Dose Finding Study of Ibrutinib Plus Lenalidomide / Rituximab in Relapsed or Refractory Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is a relatively rare subtype (3% to 6% (Zhou, 2008) of mature B
cell non-Hodgkin lymphomas (NHL), with a median age at diagnosis in mid to late 60's, a male
predominance (3/1) and typically advanced stage presentation though only about 1/3 of
patients are truly symptomatic at baseline (Armitage, 1998). Although significant
controversies remain in the management of MCL, all would agree that the challenges associated
with MCL, particularly the poor results with standard chemotherapy and frequent
chemoresistance have pushed the community to be more innovative and active in clinical
research. Hence the median OS has clearly improved over the last 3 decades (from 2-3y to >5y)
(Goy, 2011a), thanks to deeper responses obtained with intensive regimens in younger patients
(an early CR translates into clearly better outcome) and also better salvage therapies with
now MCL being the only lymphoma with 4 new biologicals approved (3 in the US and 1 in EU).

Inclusion Criteria:

- Age greater than or equal to 18 years.

- Histologically or cytologically confirmed diagnosis of MCL.

- Relapsed or refractory MCL patients who have received at least one prior therapy are
eligible. Patients who have previously received high-dose chemotherapy with peripheral
stem cell support are eligible.

- Presence of at least one lymph node evaluable or mass measurable for response.

- Eastern Cooperative Oncology Group Performance Status greater than 2.

- Platelets > 75,000/μL and absolute neutrophils count (ANC) > 1,000/μL within 14 days
of study registration (unless the treating physician deems the neutropenia is related
to bone marrow involvement, then an ANC of > 750/mm 3 is allowed)

- Normal renal function defined as serum creatinine less than 2.

- Recovery from any previous treatment therapy.

- Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy
test

- All study participants must be registered into the mandatory Revlimid REMS® program,
and be willing and able to comply with the requirements of the REMS® program.

- Females of reproductive potential must adhere to the scheduled pregnancy testing as
required in the Revlimid REMS® program.

- Ability to understand, and willingness to sign, a written informed consent document.

- Able to take aspirin (81 or 325 mg) daily as prophylactic anti-coagulation (patients
intolerant to ASA may use low molecular weight heparin).

- Normal organ and bone marrow function parameter:

Laboratory tests Required value WBC >3000/μL* Absolute neutrophils count >1,000/μL*
Platelets >75,000/μL Total bilirubin < 1.5Within normal institutional limits AST (SGOT) and
ALT (SGPT) <3 x institutional upper limit of normal Creatinine or creatinine clearance <1.5
within normal institutional limits >60 mL/min/1.73 m2 for patients with creatinine levels
above institutional normal (calculated by Cockcroft-Gault formula)

Exclusion Criteria:

- Concomitant use of warfarin or other Vit K antagonists

- Central nervous system (CNS) involvement by lymphoma at time of enrollment.

- Other medical conditions that would potentially interfere with patient participation
in this trial.

- A second malignancy, other than basal cell carcinoma of the skin or in situ carcinoma
of the cervix (unless for other tumor type patient was treated with curative intent at
least 2 years previously.)

- Known human immunodeficiency virus (HIV-1) infection or chronic hepatitis B, or C (Hep
B serology positive without active infection will be eligible)

- Active, clinically serious infection > CTCAE grade 2. Patients may be eligible upon
resolution of the infection.

- Major surgery or significant traumatic injury within 28 days of the first dose of
study drug.

- Use of any other standard chemotherapy, radiation therapy, or experimental drug
therapy for the treatment of MCL within 21 days of starting treatment or 5 half life
times (whatever is shorter)

- Patients with grade 3/4 cardiac problems, as defined by the New York Heart Association
(NYHA) criteria:

- History of uncontrolled or symptomatic angina

- History of uncontrolled arrhythmias

- Myocardial infarction < 6 months from study entry

- Uncontrolled or symptomatic congestive heart failure

- Ejection fraction below the institutional normal limit

- Any other cardiac condition that, in the opinion of the treatment physician, would
make this protocol unreasonably hazardous for the patient

- Patients unwilling or unable to comply with the protocol.