Trial Information

Phase I/II Study of Oral Bexarotene in Combination With Photopheresis for Treatment of Cutaneous T-Cell Lymphoma

Photopheresis is FDA-approved as a device in the treatment of patients with cutaneous T-cell
lymphoma. Using treatment schedules of once monthly treatment, with each treatment
consisting of two consecutive days of photopheresis, initial response rates of 20-60% have
been reported. However, in publications, for those who attained a complete response, median
time to response was 11 months (range 5 to 14 months). Response has been shown to correlate
with intact immune function in patients with normal CD8+ cell prior to therapy. The
mechanism of activity of photopheresis in cutaneous T-cell lymphoma while not fully
understood involves apoptosis of malignant tumor cells. Modifications in the original
scheduling of photopheresis, with shorter cycles of 2 or 3 weeks, have met with success.
Several centers have been using an accelerated delivery schedule of treatments, treating
patients every 2 weeks.

Bexarotene was FDA approved for patients with CTCL. It is an RXR selective retinoid.
Retinoids can serve as physiologic rather than cytotoxic drugs to arrest or reverse the
process of carcinogenesis. There is a growing body of evidence that supports a role for
retinoids in the induction of apoptosis. In the two, completed Phase II-III studies that
formed the basis of approval (approved dose is 300mg/m2/day) of bexarotene capsules, 193
patients with previously treated CTCL were administered bexarotene capsules. Response rates
were in the order of 50% for the 300mg/2/day, however, 79% of patients had hyperlipidemia.

This study will therefore primarily examine the safety and tolerability of using increasing
doses of bexarotene in combination with photopheresis. As a secondary endpoint, we will
attempt to establish whether bexarotene can upregulate the immune response and therefore
potentially enhance the response rates to photopheresis in patients with CTCL.

Six cohorts of patients will be treated:

Dose level cohorts enrollment will be sequential with centralized dose assignment at Boston
Medical Center

To establish safety, a 30 day pause will occur between cohorts. During the 30 day waiting
period, additional patients will be able to enter the open cohort, provided that there is no
grade 3 or 4 toxicity in the 3 patients already entered into the cohort. Once the 30 day
period has ended, new patients will be able to enter the next cohort.

Cohort 1 (3 patients): Bexarotene will be given at the dose of 75mg po per day with food for
7 days prior to beginning photopheresis(Day –6 to 0, day 1 being the day when photopheresis
begins on first day of cycle 1). Photopheresis will be performed on 2 consecutive days the
first 2 days of each 21 day cycle. Bexarotene will be given concurrently with photopheresis
for 4 cycles. The duration of the study is 3 months with premature discontinuation for
toxicity at the discretion of the investigator, or progressive disease.

Cohort 2 (3 patients): Bexarotene will be given at the dose of 150 mg po per day with food
for 7 days prior to beginning photopheresis (Day –6 to 0, day 1 being the day when
photopheresis begins on first day of cycle 1). Photopheresis will be performed on 2
consecutive days the first 2 days of each 21 day cycle. Bexarotene will be given
concurrently with photopheresis for 4 cycles. The duration of the study is 3 months with
premature discontinuation for toxicity at the discretion of the investigator, or progressive
disease.

Cohort 3 (3 patients): Bexarotene will be given at the dose of 225 mg po per day with food
for 7 days prior to beginning photopheresis (Day –6 to 0, day 1 being the day when
photopheresis begins on first day of cycle 1). Photopheresis will be performed on 2
consecutive days the first 2 days of each 21 day cycle. Bexarotene will be given
concurrently with photopheresis for 4 cycles. The duration of the study is 3 months with
premature discontinuation for toxicity at the discretion of the investigator, or progressive
disease.

Cohort 4 (3 patients): Bexarotene will be given at the dose of 300 mg po per day with food
for 7 days prior to beginning photopheresis (Day –6 to 0, day 1 being the day when
photopheresis begins on first day of cycle 1). Photopheresis will be performed on 2
consecutive days the first 2 days of each 21 day cycle. Bexarotene will be given
concurrently with photopheresis for 4 cycles. The duration of the study is 3 months with
premature discontinuation for toxicity at the discretion of the investigator, or progressive
disease.

