), and UV-B all
are effective in some patients with MF-type CTCL.10-11
However, all patients do not respond to these individual therapies, and cutaneous
disease often becomes refractory to specific therapies over time. Phototherapies
and radiation therapy can be inconvenient to use. Topical mechlorethamine
and, less frequently, topical BCNU may induce hypersensitivity reactions that
limit their use. In addition, these therapies all increase the risk of secondary
skin cancers. This risk increases with the duration of treatment and also
with the number of treatment modalities received. Because adverse effects
and loss of therapeutic effectiveness are common problems for patients, additional
effective skin-directed therapies are still needed.12
This article presents the results of a phase 1 and 2 clinical trial
of bexarotene gel (Targretin; Ligand Pharmaceuticals Inc, San Diego, Calif)
for patients with MF. Retinoids affect gene expression by binding 1 or more
of the 3 retinoic acid receptors  ,  ,  or 3 retinoid X
receptors , , nuclear receptors to form transcription
factors. Bexarotene selectively binds retinoid X receptors with high affinity,
in contrast to retinoic acid, which binds the 3 nuclear retinoic acid receptors.
Selective affinity to retinoid X receptors is believed to give bexarotene
different properties from retinoic acid receptor–binding retinoids,
such as all-trans-retinoic acid or 13-cis-retinoic acid.13-14
Retinoic acid receptor–type retinoids such as isotretinoin and etretinate
have demonstrated clinical activity in CTCL,9
and a retinoid X receptor–selective retinoid may have improved antineoplastic
properties. Topical application of bexarotene in gel form was chosen for initial
clinical trials in MF because it allowed a high concentration of drug at lesional
skin sites while minimizing systemic exposure.
PATIENTS AND METHODS
A phase 1 and 2 multicenter trial of topical bexarotene gel was conducted
in 67 patients with early-stage (TNM stages IA, IB, and IIA) CTCL enrolled
from January 11, 1995, to March 23, 1998. The trial was conducted at 3 US
study centers (Department of Dermatology, University of Cincinnati; Department
of Dermatology, The University of Texas and M.D. Anderson Cancer Center; and
Department of Oncology, Northwestern University) that had protocols of identical
design approved by local institutional review boards.
STUDY DESIGN
The trial design was an open-label, dose-escalation, safety and efficacy
evaluation of topically applied 0.1%, 0.5%, and 1.0% bexarotene gel concentrations.
Patients began receiving 0.1% bexarotene gel once daily (QD) initially and
escalated in dose every 2 weeks if tolerated to 0.1% twice daily (BID), 0.5%
QD, 0.5% BID, 1.0% QD, and 1.0% BID, with the option to increase applications
to up to 4 times a day (QID). After the safety and tolerability of 1.0% gel
was established in the first 49 study patients, a protocol amendment required
the remaining 18 patients to begin treatment at 1.0% gel every other day and
to escalate gel applications stepwise (QD, BID, 3 times daily, and QID) at
1- to 2-week intervals, as tolerated.
PATIENT POPULATION
Adults 18 years or older with early-stage (stages IA-IIA, according
to the TNM staging system) CTCL (MF) confirmed by histopathological analysis
and involving up to 50% body surface area were eligible for the study. (Patients
with Sézary syndrome, visceral involvement with CTCL, histologically
positive lymphadenopathy, or cutaneous tumors were excluded by the early-stage
designation.) Participants were to be free of other illness or infection,
to meet laboratory criteria, and to be adequately washed out of topical CTCL
therapies for 3 weeks and from systemic CTCL therapies for 4 weeks. Patients
were required to use contraception during the trial, and women could not be
pregnant or breastfeeding. All patients gave informed consent and met the
entry criteria for enrollment except for one, who obtained a waiver for study
entry with stage IIB disease. The patients' overall disease severity, extent
of disease, and global assessment of clinical condition compared with baseline
were evaluated every 2 or 4 weeks.
