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© 2001 American Society for Clinical Oncology Bexarotene Is Effective and Safe for Treatment of Refractory Advanced-Stage Cutaneous T-Cell Lymphoma: Multinational Phase II-III Trial ResultsFrom the M.D. Anderson Cancer Center, Houston, TX; New York University and Memorial Sloan-Kettering Cancer Center, New York, NY; Yale University, New Haven, CT; University of Cincinnati, Cincinnati, OH; Washington University, St. Louis, MO; and Ligand Pharmaceuticals Inc., San Diego, CA. Address reprint requests to Madeleine Duvic, MD, Chairman ad interim, Department of Dermatology, M.D. Anderson Cancer Center, Box 434, 1515 Holcombe Blvd, Houston, TX 77030; email: mduvic@ mdanderson.org.
PURPOSE: Cutaneous T-cell lymphomas (CTCL) are malignancies of T cells appearing as skin lesions and are responsive to retinoid therapy. Safety and efficacy of a novel RXR-selective retinoid (rexinoid) bexarotene (Targretin, LGD1069; Ligand Pharmaceuticals Inc, San Diego, CA) was evaluated as a single-agent oral therapy administered once daily in an open-label study in patients with refractory advanced-stage CTCL. PATIENTS AND METHODS: Ninety-four patients with biopsy-confirmed CTCL in advanced stages (IIB-IVB) were enrolled at 26 centers. Fifty-six patients received an initial dose of 300 mg/m2/d oral bexarotene and 38 started at more than 300 mg/m2/d. RESULTS: Clinical complete and partial responses were reported by Primary End point Classification for the study in 45% (25 of 56) of patients enrolled at 300 mg/m2/d dosing. At more than 300 mg/m2/d, 55% (21 of 38) of patients responded, including 13% (five of 38) clinical complete. For the 300 mg/m2/d initial dose group, the rate of relapse after response was 36% and the projected median duration of response was 299 days. Improvements were also seen in overall body-surface area involvement, median index lesion surface area, adenopathy, cutaneous tumors, pruritus, and CTCL-specific quality of life. The most frequent drug-related adverse events included hypertriglyceridemia (associated rarely with pancreatitis), hypercholesterolemia, hypothyroidism, and headache. CONCLUSION: Bexarotene is the first in a novel class of pharmacologic agents, the RXR-selective retinoids, or rexinoids. Bexarotene is orally administered, safe, and generally well tolerated with reversible side effects, and is effective for the treatment of advanced, refractory CTCL.
CUTANEOUS T-CELL lymphomas (CTCL) are a subset of generally indolent, extra-nodal non-Hodgkin’s T-cell lymphomas presenting with skin lesions. The incidence of extra-nodal non-Hodgkin’s lymphomas is increasing faster than any other cancer; however, the rapid rate of increase in CTCL seems to be leveling off to some degree, and patients may be living longer or be diagnosed earlier in their course of the disease.1 Immunohistophenotyping has expanded our understanding of subtypes of CTCL that include CD30+ anaplastic large cell lymphoma and lymphomatoid papulosis, indolent HTLV-1 associated T-cell lymphoma, and rare, nonepidermotrophic peripheral T- or T-like NK lymphomas presenting as subcutaneous, panniculitic, or angiocentric lesions.2,3 Mycosis fungoides (MF), the most common and the most indolent form of CTCL, is characterized by epidermotropism of helper/memory (CD4+CD45Ro+) T cells.4 MF usually evolves over many years from chronic eczematous or psoriasiform dermatitis before a defining and diagnostic biopsy is performed and the emergence of a recognizable T-cell clone. MF may be a skin-associated lymphoid tumor that, like mucosal-associated lymphoid tumor, arises through persistent antigen or superantigen stimulation by skin flora or other unidentified agents.5 The presence of a cytotoxic T-cell infiltrate may improve the prognosis in patch and plaque stage patients.6 MF can present with erythroderma or with de novo tumors. Large cell transformation occurring in patients within 2 years of diagnosis has a poor prognosis.7 Erythrodermic MF may present without large numbers of atypical cells or may be diagnosed as the leukemic form, Sézary syndrome (SS). An exact number of atypical cells and the method of detecting them to make a diagnosis of Sézary syndrome are controversial. More sensitive polymerase chain reaction and fluorescent-activated cell sorting techniques have shown that half of early-stage patients may have evidence for clonal T-cell expansion in peripheral blood, highlighting the systemic nature of this disease.8,9 Although the T-cell receptor rearrangements are conserved with progression of the disease from patch to tumor stage, the severity of patients’ lesions may reverse with treatment.10 The prognosis for CTCL patients depends on tumor (T) stage at presentation.11 It has recently been recognized that patients with stage IA (T1, patches and/or plaques involving less than 10% of their body-surface area [BSA], with no palpable adenopathy) have a median survival no different from aged-matched controls.12,13 Even patients who are stage IB (T2, patches and/or plaque involving at least 10% BSA, with no palpable adenopathy) to stage IIA (clinically abnormal lymph nodes) have a median survival of 67% or greater compared with matched controls at 10 years.12,13 In contrast, patients with intermediate disease including stage IIB (T3, cutaneous tumors) to stage III (T4, generalized erythroderma) have a 5-year median survival and in stages IVA-B (pathologically involved lymph nodes or visceral involvement) the median survival may be only 2.5 years.14 Although it is not known how choice of therapy impacts overall survival, use of early aggressive chemotherapy versus sequential conservative treatment did not show an overall survival benefit in the only randomized study of active therapies in this disease.15 Extracorporeal photopheresis has been reported to increase overall survival for advanced-stage patients and is thought to work through vaccination by tumor antigens.16 There is great interest in developing biologic response modifiers for CTCL to correct the profound immunodeficiency of late stages of disease and impact clonal T-cell proliferation.16-20 The most frequent cause of death in CTCL patients is infection. Oral agents avoid catheter placement through chronically infected skin and thus may reduce high rates of iatrogenic infection leading to death in these patients.21,22 Bexarotene is a rexinoid, the first RXR-selective retinoid agonist to be studied in humans, and was recently approved in the United States for the treatment of cutaneous manifestations of CTCL in patients who are refractory to at least one prior systemic therapy. The findings from this clinical trial support the conclusion that bexarotene is a safe and effective novel oral therapy for treating patients with refractory, advanced-stage CTCL.
