Phase 3 Randomized, Double-Blind, Placebo Controlled, Multicenter Study to Compare the Efficacy and Safety of Lenalidomide (CC-5013) Plus R-CHOP Chemotherapy (R2-CHOP) Versus Placebo Plus R-CHOP Chemotherapy in Subjects With Previously Untreated Activated B-Cell Type Diffuse Large B-Cell Lymphoma

CHOP chemotherapy in combination with the anti-CD20 monoclonal antibody
rituximab on a 21-day schedule is a standard of care in newly diagnosed cases
in most countries worldwide. While approximately 50% to 60% of patients are
cured, for those patients who are refractory or who progress following R-CHOP,
treatment options are limited and outlook is poor; most die within the next two
years. Since roughly 40% to 50% of patients are not cured on initial therapy,
evaluating other front line treatment options is warranted. Other attempts to
improve cure rate, including R-ACVBD, CHOEP, dose dense regimens (R-CHOP14),
and high dose regimens (DA-EPOCH), have not replaced R-CHOP21 as a standard of
care.

The R2-CHOP efficacy data from previous studies compare favorably to historical
R-CHOP21 data with a better Complete Response (CR) rate at the end of induction
therapy and better Progression Free Survival (PFS). Furthermore, promising
efficacy results were also demonstrated in the non-GCB subtype, which generally
has a poorer outcome when treated with R-CHOP alone. Clinically meaningful
improvements as demonstrated by higher CR rate and longer PFS in non-GCB DLBCL
subjects are considered significant in this difficult to treat sub-population.
The addition of lenalidomide could ameliorate the poor prognosis effect of the
ABC phenotype and improve treatment outcome in this subgroup of subjects.
From a safety perspective, this combination is tolerable, without unexpected
toxicities. The Grade 3 and 4 toxicities are primarily hematological in nature,
and manageable with supportive care.

To evaluate the efficacy and safety of lenalidomide, rituximab,
cyclophosphamide, doxorubicin, vincristine, and prednisone (R2-CHOP)
chemotherapy versus placebo, rituximab, cyclophosphamide, doxorubicin,
vincristine, and prednisone (placebo-R-CHOP) chemotherapy in subjects who have
previously untreated ABC type DLBCL.

Primary Objective
The primary objective of the study is to compare the efficacy of R2-CHOP versus
placebo-RCHOP.

Secondary Objective
The secondary objective of this study is to compare the safety of R2-CHOP
versus placebo-RCHOP.

Exploratory Objectives
The exploratory objectives of this study are to compare the progression free
survival 2 and genetic mutations of subjects receiving R2-CHOP versus
placebo-R-CHOP; to explore minimal residual disease and clonal
heterogeneity/succession in subjects receiving R2-CHOP versus placebo R-CHOP
who achieve a CR; and to explore molecular markers related to lenalidomide
mechanism of action.

This randomized, placebo controlled study is designed to evaluate the efficacy
and safety of R2-CHOP chemotherapy versus placebo-R-CHOP chemotherapy in
previously untreated ABC type DLBCL. The study is divided into the Screening
Period, Treatment Period, and Follow-up Period. Approximately 560 subjects will
be randomized over approximately a 34-month accrual period.

The Screening Period for eligibility determination may begin after the subject
signs the informed consent form. During the Screening Period subjects will
undergo safety and other assessments, including central pathology confirmation
of DLBCL diagnosis and determination of ABC type. Following confirmation of
eligibility, subjects will undergo randomization to either the experimental or
control arm in a 1:1 ratio.

The Treatment Period begins with Cycle 1 Day 1 dosing. Subjects will receive
protocol-specified treatments for 6 cycles. Treatment will continue to
completion; or until the outcome of the computed tomography (CT) scan between
Weeks 9 - 12 (after Cycle 3 but before Cycle 4) indicates a treatment change
based on response assessment; disease progression; unacceptable toxicity;
death; or withdrawal of consent, whichever occurs first.

The Follow-up Period begins upon study treatment completion or upon early
discontinuation of study treatment. Subjects will be followed for first and
second progressions, subsequent antilymphoma therapy, development of any second
primary malignancies (SPMs), and overall survival according to the schedule
described in Table 5 of the protocol.

Study treatments in a 21-day cycle are: lenalidomide / placebo Days 1 - 14;
rituximab, cyclophosphamide, doxorubicin, and vincristine Day 1; prednisone
Days 1 - 5. Refer to Table 7 of the protocol for complete details.

The subjects will undergo the following procedures:
1x CNS lymphoma evaluation (is applicable)
1x Hepatitis B test
1x creatinine clearance
1x ECG
2x MUGA/echocardiogram
1 of 2x bone marrow biopsy
1x bone marrow aspirate (optional)
1x saliva sample
1x tumorbiopsy
25x physical exam
25x vital signs
25x blood sampling (not all parameters are assessed during each visit)
Max. 19x pregnancy test, depending on regularity of menstrual cycle
19x QoL questionnaire
18x CT
2x PET
18x B symptoms

Side effects which have been reported in more than 10% of the patients
participating in studies sponsored by Celgene investigating Lenalidomide:
• Low number of white blood cells (with owithout fever)
• Anemia; Decrease in cells that help your blood clot
• Vision Blurred
• Diarrhea
• Pain (Upper abdominal pain, Abdominal pain, Toothache)
• Constipation
• Indigestion
• Nausea
• Vomiting
• Feeling weak and unwell
• Tired
• Swelling
• Fever
• Chills
• Pneumonia or other infections
• Sore throat
• Stuffy nose
• Weight loss
• Decreased appetite
• High blood sugar
• Chemical imbalance in blood
• Abnormal liver lab tests
• Pain including muscles, joints, and non-cardiac chest pain
• Dizziness
• Altered sense of taste
• Headache
• Eye lens cloudiness (cataract)
• Abnormal sense of touch
• Pain and decreased sensation in nerves
• Shaking
• Cough
• Shortness of breath
• Nosebleed
• Blood clot in lower extremities, lungs, heart, brain, and other organs
• Dry skin
• Itching
• Allergic reaction
• Feeling sad
• Not sleeping well
Furthermore, subjects will experience possible risks of study procedures: Tumor
biopsy, Bone marrow aspirate and biopsy, CSF Sampling, Blood Tests / IV needle
insertion, CT scans,
PET scans, MUGA, GEP typing test.