RESPONSE CRITERIA
Response was determined by using standard oncology criteria for a clinical
complete response (CCR) (100% clear, a complete cutaneous remission) and a
partial response (PR) (50% but <100% improvement). Response was scored
on the 7-point scale of the Physician's Global Assessment (PGA) of clinical
condition relative to baseline (Table 1). Clinical significance was defined as a 1-point or greater improvement
from baseline in overall severity of all lesions' signs and pruritus, which
were graded on 9-point scales (grades 0-8; none, mild, moderate, severe, and
very severe, with midpoints between each described grade). Because this was
a study of early-stage disease, it was expected that baseline overall disease
severity grades were likely to range from grades 2 to 5 (mild to moderate
severity). In addition, 3 individual index lesions, selected as being representative
of overall disease for each patient, were followed for signs of CTCL using
the same 9-point grading scales. The effects of treatment were assessed for
plaque elevation, erythema, scaling, and pruritus of lesions. If the patient
did not have sufficient disease for 3 index lesions, 2 index lesions were
followed (11 patients). Response evaluations were made at least every 4 weeks.
The protocol-defined evaluation lasted a minimum of 12 weeks, with provisions
for patients to continue treatment if they were benefiting from bexarotene
gel.
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Table 1. Criteria for Response From the Physician's Global Assessment
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Standard laboratory tests of blood (ie, chemistries, triglyceride levels,
complete blood cell counts, and differential white blood cell counts) and
urine (ie, urinalysis), physical examinations, and adverse event (AE) monitoring
were used to evaluate patient safety. Blood samples were obtained every 4
weeks to measure the systemic level of bexarotene. Adverse events were coded
to preferred terms using the Ligand Pharmaceuticals Inc–modified COSTART
5 (coding symbols for a thesaurus of adverse reaction terms) dictionary. For
example, investigators' verbatim AE terms "redness," "irritation," and "erythema"
were coded as "rash"; "burning," "stinging," "aches," and "lesion pain" were
coded as "pain"; and "itching" and "pruritus" were coded as "pruritus." Treatment-limiting
toxic effects were defined as grade 3 or 4 on a 4-point scale for cutaneous
irritation and as grade 3 or 4 on the National Cancer Institute common toxicity
table for systemic events.
RESULTS
BASELINE CHARACTERISTICS
At 3 study centers, 21, 33, and 13 patients were enrolled, for a total
of 67 patients. Participants included 37 men (55%) and 30 women (45%) with
a median age of 61 years (range, 30-87 years) and stages IA through IIA MF
(and 1 protocol deviation of stage IIB). Fifty-seven patients (85%) were white,
8 (12%) were black, and 2 (3%) were Hispanic. Patient demographics, disease
burden, and treatment histories were consistent across all 3 study centers.
At baseline, patients had a mean body surface area involved with disease of
11.7% (median, 5.0%; range, 0.1%-50.0%).
There were 41 patients (61%) with stage IA CTCL, 20 (30%) with stage
IB, 5 (8%) with stage IIA, and 1 with stage IIB who entered the study under
a protocol waiver. Fifty-five patients underwent 1 to 6 therapies before entering
this study. Most patients, 36 (54%) of 67, had 1 or more previous local therapies
for MF-type CTCL, including topical mechlorethamine (33 patients [49%]), topical
corticosteroids (30 patients [45%]), and other skin-directed therapies (PUVA,
UV-B, or electron-beam radiotherapy). Nineteen patients (28%) had received
systemic (eg, interferon, methotrexate, mechlorethamine, etretinate, isotretinoin,
corticosteroids, CHOP [cyclophosphamide, doxorubicin, vincristine sulfate,
prednisone], or CMED [cytoxin, methotrexate, etopiside, dexamethasone]) and
topical therapies, including combined modality therapies. Previous therapies
in these patients were often discontinued because of "stable disease," with
no further improvement or relapse after months of treatment. In addition,
there were 24 patients recorded as "refractory" to corticosteroids, 15 to
mechlorethamine, 14 to UV-B or PUVA, 4 to radiation, and 1 to carmustine and
8 as intolerant to mechlorethamine, 4 to UV-B or PUVA, 2 to carmustine, 2
to isotretinoin, 2 to methotrexate, and 2 to interferon. Twelve patients (18%)
entered the study having undergone no previous therapy for CTCL.