Patients Eligible patients were at least 18 years of age with a diagnosis of stage IIB-IVB CTCL ( Table 1) that was confirmed by a biopsy within 30 days of entry. Patients with any one of the following conditions were not eligible: CNS involvement; serious infection or illness including human immunodeficiency virus infection; a history of pancreatitis; women who were pregnant, lactating, or unable/unwilling to use contraception; or a Karnofsky performance less than 60. Patients were required to be refractory to at least one systemic anticancer therapy for CTCL. Refractory was defined as resistance to therapy due to lack of response of at least 50% improvement or progression of disease while still on therapy after an initial response. Patients were required to have had no use of topical agents for CTCL or systemic antibiotics for 2 weeks or to be on a stable regimen for at least 2 weeks before study entry. Prior therapy for CTCL required wash-out periods of 2 weeks (topical therapy), 3 weeks (phototherapy), or 30 days (electron beam therapy, photopheresis, systemic anticancer therapy, systemic vitamin A more than 15,000 IU daily, or investigational therapy). Oral retinoids were not permitted within 3 months of study entry, and oral etretinate required a 1-year wash-out period. Informed consent was to be obtained from each patient after approval by the appropriate institutional review board or ethics committee.
Drug Administration Bexarotene (Targretin; LGD1069; 4-[1-{5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl} ethenyl] benzoic acid) is a rexinoid, a synthetic retinoid that selectively activates the RXR subfamily of receptors.23 Targretin capsules, manufactured by Ligand Pharmaceuticals Inc (San Diego, CA), were supplied as a 75-mg soft gelatin capsule for once-daily oral administration with the evening meal. Initially, the study was to enroll up to 72 patients in order to provide at least 60 assessable patients at a starting dose of 650 mg/m2/d. Because of dose-limiting toxicities (primarily hypertriglyceridemia) observed in the earliest patients enrolled, the starting dose was subsequently reduced by protocol amendment to 500 mg/m2/d and then to the final and optimal starting dose of 300 mg/m2/d. Dose modifications were allowed for individual patients, including dose reductions for toxicity and dose increases (to a maximum of 400 mg/m2/d) in the case of no response, loss of response, or progression on a reduced dose. Dose modifications were generally in increments of 100 mg/m2/d.
Tumor Response
The composite assessment (CA) ( Tables 3 and 4) evaluated up to five representative index lesions using a 0 to 8 point scale for each clinical sign (scaling, erythema, plaque elevation, hypo- or hyper-pigmentation) and measurements of area (converted to a scale of 0-18). The CA response, to which the investigator was blind, was then calculated as the ratio of summation (  ) of all clinical signs for these index lesions at each visit compared with baseline. CA also considered cutaneous tumors and all extra-cutaneous manifestations of disease (Table 2). Complete clinical response (CCR) required a CA ratio = 0 with no evidence of disease present over two visits. Partial response (PR) was defined as a CA ratio  0.5, with no new clinically abnormal lymph nodes, no progression of existing clinically abnormal lymph nodes (< 25%), no cutaneous tumors, and no new pathologically positive lymph node or visceral disease in an area previously documented to be negative. Progressive disease (PD) was defined as a  25% increase in the CA ratio, 25% increase in the number or area of clinically abnormal lymph nodes, new tumor, or new pathologically positive node or visceral disease. The development of any new or progressive adenopathy would thus override a response according to the CA ratio.
Complete responses (CR) by either end point required confirmation by biopsy. Patients who developed PD before a response were classified as PD, even in the event of later improvement. A patient was classified as a responder according to PEC if response criteria for either PGA or CA were satisfied, as long as the patient did not progress by either end point before the confirmation of response.