Cohort 5 (3 patients): Bexarotene will be given at the dose of 375 mg po per day with food
for 7 days prior to beginning photopheresis (Day –6 to 0, day 1 being the day when
photopheresis begins on first day of cycle 1). Photopheresis will be performed on 2
consecutive days the first 2 days of each 21 day cycle. Bexarotene will be given
concurrently with photopheresis for 4 cycles. The duration of the study is 3 months with
premature discontinuation for toxicity at the discretion of the investigator, or progressive
disease.

Cohort 6 (3 patients): Bexarotene will be given at the dose of 450 mg po per day with food
for 7 days prior to beginning photopheresis (Day –6 to 0, day 1 being the day when
photopheresis begins on first day of cycle 1). Photopheresis will be performed on 2
consecutive days the first 2 days of each 21 day cycle. Bexarotene will be given
concurrently with photopheresis for 4 cycles. The duration of the study is 3 months with
premature discontinuation for toxicity at the discretion of the investigator, or progressive
disease.

Toxicity will be assessed using the National Cancer Institute common Toxicity Criteria at
the beginning of each 21 day cycle. Assessments will be every 3 weeks and at the final
follow-up visit.

All patients will undergo a skin biopsy from lesional skin prior to entry to confirm active
disease. A portion of the biopsy will be used for immunohistochemical studies to identify
populations of activated lymphocytes in the skin and to identify apoptotic markers (TUNNEL
METHOD). A skin biopsy will be subsequently obtained after 7 days of bexarotene, and at the
end of the study. A portion of each skin biopsy will be used for immunohistochemical studies
to identify populations of activated lymphocytes in the skin (TGF-B and Fas on malignant T
cells) and to identify apoptotic markers (TUNNEL method)

All patients will undergo baseline studies of immune function, including a FACS analysis of
circulating lymphocyte populations to identify activation antigens on T-lymphocytes, as well
as in vitro assays of T-cell function such as proliferation assays and cytokine production
by cultured T-cells. These studies will be repeated after the second and fourth. For these
assays, one green top tube will be drawn on day 1 before photopheresis and on day 2 at the
completion of therapy. One serum tube (one red top) will be drawn on days 1 and 2 and serum
will be stored at -20° until the assays are performed.

In summary, the following research skin biopsies and labs will be obtained:

Baseline (Day –6): one green top and one red top Baseline (Day –6): skin biopsy from
lesional skin

Day 1 of cycle 1: skin biopsy from lesional skin

Cycles 2 and 4: Day 1: one green top and one red top Day 2 one green top and one red top

End of cycle 4: skin biopsy from lesional skin

In addition to the following evaluations, the BASELINE visit will include a history with
patient demographic. At the baseline, tri-weekly, and final visits, the following
information will be collected:

- Patient weight.

- Serum chemistries, including LDH, LFTS, albumin, uric acid, Ca, Phos, Mg, Cholesterol,
Triglycerides, Thyroid function (T4, TSH)

- CBC differential, Sezary count if applicable

- ECOG score.

- Skin assessment (previously published weighted skin score) and a description of other
symptoms attributed to CTCL, and at the final visit, an overall assessment

- Names and doses of all concomitant medications

- Quality of Life assessment (Skindex-29 and FACT-G)

The investigator will also evaluate patient’s response by organ system involvement, with an
overall assessment, as follows:

- Complete Response (CR): Resolution of all manifestations of CTCL lasting one month.

- Partial Response (PR): A 50% improvement of the sum total of all disease (CTCL)
lasting one month.

- No Change (NC): Failure to meet criteria for either response or progressive disease.

- Progression: a 25% or more progression of existing disease or the appearance of any
new disease (disease worsening).

- Flare: After an initial response (either CR or PR), an increase in the manifestation
of CTCL requiring additional treatment.