SAFETY AND TOLERANCE
Bexarotene gel was well tolerated over a median treatment duration of
315 days (10.5 months) and a maximum ongoing treatment duration of more than
59 months (4.9 years). Sixty-five patients (97%) in these studies had at least
1 AE, and 58 (87%) had a local AE (eg, erythema or irritation) assessed as
at least possibly related to treatment (Table 2). Most AEs were mild to moderate and were confined to the
cutaneous treatment area. Adverse events at least possibly related to bexarotene
use experienced by 5% (3/67) or more of patients were rash, pruritus, pain,
vesiculobullous rash, and headache. Adverse events coded as rash could be
confused with the signs of CTCL, but the onset of rash after 2 to 6 weeks
suggests that investigators could generally distinguish between retinoid irritation
and signs of CTCL. For 43 patients who had an initial AE of rash (eg, erythema
or irritation) within 100 days of baseline, the median time to onset was 45
days of treatment (range, 8-99 days). Ten other patients had an initial AE
of rash beginning 120 to 491 days after onset of treatment. Adverse events
coded as rash often continued intermittently or continuously for most of the
duration of treatment. Rash was typically a mild, tolerable AE, and 25 patients
had it recorded for 100 days or more and a few for as long as 600 days.
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Table 2. Drug-Related Adverse Events (AEs) Occurring With 5% Incidence
in 67 Patients With Cutaneous T-Cell Lymphoma
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Laboratory abnormalities not necessarily related to gel application
with an incidence of 5% or greater were observed for glucose levels above
or below the reference range in 25 patients (37%), phosphorus levels below
normal in 21 (31%), lymphocyte counts below normal in 14 (21%), creatine kinase
levels above normal in 7 (11%), bilirubin levels above normal in 4 (6%), and
triglyceride concentrations above normal in 3 (5%). Adverse events, detected
from abnormal laboratory findings, were recorded for abnormal liver function
in 4 patients (6%) and for 1 patient (1%) each for polycythemia, hyperglycemia,
albuminuria, and increased creatinine phosphokinase, alkaline phosphatase,
aspartate aminotransferase (AST), and alanine aminotransferase levels (ALT).
Treatment-limiting toxic effects occurred in 16 patients (Table 3). The incidence of application site treatment-limiting toxic
effects increased with the concentration of gel being used. With the exception
of 1 patient with trigeminal neuralgia, these were all application site events
associated with dermal irritation (eg, pain, edema, or rash). The neuralgia
of undetermined origin in 1 patient at week 18 of treatment was recorded as
a possible treatment-limiting toxic effect before the patient was withdrawn.
Serious AEs were reported for 8 patients during the study, but none of these
was classified as related to treatment by the investigator or the sponsor.
Serious AEs included infections, cardiovascular events, and skin cancers,
which are not uncommon for the age and previous treatments of the study population.
No deaths were reported during treatment or within 30 days thereafter.
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Table 3. Treatment-Limiting Toxic Effects (TLTs) by Dose Regimen in
16 Patients With Cutaneous T-Cell Lymphoma*
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Four patients withdrew from the study because of an AE at least possibly
related to treatment. Three of these withdrawals were due to cutaneous conditions
associated with treated areas (rash, pruritus, or skin necrosis [leukocytoclastic
vasculitis]), and 1 was the patient with trigeminal neuralgia. The withdrawal
because of rash occurred at week 20 with 1.0% gel BID in a 72-year-old woman
with a CCR. Pruritus caused withdrawal at week 20 of a 57-year-old woman with
a PR who was using 0.5% gel QD. Withdrawal because of leukoblastic vasculitis
occurred at week 10 in a 63-year-old woman who had a PR and was applying 1%
gel QD.
EFFICACY RESULTS
Bexarotene gel produced 50% improvement or more (CCR and PR) in 42 treated
patients (63%) based on the PGA of cutaneous disease as the primary end point
(Table 4). The 95% confidence
interval using the exact method was 50% to 74%. The CCR rate was 21% (14/67)
based on patients who fully cleared of cutaneous disease for at least 4 weeks
during treatment. An additional 28 patients (42%) had a PR. Of the remaining
patients, 14 (21%) had stable disease and only 11 (16%) developed progressive
disease during treatment.
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Table 4. Response to Bexarotene Gel Treatment According to the Physician's
Global Assessment
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A few patients had no previous CTCL therapy and achieved a PGA response
rate of 75% (9/12), which was higher than the 67% (24/36) rate for patients
who had previously received topical or radiation therapies only and the 47%
(9/19) response rate for patients who had previous topical or radiation therapies
and systemic therapies (Table 5).