Other Assessments
Up to five designated index lesions, representative of the patient’s overall extent of disease, were selected at baseline and measured, graded, and photographed using a wide-angle standardized camera system. Photographs were repeated every 4 weeks. Tumors and nodes were recorded every 4 weeks. BSA involvement by patch, plaque, and tumor was assessed at each visit and was expressed as a percentage of the patient’s total BSA. Patches were defined as abnormal skin not elevated from normal skin. A plaque elevated Plasma samples were to be obtained to determine bexarotene levels before and after 2 and 4 weeks and every 4 weeks thereafter. Predose and multiple postdose plasma samples were obtained from two patients on day 1 and after repeated daily-dose administration (week 5-6) for determination of bexarotene pharmacokinetic parameters. The majority of the samples were assayed by a reverse-phase high-performance liquid chromatography (HPLC) method25 and the remainder by a gas chromatographic method.26 The lower limits of quantification were 3 and 1 ng/mL, respectively.
Statistical Methods Response duration was assessed in all patients who had PR or CCR. Time to response was determined from the first day of treatment to the time of onset of first confirmed response (CR, CCR, PR). Time to relapse was the time interval from onset of treatment to the time of relapse. Time to disease progression was the time interval from first day of treatment to the time of the first observation when the patient met criteria for PD. Time-to-event end points were estimated by Kaplan-Meier methodology.
The intent-to-treat analysis is based on all 94 of 102 patients screened for the study who received at least one dose of oral bexarotene. The study was conducted at 26 multinational study centers between November 8, 1996, and July 30, 1998. Fifty-six patients were treated at an initial dose of 300 mg/m2/d. Thirty-eight earlier enrolled patients were treated at initial doses of more than 300 mg/m2/d (ie, 500 or 650 mg/m2/d). As of the database cutoff date of November 20, 1998, 63 (67%) of patients had withdrawn from the study. Patient demographics at baseline ( Table 5) were characteristic of the known disease demographics. The median age was 64 years (range, 27 to 89). Patients enrolled by tumor-node-metastasis stages (Table 1) were classified as stage IIB (cutaneous tumors, 43%), stage III (generalized erythroderma, 31%), stage IVA (T1-4 with histologically confirmed lymph nodes, 16%), and stage IVB (T1-4, with known visceral involvement, 10%). One patient, a protocol deviation, was classified as stage IIA.
At the time of entry into the study, a median of 7.3 years (range, 0.8 to 31) had elapsed from the initial clinical manifestation of CTCL, 4 years (range, 0.5 to 28) from first clinical diagnosis of CTCL, and 3.4 years (range, 0 days to 28 years) from histopathological confirmation of CTCL. All but two patients (protocol deviations) had been refractory to at least one prior systemic therapy for CTCL. Patients had been exposed to a median of five prior therapies (range, one to 11). The median number of prior systemic therapies to which these patients were refractory was two (mean, 2.2; range, one to six). As listed in Table 5, 85% of patients had received at least one irradiation therapy (PUVA, electron beam, spot x-ray, or UVB), 79% had received one or more topical therapies, and 68% had received one or more therapies from each of the systemic, topical and irradiation categories. Sixty-five percent had received interferon, the most frequently administered prior systemic therapy. Clinically relevant adenopathy (defined as having a minimal diameter of at least 1 cm) was present in 40% (38 of 94) of all patients (median number of nodes was three; range, one to 13). Cutaneous tumors (defined as at least 1 x 1 cm surface diameters and 0.5 cm in height) were present at baseline in 35% (33 of 94) of enrolled subjects. Twenty-seven percent (25 of 94) of all enrolled patients were known to have Sézary cells in circulation at baseline but only 16% (15 of 94) of patients had at least 15% baseline circulating Sézary cells by history. Patch disease was defined as flat lesions, whereas plaques were elevated above normal skin. Median BSA involvement by patch was 17% (range, 0% to 100%, with 23% of patients having at least 81% BSA patch involvement), and the median BSA involvement by plaque was 8% (range, 0% to 100%, with 22% of patients having at least 30% BSA plaque involvement). The BSA involvement by CTCL lesions and also the baseline aggregate area of index lesions were more extensive in the patients who began therapy at 300 mg/m2/d than for patients enrolled at higher doses. The median BSA involvement by patch was 20% for the 300 mg/m2/d initial dose group compared with 12% for the more than 300 mg/m2/d dose group. The median BSA involvement by plaque was 9% for the 300 mg/m2/d dose group compared with 6% for the more than 300 mg/m2/d dose group. The median baseline aggregate index lesion area was 103.3 cm2 (range, 0 to 2,149 cm2) for the 300 mg/m2/d dose group compared with 80.6 cm2 (range, 1.4 to 602.7 cm2) for the more than 300 mg/m2/d dose group. Thirty-one percent of patients (29 of 94) had stage III (generalized erythrodermic CTCL).
