title: Phase 2 and 3 clinical trial of oral bexarotene (Targretin capsules) for the treatment of refractory or persistent early-stage cutaneous T-cell lymphoma.
abstract: OBJECTIVE
  To determine the safety and efficacy of oral bexarotene (Targretin capsules; Ligand Pharmaceuticals Incorporated, San Diego, Calif).
  
  
  METHODS
  The effects of 2 randomized doses of 6.5 mg/m(2) per day (with crossover for progression) vs 650 mg/m(2) per day (later modified to 300 mg/m(2) per day) were evaluated in an open-label, multicenter, phase 2 and 3 study conducted between February 1997 and November 1998.
  
  
  METHODS
  Eighteen international cutaneous T-cell lymphoma clinics at academic referral centers.
  
  
  METHODS
  Fifty-eight patients with biopsy-proven stage IA through IIA cutaneous T-cell lymphoma that was refractory to (or patients were intolerant of) treatment or had reached at least a 6-month response plateau under at least 2 forms of prior therapy (median of 3.5 prior therapies).
  
  
  METHODS
  Bexarotene (Targretin capsules) administered once daily with meal for 16 weeks or longer.
  
  
  METHODS
  Primary end point classification of overall response rate of complete and partial remissions determined by either the Physician's Global Assessment of Clinical Condition or the objective Composite Assessment of Index Lesion Severity. Body surface area, time to response, duration of disease control, time to disease progression, individual index lesion signs and symptoms, and quality of life parameters were secondary outcomes.
  
  
  RESULTS
  Responses (> or = 50% improvement) were seen in 3 (20%) of 15 patients with an initial dose at 6.5 mg/m(2) per day (95% confidence interval [CI], 0%-40%), 15 (54%) of 28 patients at 300 mg/m(2) per day (95% CI, 35%-72%), and 10 (67%) of 15 patients at above 300 mg/m(2) per day (95% CI, 43%-91%). The rate of progressive disease was 47%, 21%, and 13% at the same dose levels, respectively. Eight (73%) of 11 patients crossing over from 6.5 mg/m(2) per day to higher doses subsequently responded. The median duration of response from start of therapy could not be estimated for the 15 patients at 300 mg/m(2) per day owing to low relapse rates in 2 patients (13%); at higher doses it was 516 days. The following drug-related adverse effects were reversible and treatable: hypertriglyceridemia (46 patients [79%]), hypercholesterolemia (28 patients [48%]), headache (27 patients [47%]), central hypothyroidism (23 patients [40%]), asthenia (21 patients [36%]), and leukopenia (16 patients [28%]). No cases of drug-related neutropenic fever, sepsis, or death occurred. Pancreatitis occurred in 3 patients with triglyceride levels higher than 14.69 mmol/L (1300 mg/dL), all of whom were taking 300 mg/m(2) or more of oral bexarotene per day.
  
  
  CONCLUSIONS
  Bexarotene (Targretin capsules) (the first retinoid X receptor-selective rexinoid) was well tolerated and effective as an oral treatment for 15 (54%) of 28 patients with refractory or persistent early-stage cutaneous T-cell lymphoma at doses of 300 mg/m(2) per day. Hypertriglyceridemia and hypothyroidism require monitoring but are reversible and manageable with concomitant medication.
authors.affiliation: M. D. Anderson Cancer Center, Houston, TX 77030, USA. mduvic@mail.mdanderson.org
authors.forename: M
authors.initials: M
authors.lastname: Duvic
authors.forename: A G
authors.initials: AG
authors.lastname: Martin
authors.forename: Y
authors.initials: Y
authors.lastname: Kim
authors.forename: E
authors.initials: E
authors.lastname: Olsen
authors.forename: G S
authors.initials: GS
authors.lastname: Wood
authors.forename: C A
authors.initials: CA
authors.lastname: Crowley
authors.forename: R C
authors.initials: RC
authors.lastname: Yocum
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D016588:Anticarcinogenic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077610:Bexarotene; D002214:Capsules; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D016399:Lymphoma, T-Cell / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011788:Quality of Life; D019233:Retreatment; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D016019:Survival Analysis; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D016588:Anticarcinogenic Agents; D002214:Capsules; D013764:Tetrahydronaphthalenes; D000077610:Bexarotene