Patients who were naive to CTCL therapies had the greatest response rate to
bexarotene gel. However, 33 of 42 responding patients (10 of whom had a CCR)
underwent previous therapies. Of these 33 responding patients, 22 were refractory
or intolerant to 1 (11 patients), 2 (7 patients), or at least 3 (4 patients)
previous therapies, including the systemic treatments 13-cis-retinoic acid (2 patients) and methotrexate (1 patient) and the
skin-directed therapies corticosteroids (12 patients), mechlorethamine (13
patients), UV-B (3 patients), PUVA (4 patients), radiation (2 patients), and
carmustine (1 patient).
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Table 5. Previous Therapy and Response Rate in 67 Patients With Cutaneous
T-Cell Lymphoma*
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Evaluation of overall severity of disease, which graded the severity
of cutaneous signs of disease and area of involvement of CTCL, was a secondary
end point. By overall severity, the response rate was 51% (34/67), as assessed
by a 1-grade or more improvement on or before 16 weeks of treatment relative
to baseline. At baseline, there was a median grade in overall severity of
1.67 (range, 0.33-4.33) for all signs and symptoms, so a 1-grade improvement
was substantial (50% on average). The 95% confidence interval for this
response using the exact method was 38% to 63%. The response rate by overall
severity was more stringent because it was restricted to the initial 16 weeks
of therapy and the PGA response end point could occur anytime during treatment.
However, the confidence intervals of the 2 end points for response were similar.
Figure 1 shows a PR to treatment
with bexarotene gel at week 4 of therapy for a 50-year-old woman with stage
IB CTCL. Her right shoulder is shown at baseline (day 1, before treatment)
(Figure 1A) and at week 4 (Figure 1B). She achieved a PR at week 6 and
relapsed at week 69.
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Figure 1. Right shoulder lesion on a 50-year-old
woman with stage IB cutaneous T-cell lymphoma (25% body surface area) for
more than 5 years. A, Baseline (day 1, before treatment). B, Partial response
at week 4 of treatment with bexarotene.
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The Kaplan-Meier projected time to onset of response (50% improvement)
for all patients was a median of 20.1 weeks (range, 4.0-86.0 weeks). Of the
42 responding patients, 17 (40%) relapsed from CCR or PR to a lower response
criteria (stable or progressive disease) during treatment, but 13 (31%) responded
again with continued gel treatment. Using Kaplan-Meier analysis, the projected
median duration of response by PGA criteria from the start of gel therapy
to the time of relapse was 99 weeks (range, 12-99 weeks), and the median durability
of response from onset of response to time of relapse was 61.1 weeks.
Eleven of the 42 patients who achieved a confirmed response reverted
to stable disease on treatment, but 7 of these 11 patients again had a PR,
and 2 had a CCR. All 11 of these patients were being treated for longer than
8 months at relapse, with a median treatment duration of 73 weeks (range,
34-172 weeks). Only 4 patients terminated treatment with confirmed stable
disease after a PR. For 14 patients who achieved a CCR, the median duration
of remission was 8 weeks (range, 3-62 weeks). Six patients responded to bexarotene
gel with a confirmed CCR more than once, with periods of PR only (4 patients)
or stable disease and PR (2 patients) between CCR remissions. Six patients
remained in CCR at termination of treatment. After treatment was discontinued,
data on relapse from response criteria were not collected.
The cutaneous signs of erythema, scaling, and plaque elevation were
typically mild to moderate at baseline. They were evaluated on 3 index lesions
for 56 patients and on 2 index lesions for 11 patients who had limited disease.
On a scale from 0 to 8 (none, mild, moderate, severe, and very severe, with
midpoints between defined grades), mean grades at baseline were 1.7 for scaling
(range, 0-6.3), 2.8 for erythema (range, 0-5.3), 1.1 for plaque elevation
(range, 0-5.7), and 1.1 for pruritus (range, 0-6.3). Sixty-five patients had
signs present at baseline for erythema, 57 for scaling, 42 for plaque elevation,
and 25 for pruritus. Clinical improvement was observed in each of these signs
and symptoms for the index lesions selected on each patient at baseline. Improvement
was rapid for plaque elevation and scaling during the first 8 weeks of treatment
but was more gradual for erythema and pruritus (Figure 2). The mean grade of all patients' index lesions at week
8 as a percentage of the baseline grade was 43% for scaling (change in mean
from grade 1.7 to grade 0.73; P<.001), 30% for
plaque elevation (grade 1.1 to grade 0.34; P<.001),
79% for erythema (grade 2.8 to grade 2.21; P = .004),
and 63% for pruritus (grade 1.1 to grade 0.69; P
= .12).