Tumor Response
Responses in skin manifestations were observed for all tumor-node-metastasis stages of disease. At the initial dose level of 300 mg/m2/d, response by stage was 57% (13 of 23) for stage IIB, 32% (six of 19) for stage III disease, 44% (four of nine) for stage IVA disease, and 40% (two of five) for stage IVB disease. Responses were broadly distributed across the 26 enrolling study centers, with at least one response observed at each of eight centers enrolling more than two patients at 300 mg/m2/d and at 81% (13 of 16) of the centers enrolling more than one patient in this dose group. Primary end point responses were reinforced by positive findings in the secondary end points, including decreases in overall BSA involvement, decreases in index lesion aggregate area, improvement in cutaneous tumors and clinically abnormal lymph nodes, improvement in pruritus, and patient-assessed CTCL-specific QOL measures. In addition to the 45% (25 of 56) response rate for the primary efficacy end point PEC, 21% (12 of 56) of patients who did not meet criteria for response according to PEC benefited by a reduction in BSA involvement by CTCL in the 300 mg/m2/d initial dose group. For patients remaining on study, improvement in the total BSA involved by CTCL as well as conversion of plaque disease to patch was seen for both PEC responder and nonresponder patients combined ( Fig 1). The median index lesion aggregate surface area decreased during therapy in parallel with the decrease in overall BSA involvement, indicating that the designated index lesions were representative of patients’ overall cutaneous involvement. Pruritus decreased in index lesions regardless of patients’ use of concomitant antipruritic therapy, indicating that the improvement in pruritus could not be attributed to the use of concurrent antipruritic medications ( Fig 2).
Patients who developed new or worsened clinically apparent adenopathy were characterized as having progressive disease, although one could not determine reactive versus tumor infiltration without biopsies. Nodes could be transient and observed in the setting of substantial skin lesion improvement. In the group of PEC responding patients in the 300 mg/m2/d initial dose group, seven had clinically abnormal lymph nodes at baseline. Of these, four patients had an increase in either the number of clinically abnormal nodes or the aggregate area of the clinically abnormal nodes. Three patients had a reduction or complete resolution in the number and aggregate area of clinically abnormal lymph nodes. One of the responding patients who had no clinically abnormal lymph nodes at baseline had developed new clinically abnormal lymph nodes. Nine patients in the group of PEC responding patients in the 300 mg/m2/d initial dose group had one or more cutaneous tumors at baseline. Of these, four patients had improvement in the number and/or size of the tumors (total of four cutaneous tumors resolving completely), one had one stable tumor, three had an increase in the size of the tumors, and one developed one new cutaneous tumor. One patient with no cutaneous tumor at baseline developed one new tumor and was classified as progressive disease according to the CA end point. Post-baseline biopsies were not required in the study. However, biopsies were obtained in 15 patients, and were often done within 2 weeks of entry to confirm entry criteria rather than as an assessment of disease clearing. In patients who were in the initial dose group at the more than 300 mg/m2/d, four of 10 patients with postbaseline biopsies had evidence of histologic clearing of CTCL, including two patients with CCR and two with PR according to PEC. Figures 3 and 4 show the clinical and histologic appearance of a cutaneous tumor and histology (large cell transformation) that resolved in a patient whose ongoing duration of response was continuing for 3 years.
For the five patients with a prestudy and at least one postbaseline Sézary cell determination, the Sézary counts appeared to substantially improve for one patient, modestly improve for another, fluctuate with no clear trending for two patients, and show little change in the fifth patient. For three other patients who lacked a prestudy determination but had serial postbaseline determinations, the Sézary counts substantially improved for two and worsened in the third. For patients with stage III disease (generalized erythroderma) at baseline, the response rate according to PEC was 32% (six of 19) for patients at the 300 mg/m2/d initial dose group and 40% (four of 10 for the > 300 mg/m2/d initial dose group. For those patients who were known to have Sézary syndrome (either stage III disease or stage IV disease with at least 95% BSA involvement, plus at least 10% circulating Sézary cells), the response rate according to PEC was 24% (four of 17). Of the nine (10%) patients identified as stage IVB at baseline, four were staged as IVB on the basis of internal adenopathy; two on the basis of lung involvement; and one each on the basis of lung, bone marrow, and diffuse skeletal involvement. One patient had a positive lymph node biopsy. Forty-four percent (four of nine) of these patients met criteria for response according to PEC. Two patients with documented prestudy visceral disease on imaging evaluation (one lung and one liver) failed to meet response criteria. One of these patients had a follow-up imaging evaluation that showed a mixed response of the hepatic lesions. Six patients had both prestudy and postbaseline imaging evaluations, and none were positive for visceral disease. Other than the mixed response noted for the patient with liver involvement, no patient had documentation of new or progressive visceral disease, or documentation of improved/resolved visceral disease. Overall, these data are insufficient to draw any conclusions about efficacy with regard to visceral disease. Time to response was defined as the time interval from the first day of therapy to the first observation when the patient met criteria for CCR or PR according to PEC. Median time to response estimated by Kaplan-Meier analysis (Fig 5) was 180 days (range, 14 to 197) for patients entered at 300 mg/m2/d and 59 days (range, 22 to 169) for more than 300 mg/m2/d. The median time to relapse represents the time interval from start of therapy to the time of relapse, with all 46 PEC-responding patients included in the calculation. Nine of 25 responding patients (36%) on 300 mg/m2/d and 38% (eight of 21) of patients on higher-dose therapy had relapsed, for a projected median time to relapse of 299 days (range, 57 to 299) and 385 days (range, 94 to 456), respectively ( Fig 6). The rate of progressive disease according to PEC was 39% (22 of 56) and 32% (12 of 38) among patients entered at 300 mg/m2/d or higher doses, respectively ( Fig 7).
