Trial Information

A Phase II Clinical Trial of Lenalidomide for T-cell Non-Hodgkin's Lymphoma

Background: T-cell lymphomas comprise 10-15% of all non-Hodgkin's lymphomas and include a
variety of histological subtypes. These diseases have variable clinical behaviour, response
to therapy, and long-term outcomes. In general, T-cell lymphomas are characterized by
inferior response to therapy and prognosis compared to the more common B-cell lymphomas.
Because T-cell lymphomas are uncommon, they are not generally well studied and current
treatment approaches are borrowed from established protocols for B-cell lymphoma. New
therapies are needed for T-cell lymphoma, and should be studied separately for their
effectiveness in T-cell lymphoma.

Lenalidomide (CC-5013, Revlimid; Celgene Corporation) is an oral thalidomide analogue with
anti-cancer activity. Lenalidomide is generally well tolerated, with rash, myelosuppression
and venous thrombosis being the most notable and common potential side effects. Lenalidomide
has demonstrated impressive anti-cancer activity against mycosis fungoides (cutaneous T-cell
lymphoma), multiple myeloma, chronic lymphocytic leukemia and myelodysplasia. The drug is
currently under review by Health Canada as a potential new standard therapy for multiple
myeloma. We are encouraged by the efficacy and tolerability of lenalidomide in patients with
related diseases, to study its role in the treatment of T-cell lymphomas other than mycosis
fungoides.

Primary Objective: To determine the overall response rate to single agent lenalidomide at
standard doses (25 mg po daily for 21 days of a 28-day cycle), as a treatment for T-cell
lymphoma.

Secondary Objectives: To determine the complete response rate, time to progression, overall
survival and tolerability for patients with T-cell lymphoma treated with lenalidomide.

Study Design: A multi-centre, Canadian, Phase II, investigator-initiated clinical trial.

Inclusion Criteria:

" Patients with the following subtypes of T-cell lymphoma:

- Peripheral T-cell lymphoma, unspecified

- Angioimmunoblastic T-cell lymphoma

- Enteropathy-type T-cell lymphoma

- NK/T-cell lymphoma

- Hepatosplenic T-cell lymphoma

- Subcutaneous panniculitic-like T-cell lymphoma

- Anaplastic large cell lymphoma

- Lymphoblastic T-cell lymphoma " Measurable disease (See section 6.2) " WHO performance
status of 0-2 " Both untreated patients with contraindications to chemotherapy, and
patients with relapsed/refractory disease after at least one line of chemotherapy are
allowed; no restriction on the number of prior therapies " Patients with prior
radiotherapy, autologous or allogeneic stem cell transplant are allowed " Age >18
years, able to give informed consent " Acceptable hematological and biochemical
parameters (see section 6.2)

Exclusion Criteria:

" Mycosis Fungoides/Sezary Syndrome " Pregnant or lactating females " Concurrent use of
other anti-cancer therapies " Other serious co-morbid illness that would compromise
participation in the study " Prior therapy with lenalidomide " Prior hypersensitivity to
thalidomide

It is intended to enroll patients who have relapsed in spite of chemotherapy, radiotherapy
and/or high dose therapy with stem cell transplant, or patients who are not eligible for
these standard therapies. It would be encouraged that patients are initially treated with
standard therapy if possible. However, we wish to allow untreated patients to participate
because older, frail patients with disseminated T-cell lymphoma or patients with significant
comorbidities may not be eligible for aggressive chemotherapy but may tolerate lenalidomide
quite well. In this regard, it is left to the discretion of the investigator to determine
whether or not an individual patient should be considered for enrollment on this clinical
trial, or whether that patient would be better served with standard treatment approaches.

Recruitment will take place in the outpatient clinics of the Cross Cancer Institute and five
other Canadian cancer clinics (Vancouver, Calgary, Winnipeg, Ottawa, Halifax). The Cross
Cancer Institute will be the lead site for the trial and our team will be responsible for
oversight of the trial, collation of patient case report forms, communication with Health
Canada and Celgene, and data analysis. Celgene will monitor all the sites involved in the
trial every 3-4 months.

Statistical Analysis will use standard methods and will include a data safety and monitoring
committee (DSMB) who will perform interim safety analyses after ten and 22 patients have
been enrolled on trial. An interim efficacy analysis will be performed after 22 patients
have been enrolled. The trial will be stopped if fewer than 2 of the first 22 patients
enrolled achieve an objective response to therapy according to standard criteria. If two or
more responses occur, the trial will continue until the remaining 18 patients will be
accrued in the absence of safety concerns. There are no pre-specified criteria for stopping
the trial on the basis of safety concerns, but the investigators and the independent DSMB
will each have the power to halt enrollment if serious safety concerns arise at any point
during the trial. Patients will be required to stop the study treatment if severe adverse
reactions occur, the lymphoma progresses, serious intercurrent illness interferes with
treatment, suspected pregnancy occurs, or for major study protocol violations.

Sample size: For a total of 40 subjects, 22 will be accrued during stage 1 and 18 during
stage 2. If 1 or fewer responses are observed during the first stage then the trial is
stopped early. Given that the 'true' response probability is 5%, there is a 70% probability
of ending the trial during stage 1. However, if the 'true' response probability is 20% then
there is a 5% probability that the trial will be stopped in stage 1. The alpha level of the
design is 0.04 and the power is 0.9. If fewer than 4 of 40 patients respond, this will be
considered evidence that lenalidomide is inactive in the population studied.