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Figure 2. Change in the mean of grades of
index lesions for signs and pruritus of cutaneous T-cell lymphoma. P<.05 for scaling, erythema, and plaque elevation at weeks 8, 24,
and 32 and for pruritus at week 32.
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Forty-nine study patients were enrolled on the initial dose escalation
regimen from 0.1% QD to 1.0% QID. For the last 18 patients, a protocol amendment
changed the treatment regimen to escalate stepwise from an initial dose of
1.0% every other day to 1.0% QID. On the initial dose escalation regimen,
most patients (37 of 49) reached and tolerated treatment with the 1.0% gel
concentration for at least 4 weeks, with minor adjustments for irritation.
Three patients did not tolerate 1.0% gel for 4 weeks and were reduced in dose,
and 9 patients were never treated with the 1.0% gel and remained at 0.5% (n
= 5) or 0.1% (n = 4). Five of these 9 patients were studied for 20 weeks or
less. Median treatment duration with bexarotene gel was 10.5 months. Thirty-five
patients remained in the study with only bexarotene gel therapy for more than
1 year, 20 remained for more than 2 years, 10 remained for more than 3 years,
and 3 have been studied for more than 4 years. Some patients continued therapy
with commercial bexarotene gel, and several of these have been treated for
5 years.
Patients responded at all concentrations of bexarotene gel, and the
response rate increased in relation to the concentration and frequency of
the dose regimen administered before response (Table 6). Eighteen patients did not have the opportunity to respond
at the 0.01% or 0.5% gel exposures because a protocol amendment restricted
them to 1.0% gel. For 22 (52%) of 42 responding patients, the initial response
was confirmed after beginning 1.0% gel treatment, in contrast to 13 patients
(31%) who responded to 0.5% gel and 7 (17%) to 0.1% gel. Three responses at
0.1% bexarotene gel occurred at weeks 33, 33, and 86 of treatment, later than
observed for the higher gel concentrations of bexarotene gel. The 4 other
patients responded at 0.1% gel during the biweekly dose escalation scheme
of the protocol. Patients who eventually attained CCR were applying 1.0% gel
BID at or just before total clearing except for 1 patient using 0.5% BID and
1 patient using 0.1% QD. These data suggest a correlation of response with
the intensity of bexarotene gel exposure.
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Table 6. Dose Regimen of Bexarotene Gel at Onset of Response*
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Plasma levels of bexarotene were evaluated from 66 patients every 2
to 4 weeks. Forty-two (64%) of 66 patients had at least 1 blood sample quantifiable
for bexarotene (1 ng/mL limit of detection). Despite long-term study treatment,
bexarotene was quantifiable in only 169 (21%) of 807 postdose samples. It
was present at low serum levels (<5 ng/mL) in 129 (16%) of samples (quantifiable
serum concentrations ranged from 1-28 ng/mL). Only 3 samples were found to
have a bexarotene concentration greater than 20 ng/mL. Bexarotene was not
detected in 638 (79%) of postdose samples. The level of systemic exposure
detected in plasma seemed to be associated with the body surface area treated
with bexarotene gel. This is consistent with its short plasma half-life (2-7
hours) as determined by orally administered bexarotene capsules.15
COMMENT
This phase 1 and 2 trial demonstrated the clinical benefit of using
bexarotene gel in patients with early-stage MF-type CTCL. Bexarotene is a
novel retinoid X receptor–selective ligand whose exact mechanism of
action in CTCL is not yet defined. It may have a direct effect on transformed
T cells of CTCL, or it may work indirectly, such as through cytokine modulation
or receptor induction in the CTCL skin lesions.16
Pivotal studies with oral bexarotene capsules in patients with CTCL at an
initial dose of 300 mg/m2 per day had a response rate of 54% in
early-stage disease and of 45% in advanced disease.17-18
When applied topically, bexarotene gel may lead to a local concentration of
drug in cutaneous lesions higher than that induced by oral administration
and with negligible systemic exposure for patients with early-stage disease.