Thirty percent (28 of 94) of the patients enrolled in this study had been previously treated with one or more other orally administered retinoids, including three patients who had been treated previously with two different retinoids. The prior retinoid therapies consisted of isotretinoin (19 patients), etretinate (seven patients), acitretin (three patients), 13-cis-retinoic acid (one patient), and retinoid plus PUVA (one patient). Five of these patients (18%) had responded to the prior retinoid therapy, but four of these five responders were known to have relapsed while still receiving that therapy. Sixty-one percent (17 of 28) never achieved a response to prior retinoid, 18% (five of 28) were intolerant to the prior retinoid therapy, and the response for one patient was unknown. For this subset of 28 patients who had been treated previously with other oral retinoids, 54% (15 of 28) responded to oral bexarotene, including 14% with CCR and 39% with PR. Thus, prior retinoid therapy did not seem to influence the response to subsequent therapy with oral bexarotene. In summary, oral bexarotene produced durable responses with a low rate of relapse. A number of patients experienced breakthroughs in CTCL signs or symptoms when the doses were reduced due to toxicity. Titration of the dose was often effective to optimize therapeutic effect and safety in individual patients.
QOL Assessment Patients’ assessment of their change in CTCL compared with baseline was graded on a five-point scale of 1 (much worse) to 5 (much improved). For patients on 300 mg/m2/d or more than 300 mg/m2/d, 79% and 82%, respectively, rated themselves at least moderately or much improved by week 16. Level of satisfaction with the oral bexarotene therapy was similarly highly rated by patients in both dose groups, with 72% and 91% of patients, respectively, at least moderately or very satisfied. Importantly, the QOL assessments generally remained high for patients treated with oral bexarotene, regardless of whether they were judged as responders or nonresponders.
Pharmacokinetics
Single-dose and repeated daily-dose plasma concentration profiles were obtained from two patients at the optimal starting dose level of 300 mg/m2/d ( Fig 8). Mean single-dose and repeat-dose Cmax and AUC values were similar, suggesting there was no alteration of bexarotene pharmacokinetics with repeated dosing or accumulation with repeated daily dosing ( Table 8). After either single or repeated daily dosing, plasma elimination half-life values were 2 to 5 hours.
Safety All patients who received at least one dose of oral bexarotene were evaluated for safety. Fifty-six patients who started at 300 mg/m2/d were monitored for a median of 19.1 weeks (range, 2.1 to 48.4 ) and 38 patients starting at more than 300 mg/m2/d were monitored for a median of 34.3 weeks (range, 2.3 to 96.6). A total of 99% (93 of 94) of enrolled patients experienced at least one adverse event (AE) regardless of relatedness of AE to oral bexarotene. The severity of most AEs was mild to moderate, as listed in Table 9. The most common drug-related AEs (in COSTART 5 dictionary terms) reported in patients starting at 300 mg/m2/d and with incidence of more than 10% were hyperlipemia (primarily hypertriglyceridemia, 82%), hypercholesteremia (30%), hypothyroidism (29%), headache (20%), asthenia (16%), pruritus (13%), leukopenia (11%), skin disorder (11%), and rash (11%).
The frequency of AEs was generally related to the initial dose level, with the incidence of a drug-related serious AE (SAE) of 4% and 8% and the incidence of withdrawal from study for a primary reason of a drug-related AE of 7% and 13% for the 300 and more than 300 mg/m2/d initial dose groups, respectively. The most common SAEs, regardless of relatedness to oral bexarotene, were progression or worsening of CTCL (6%, or 6/94), pneumonia (5%), fever (4%), infection (3%), and pruritus (3%). No other SAE occurred in more than two patients. For those SAEs judged to be at least possibly related to oral bexarotene, there were a total of five SAEs among two patients in the 300 mg/m2/d initial dose group (hemorrhage, liver failure, coagulation disorder, bilirubinemia, and pruritus) and three SAEs among three patients in the more than 300 mg/m2/d initial dose group (fever, pancreatitis, and herpes zoster infection). Pancreatitis occurred in one patient (initial dose 650 mg/m2/d) in association with hypertriglyceridemia. This patient had additional pancreatitis risk factors consisting of pretreatment hyperlipidemia and concurrent administration of omeprazole and recovered fully from the pancreatitis. With regard to infections, there was one case of neutropenic fever, two of septicemia, two cases of herpes zoster, and five patients with pneumonia judged as SAEs, none of which were related to drugs except for one case of herpes zoster infection judged as possibly related. Filgrastim was administered concurrently to 9.6% (nine of 94) of patients. Therefore, leukopenia, which was mild and occurred at a relatively low incidence during treatment with oral bexarotene treatment, only occasionally required medical intervention with granulocyte colony stimulating factor support and was not associated with fever or septic sequelae. For patients in the optimal initial dose group of 300 mg/m2/d, severe AEs (in COSTART 5 dictionary terms) reported in more than one patient were limited to hyperlipemia (11%, or