Medical Summary
This is a multicenter, open label, Phase 2-3 study of patients with refractory or persistent early stage cutaneous T-cell lymphoma (CTCL) asssessing the tolerability, safety, and antitumor efficacy of two different dose levels of TARGRETIN capsules.

Retinoids play critical roles in normal development and physiology by modulating cell growth, reproduction, differentiation, and immune function. They are also capable of inducing differentiation, apoptosis (programmed cell death) and inhibiting cell growth in a variety of tumor cell lines. TARGRETIN drug substance (LGD1069) is a novel synthetic retinoid analogue. It is a subtype-specific ligand since it binds preferentially to the members of the RXR subclass of receptors. These receptors play a role in the regulation of cell division and differentiation via their ability to regulate transcription. There is clinical evidence of CTCL antitumor activity with both topical and systemic administration of TARGRETIN drug substance in Phase 1-2 studies.

Patients will be randomly assigned to a once daily dose of TARGRETIN capsules in one of two treatment groups (6.5 or 500 mg/m2/day) for a minimium of 16 weeks. The higher dose may be adjusted as necessitated by toxicity. The first dose was selected to approximate the dose level at which resposes were observed in the Phase 1 trials. The second dose was chosen to investigate the hypothesis that with a sufficient patient sample size , the response rate at this dose level would be the same or higher as the response rate at the lower dose level.

The primary efficacy endpoints for each of the two dose level groups are the tumor responses. Clinical and laboratory safety will be monitored. The most common side effects reported include headache, loss of strengh, dry skin and dry mouth. Laboratory abnormalities which were not present at baseline include elevated blood levels of cholesterol and triglycerides and decrease in white blood cells.

This trial is to be based at the Jewish General Hospital and will be coordinated through the Clinical Research Unit. It should also be noted that in addition to the pre-case funding, all pharmaceutical costs as well as compensation for radiologic tests required specifically for the protocol, will be provided .

References:

1. Sporn M, Roberts A.Role of retinoids in differentiation and carcinogenesis. J. Natl. Cancer Inst.73:1381-1387, 1984.
2. Miller V.A., Benedetti F.M., Rigas J.R., et al. Initial clinical trial of a selective retinoid X receptor (RXR) ligand, 3-methyl TTNEB (LGD 1069). Proc. Am. Soc. Clin. Oncol. 14:172,1995.

Lay Summary
This study is designed to examine the safety, tolerability and anti-tumor effect of Targretin capsules in the oral treatment of early stage cutaneous T-cell lymphoma. Retinoids, which are a class of drugs chemically related to Vin A , plays a critical role in normal cell development. Targretin has previously been shown to interfere with tumor cell growth and will be tested further here. Patients will take Targretin capsules once a day and on day 1 of treatment only, patients will be required to provide frequent blood samples throughout the day in order to measure the levels of the drug in their system. Patients will return to the clinic every 4 weeks for at least 16 weeks, and may continue to be treated as long as they are showing a response to the treatment.

1. A clinical Diagnosis of cutaneous t-cell lymphoma (CTCL, mycosis fungoides), stage IA, IB, or IIA and confirmed by a current biopsy (within 30 days prior to entry) to be histologically consistent with CTCL by a dermatopathologist, in whom systemic therapy indicated.
2. Refractory to, or a response plateau for at least six months on at leas two prior therapies from the following list: PUVA, UVB, EBT, photopheresis, interferon, systemic cytotoxic chemotherapy, topical nitrogen mustard or topical carmustine (BCNU). At least one of these treatments must have been topical nitrogen mustard, topical carmustine or a phototherapy (UVB, PUVA, or EBT). Topical steroids and systemic retinoids DO NOT qualify.
   (Refractory is lack of response of at least 50% improvement or progression of disease on therapy after an initial response. Intolerant is discontinuation of therapy due to side effects, whether or not a response occurred) .
3. Complete avoidance of systemic and dermatoiogically-applied antihistamine and antiprurtic agents for at least one (1) week, or, if such agents cannot be avoided, systemic and dermatologically-applied antihistamine and antipruritic agent must be administered using a stable dose regimen for at least one week prior to initiation of study drug treatment and throughout the study, unless a discontinuation or reduction in dose is indicated. .
4. A Karnofsky performance score >=60
5. Age >=18 years
6. Acceptable organ function defined as follows:
   Hemoglobin >=9 g/dL and WBC >=2000/mm³
   Bilirubin <1.5 times the upper limit of normal
   Creatinine <=2 times the upper limit of normal
   SGOT (AST) and SGPT (ALT) <=2.5 X the upper limit of normal
   Fasting serum triglyceride <=800 mg/dL
   
7. Must be free of serious concurrent illness.
8. Women of child-bearing potential must have negative serum pregnancy test (B-HCG) within seven (7) days prior to the initiation of treatment and must have used an effective means f contraception or must have been sexually abstinent for at least four (4) weeks prior to the negative pregnancy test through entry in the study.
9. Female patients and male patients with female partners of child bearing potential must agree to practice an effective methods of contraception during the entire period of treatment and for at least three (3) months after treatment ends. Male patients with female sexual partners who are pregnant or potentially pregnant must agree to use condoms during sexual intercourse during the entire period of treatment and for at least three (3) months after.
10. Must be willing and able to give informed consent.