A placebo control group was not part of this phase 1 and 2 study. The
spontaneous remission rate is assumed to be low (<10%), especially considering
the number of patients who had failed previous therapies. Spontaneous remission
rates for CTCL or placebo-controlled trials from which they could be projected
have not been published, to our knowledge. However, the safety of bexarotene
gel and its potential therapeutic utility in CTCL were demonstrated in this
study. Of 14 patients (21%) who achieved a CCR (100% clear) in this trial,
10 underwent previous therapies for CTCL that were unsatisfactory because
of incomplete response, intolerance, or relapse. By the overall disease severity
end point, 51% of patients responded within 16 weeks of beginning treatment;
by the PGA, 63% of patients responded at any time during treatment. These
response rates suggest that bexarotene gel can be considered a therapeutic
alternative in early-stage disease and can also be used as adjunctive therapy
in recalcitrant or relapsed lesions.
Bexarotene gel had a generally tolerable safety profile. Adverse effects
from using bexarotene gel were generally restricted to the site of application.
Adverse events deemed at least possibly related to therapy were rash or irritation,
pruritus, pain, and headache. These events were temporary and easily managed.
Some patients developed an asymptomatic "retinoid erythema" in treated areas
that was coded to rash. For significant irritation, a decrease in application
frequency or a temporary suspension of treatment was instituted. Treatment-limiting
toxic effects were generally related to the dose regimen of the gel and manifested
as cutaneous irritation. In practice, these events were self-limiting in severity,
as patients tended to limit their exposure to the application frequency that
was within tolerance. Application frequency alone was used for dose adjustments
in patients whose treatment was limited to 1.0% gel. Eleven patients with
20% to 50% body involvement responded to treatment, demonstrating that irritation
on skin lesions can be safely managed for patients with large areas of MF.
Only 2 patients withdrew from the study because of cutaneous irritation related
to treatment; 2 others withdrew because of leukocytoclastic vasculitis and
trigeminal neuralgia.
The PGA used as the primary end point in this study was supported by
the overall severity of disease score, and both 95% confidence intervals were
similar. The overall severity was a grade for signs of disease from all treated
lesions (both index and nonindex). The overall severity end point produced
a 51% response rate at 16 weeks of therapy (a protocol measure of clinical
significance) compared with a response rate of 39% by PGA at 16 weeks that
increased to 63% with longer treatment. The PGA is a reliable end point that
has also been used in trials of other dermatological disorders, such as psoriasis
and atopic dermatitis, which also have clinical presentations that are difficult
to quantitate.19-20
The improvement in patients from the start of therapy to the time of
response can be seen in the decrease in the mean grades for the individual
signs of disease over time, including erythema, scaling, and plaque elevation.
Scaling and plaque elevation were much improved by 8 weeks in most patients.
The erythema grade did not decrease as much or as rapidly as the other signs,
at least partly because bexarotene commonly induced a retinoid erythema at
the site of application, which could be difficult to differentiate during
therapy from erythema due to the disease. Responses were generally stable
during treatment. Only 4 of the 28 patients who achieved a PR left the study
with a confirmed relapse to stable disease. Five other patients who relapsed
from PR responded again with continued treatment. The treated lesions were
well controlled by bexarotene gel, and relapse with subsequent responses were
sometimes due to new lesions in areas not being treated with gel. The subset
of patients who relapsed from response was treated for 34 to 172 weeks (0.65-3.0
years).
The complete skin remissions (CCRs) that occurred in 14 patients lasted
up to 77 weeks (median, 11 weeks) from the start of remission to the time
of relapse. In 5 of these patients, a CCR was achieved several times during
treatment. This reflected the systemic nature of CTCL and the formation of
new skin lesions. When patients who achieved a CCR relapsed, it was primarily
to a PR relative to baseline, and none left the study without being in response
(50% improvement compared with baseline). These data indicate that continued
treatment with bexarotene gel may be warranted for patients who develop a
few new lesions or who have a temporary decrease in response, as patients
are likely to achieve their previous maximum response again. Bexarotene gel
can be considered for control of limited cutaneous CTCL patches or plaques
for extended periods. Fifteen patients up to 86 years of age had longer response
durations than the study-determined median of 99 weeks and had been treated
with bexarotene gel for 2 to more than 4 years.