six of 56), pruritus (7.1%), rash (3.6%), and skin disorder (3.6%). Nine patients (10%) withdrew for a primary reason of an AE at least possibly related to oral bexarotene, including 7% of patients (four of 56) at the 300 mg/m2/d initial dose group and 13% (five of 38) at more than 300 mg/m2/d. The related AEs leading to withdrawal included four patients (4%) with hypertriglyceridemia. No other AE was reported for more than one patient as the primary reason for withdrawal. Overall, the most common reason for withdrawal was for progressive CTCL, in 51% (32 of 63) of patients withdrawn, or 34% (32 of 94) of all patients enrolled. Dose-limiting toxicities (DLTs) were experienced by 66% (62 of 94) of the enrolled patients, and the frequency of observing DLT was dependent on the initial dose level: 31 DLTs were reported for 50% (28 of 56) of patients in the 300 mg/m2/d initial dose group compared with 54 DLTs reported for 89% (34 of 38) of patients in the more than 300 mg/m2/d initial dose group. The most common DLTs were hypertriglyceridemia/hypercholesteremia in 43% (40 of 94) and neutropenia/leukopenia in 9% (eight of 94) of all enrolled patients, with no other DLT reported in more than three patients each. The incidence of DLTs with the higher doses resulted in adjustments to the starting dose level with a final optimal initial dose of 300 mg/m2/d. The laboratory abnormalities reflected the profile of reported AEs and DLTs. Sixty-four percent (60 of 94) and 51% (48 of 94) of patients had elevated triglyceride or cholesterol levels, respectively, that developed during the study or worsened compared with baseline. High triglyceride or cholesterol levels occurred within 2 to 4 weeks after initiation of therapy. At 12 to 16 weeks, 86% of patients had elevated triglyceride levels and the median values of cholesterol and triglycerides were 278 and 522 mg/dL, respectively. For those patients who had biochemical determination of thyroid function, TSH levels shifted to below normal levels for many of the patients in the 300 mg/m2/d and more than 300 mg/m2/d initial dose groups (54% [15 of 28] and 86% [six of seven], respectively) for the 2 to 4 week time period and (38% [six of 16] and 75% [six of eight], respectively) for the 12 to 16 week period. Changes in total thyroxine levels generally paralleled those of TSH. Shifts in hepatic function tests (ALT, AST, and LDH) occurred at both dose levels. A total of 21% (eight of 39) and 19% (five of 26) of patients beginning at doses of 300 and more than 300 mg/m2/d, respectively, with normal AST levels at baseline developed elevations of AST above normal within the first month of therapy. After bexarotene administration was found to be associated with cataract formation in animal studies, serial slit-lamp eye examinations were added to the study by protocol amendment. The background prevalence of lens opacities was high, with a baseline lens opacity in at least one eye detected in 60% (29 of 48) of patients examined before or on the first day of the study. No unexpected loss of visual acuity was observed, and only sporadic examples of the normal sequence of increasing lens opacity as expected in a population of similar age and lens status were reported. Observed changes in the lens were not in a location anatomically known to be generally associated with drug toxicity. Therefore, the observed changes in lens opacities could not be attributed to oral bexarotene. Seventeen deaths were reported among all 107 patients enrolled (including the 13 patients enrolled after the cutoff date for data analysis). Only one death was judged as possibly drug-related by the investigator, which was a patient who developed liver failure with coagulopathy, severe bleeding, and hemorrhage. This stage IV patient had multiple possible etiologies for liver failure (ie, underlying congestive heart failure/liver congestion, Staphylococcal bacteremia, post-transfusion reaction, acute hypoxic injury, and probable lymphoma infiltration on liver biopsy), the liver histology was not specific for drug toxicity, and the clinical picture was purely cholestatic without hepatocellular injury. All 16 patients for whom the last treatment date is known had had discontinuation of oral bexarotene before the date of death. Six of these deaths occurred within 1 month of treatment discontinuation, three deaths occurred between 1 month and 2 months after discontinuation, three deaths occurred between 2 and 3 months after discontinuation, two deaths occurred between 3 and 4 months after discontinuation, and three deaths occurred in the range of 4 to 4.5 months after discontinuation of oral bexarotene treatment. The incidence of death observed for patients in this study did not exceed the expected incidence for patients with advanced-stage CTCL, given their median duration of disease since diagnosis (7.3 years) and their expected median survival (5 years or less). Eight of the deaths were attributed to disease progression (the sole cause for seven patients and a contributing cause for another), five to infection, and one each to liver failure, hemorrhage secondary to liver biopsy, congestive heart failure, automobile accident, and an unknown cause. In summary, the deaths reported for patients in this study were not unusual for patients with advanced-stage CTCL, especially for patients who are refractory to one or more prior systemic anticancer therapies.
Bexarotene (Targretin capsules) is the first and only retinoid to be approved by the United States Food and Drug Administration for cutaneous T-cell lymphoma. Oral bexarotene provides a novel, convenient, noninvasive, and nonimmunosuppressive therapy for the treatment of all stages of CTCL in patients refractory to at least one systemic therapy. In the initial, dose-ranging phase I-II trial program in patients with various advanced cancers, two of nine patients with CTCL experienced major antitumor responses26 and stabilization of tumor progression was observed in patients with non–small-lung cancer and head and neck cancer.27 We report the results of a multinational phase II-III study showing that bexarotene was generally well tolerated, safe, and effective when used once daily in patients with advanced-stage (IIB to IVB) CTCL refractory to at least one (median of two) prior systemic anticancer therapy. Although this study was not powered to statistically confirm differences based on dose level, there are strong indications of a dose-response relationship, with overall (complete plus partial) response rates of 45% and 55% among patients starting at 300 mg/m2/d or higher doses, respectively. Similarly, the CCR rates were 2% and 13%, respectively, for these two initial dose groups. A dose relationship was also demonstrated by the differences in the rate of progression, time to onset of response, time to progression, and many adverse events seen at the 300 and more than 300 mg/m2/d initial dose groups. A possible dose effect was also seen in a parallel, phase II-III study of patients with refractory or persistent early-stage CTCL whose overall response rates were 20%, 54%, and 67% at starting doses of 6.5, 300, or more than 300 mg/m2/d, respectively.28 The starting dose of 300 mg/m2/d shows the best risk-benefit ratio. Some patients may require individually titrated dose adjustments up for inadequate efficacy or down for control of side effects. The response rate to oral bexarotene may be higher in a population of patients with classic MF than the response rate that was observed in this study. Not all CTCL patients in this study had classic MF and, of those who did, many had received a large number of previous therapies. The more rare forms of CTCL can be more difficult to classify and to treat effectively. Several patients had large cell lymphoma de novo or transformed MF that carries a poor prognosis;7 one had panniculitic NK/T-cell lymphoma. Of those with MF, nine had known visceral disease at baseline and 29 had either erythrodermic MF or Sézary syndrome. One patient with diffuse large cell lymphoma lesions had a mixed response, and one MF patient with large cell transformation in a tumor had a durable complete response. Of the subset of patients with erythrodermic MF or Sézary syndrome, oral bexarotene demonstrated benefit in reducing the skin erythema and scaling within 8 weeks and was associated with a temporary reduction in the population of CD4+CD7- cells in some patients. In this study, oral bexarotene was helpful in reducing the cutaneous manifestations of CTCL, even in some patients who had tumors with large cell transformation or exfoliative erythroderma refractory to photopheresis or other agents. A median overall response rate in the range of 50% is unexpectedly high, especially for a single-agent therapy, given the advanced disease stage and the refractory nature of the patients enrolled on this study. The patients enrolled in this study had a median duration of disease of 7.3 years, with an expected median survival of less than 2.5 to 5 years, depending on clinical stage.14 Response rates in the range of 50% to 60% have been reported for oral retinoids administered as single agents,29 but the previous studies of retinoids did not necessarily require biopsy confirmation, did not use the same rigid response criteria, and were not limited to refractory or previously treated patients.30-36 Bexarotene differs from previously used and other currently available retinoids; it is the first in a new subclass of retinoids, a rexinoid, that works through the selective binding and activation of the RXR receptors.37 More than half of the 28 patients in this study who had been previously treated with other, non-RXR-selective retinoids achieved a response on oral bexarotene, despite the fact that all but one or two of these patients had failed treatment with the prior retinoid. As a single agent, oral bexarotene has a high response rate and a time to relapse in responding patients that is quite long. In current clinical practice, retinoids are commonly used in combination with interferon, phototherapy, or radiation with excellent results.38-43 Oral bexarotene has not yet been studied in humans in combination with other agents for this indication. Recent studies have suggested that retinoids may induce interleukin-2 (IL-2) receptor expression on T cells.44 The high-affinity IL-2 receptor is the target molecule for ONTAK (denileukin diftitox, DAB389IL-2), a diphtheria-IL-2 fusion protein recently approved by the Food and Drug Administration for the treatment of patients with persistent or recurrent CTCL whose malignant cells express the CD25 component of the IL-2 receptor on the basis of efficacy in patients with tumors and advanced disease.45-47 Thus, there is great potential for using oral bexarotene in combination with other agents or as maintenance therapy after a response by electron beam or other therapy. Although there seemed to be a dose relationship with respect to efficacy, the higher doses were also associated with a higher rate of AEs and DLTs. The most common DLTs were hypertriglyceridemia and, to a much lesser extent, neutropenia. Elevations in the lipids occurred rapidly, often within 2 to 4 weeks, and were associated with one case of serious, but reversible, pancreatitis in this study. Protocol amendments instituting strict monitoring and management guidelines for lipids and the use of lipid-lowering agents such as atorvastatin (Lipitor) or fenofibrate (Tricor; Abbott