Patients responded to bexarotene gel whether or not they had previous
therapies for CTCL and even if they were resistant to previously used topical
or systemic agents. Twelve patients (18%) had bexarotene gel as the first
CTCL therapy, and 4 of these achieved a CCR. Another 5 of these treatment-naive
patients had a PR, for an overall response rate of 75% (9/12). This rate was
higher than for patients who had previous topical therapies (67%) and for
patients with previous topical and systemic therapies (47%). Additional study
may demonstrate that bexarotene gel is effective as an initial therapy for
CTCL and is useful in patients who have failed standard skin-directed therapies.
For patients who had experienced resistance or intolerance to previous topical
and systemic therapies, 47% responded to bexarotene gel.
Skin-directed therapies such as UV-B phototherapy, PUVA, electron-beam
irradiation, topical mechlorethamine, topical corticosteroids, and topical
carmustine have documented efficacy in early-stage CTCL. These may be delivered
to whole skin, but it is not uncommon in early-stage CTCL to apply topical
therapies such as BCNU, mechlorethamine ointment, or corticosteroids as lesion-directed
therapy. Lesion-directed therapy may be used in patients with stage IA disease
who are not progressing or to minimize treatment toxic effects in patients
who have an increased risk of secondary skin cancers from multiple treatments
or who have considerable photodamage. Topical corticosteroids are used for
lesion-directed therapy and are often the initial treatment for CTCL. Topical
corticosteroids may initially work well but in many patients lose efficacy
after months or years of therapy, and an alternative treatment is needed.
Bexarotene gel was tested as a lesion-directed therapy and may serve as an
alternative to other lesion-directed therapies.
There are several early-stage CTCL therapies with established therapeutic
profiles. Up to 83% of patients with stage I limited patch disease responded
to UV-B, with a response duration up to 22 months.10
Psoralen–UV-A has a response rate of 60% to 90% in early-stage CTCL
for 20 months or more, and topical mechlorethamine used on the whole body
has a rate of 50% to 80% with a median duration of response of 8 to 12 months
or more.21-24
Total skin electron-beam irradiation had a response rate of more than 80%
and in stage IA is believed to produce occasional cures.25
Despite these response rates, there are limitations for all therapies for
CTCL due to patient treatment histories, disabilities, and age. For such reasons,
patients need a variety of alternative treatments used in sequence or in combination
for particular situations. Patients in the present study had discontinued
previous therapies for lack of response or intolerance to topical corticosteroids,
topical mechlorethamine, topical carmustine, PUVA, UV-B, and electron beam
but then responded to bexarotene gel, suggesting that the gel can also serve
as an important treatment option.
The risk-benefit profile of bexarotene gel seems to support this agent
as a therapeutic alternative given the chronic nature of CTCL and the limitations
of all therapies in early-stage disease. The main adverse effect of topical
bexarotene, local redness and irritation, is self-limiting and easily managed
by brief suspensions from treatment, decreases in application frequency, or
concomitant use of moisturizers. The level of systemic exposure from topical
bexarotene gel is low,15 and no significant
sensitization potential has been identified. As a retinoid gel, pregnant women
should not use it. Women of childbearing potential must use reliable contraceptives
with bexarotene therapy. Bexarotene gel is approved by the Food and Drug Administration
for the topical treatment of cutaneous lesions in patients with CTCL (stages
IA and IB) who have refractory or persistent disease after other therapies
or who have not tolerated other therapies.
AUTHOR INFORMATION
Accepted for publication July 24, 2001.
Corresponding author: Victor J. Stevens, MD, Ligand Pharmaceuticals
Inc, 10275 Science Center Dr, San Diego, CA 92121.
Reprints: Debra Breneman,
PhD, University Dermatology Consultants Inc, 222 Piedmont St, Suite 5300,
Cincinnati, OH 45219.
From the Department of Dermatology, University of Cincinnati, Cincinnati,
Ohio (Dr Breneman); the Department of Dermatology, The University of Texas
and M. D. Anderson Cancer Center, Houston (Dr Duvic); the Department of Oncology,
Northwestern University, Chicago, Ill (Dr Kuzel); and Ligand Pharmaceuticals
Inc, San Diego, Calif (Drs Yocum, Truglia, and Stevens). Drs Breneman, Duvic,
and Kuzel have received financial support from Ligand Pharmaceuticals Inc
for conducting clinical trials studying bexarotene and occasionally have received
honoraria from Ligand Pharmaceuticals Inc for speaking at medical meetings.
This study was sponsored and supported by clinical research contracts from
Ligand Pharmaceuticals Inc.
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