Laboratories, Abbott Park, IL) were effective in controlling lipid levels and resulted in no further cases of pancreatitis being reported. Because bexarotene is metabolized by cytochrome P450 enzymes, the potential exists that it, like many other P450 substrates, could affect the metabolism of warfarin. In order to manage patients’ hyperlipidemia, one must obtain baseline fasting triglyceride levels and institute fenofibrate (preferably because cholesterol is not a problem) or atorvastatin to normalize elevated triglycerides before starting the medication. The antilipid therapy can be increased to the maximum doses as long at the triglyceride levels do not exceed 800 mg/dL. At that point, we recommend holding bexarotene until they fall and reinstituting therapy at a lower dose. It may be necessary to increase the antilipid therapy and find the dose of bexarotene that can control the patients’ disease. Correcting the hypothyroidism with hormone replacement will ease the hypertriglyceridemia by increasing lipid clearance and can result in stabilization of the levels. An alternate way of dosing bexarotene is to start with one or two capsules and titrate slowly upward while increasing the antilipid therapy as indicated. In this study we sometimes administered both atorvastatin and fenofibrate when necessary. However, combination therapy with an HMG-CoA reductase inhibitor agent (ie, a statin) and a fibrate warrants cautious monitoring and has the potential to induce myopathy and rhabdomyolysis with renal failure.48-52 Gemfibrozil (Lopid) administration with bexarotene was associated with higher plasma bexarotene and triglyceride levels, and was taken by several patients who subsequently developed pancreatitis. Gemfibrozil is not recommended for administration with oral bexarotene. Because bexarotene is metabolized by cytochrome P450 3A4, inhibitors of cytochrome P450 3A4 would be expected to lead to an increase in plasma bexarotene concentrations and inducers of cytochrome P450 3A4 may cause a reduction in plasma bexarotene concentrations. Bexarotene is a selective ligand and agonist for RXR receptors, which in turn form homodimers and heterodimers with retinoid acid receptors, RARs. RXRs also form heterodimers with many other nuclear receptors including vitamin D receptors, thyroid receptors, and peroxisome proliferator activator receptors.53 As previously reported, some patients with CTCL treated with oral bexarotene manifested central hypothyroidism with low TSH and free thyroxine levels within weeks of starting the medication.54 Symptoms of hypothyroidism may be subtle because they include fatigue/asthenia, depression, cold intolerance, and constipation and may be attributed to the underlying cancer. Supplementation with levothyroxine while patients were on oral bexarotene was found to alleviate the symptoms, improve tolerance to treatment, and make the lipid levels easier to stabilize. We always obtained baseline T4 and TSH levels and started replacement therapy at 0.05 mg daily initially, increasing the dose up to 0.1 to 0.2 mg to keep the T4 in the normal range (above 0.8). The TSH levels will remain sub-normal as long as the patient is treated but are reversible within 1 to 2 weeks of discontinuing oral bex- arotene therapy. Of interest, several patients who were insulin-dependent were able to reduce or stop insulin while taking oral bexarotene. Bexarotene has been found to improve insulin sensitivity through RXR-peroxisome proliferator activator receptors interactions in the db/db diabetic mouse model.55 There was a surprisingly low incidence of infections and sepsis seen in this study of advanced patients. When leukopenia occurred it was mainly due to decreases in polymorphonuclear lymphocytes. Granulocyte growth factor support was utilized in very few patients. Patients on oral bexarotene were treated as outpatients, with monthly monitoring visits, and generally tolerated this therapy with high levels of satisfaction. In the few cases where infections did occur, they could be attributed to the underlying disease and to prior immunosuppressive therapies, including fludarabine or chemotherapy. Herpes zoster appeared in two elderly patients within a month of starting oral bexarotene therapy but has been previously recognized in association with CTCL.56,57Overall, the number of patients requiring hospitalization for infection on this study was extremely low and points out the benefits of bexarotene as a nonimmunosuppressive therapy that does not require indwelling catheters for administration to patients with advanced disease. In conclusion, oral bexarotene is a safe, effective, and convenient novel therapy for all stages of advanced CTCL patients. The capsules are taken as a once-daily dose with meals. The time to response is generally within 2 months. The most common side effects, including hypertriglyceridemia and central hypothyroidism, are easily monitored by blood tests, treatable with concomitant oral medications, and promptly reversible on discontinuation of therapy. The lack of need for IV catheters, lack of immunosuppression, and low incidence of infection make oral bexarotene an attractive and convenient therapy for treating cutaneous lesions in patients with advanced disease.
APPENDIX
The investigators received research support for the conduct of the clinical trials. Part of the costs for histology and photographs were defrayed by National Institutes of Health grant nos. R21-CA74117 and CA16672. We gratefully acknowledge the help of the study site coordinators and fellows and the patients who volunteered to participate in this clinical trial. The efforts of the Ligand staff (Victor Stevens, Connie Crowley, and Carol Manifold) and PPD-Pharmaco monitors are also gratefully acknowledged. PK data were provided by G. Loewen, PhD, and A. Cato III, PhD, at Ligand.
Presented in part at the American Society of Hematology meeting in New Orleans, LA, December 5-9, 1999. C.C. and R.Y. are employees of Ligand Pharmaceuticals Inc.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
