Acalabrutinib-Lenalidomide-Rituximab in Patients With Untreated MCL

This is a single-arm phase 2 study to evaluate the preliminary evidence of efficacy and
safety of the combination of acalabrutinib, lenalidomide and rituximab (ALR) in previously
untreated mantle cell lymphoma, as well as the feasibility of treatment intensity adapted to
MRD status.

Study intervention starts with an induction phase consisting of 12 cycles of ALR. Subjects
that do not experience progressive disease will be eligible to enter a maintenance phase
involving continued ALR until they achieve an MRD-negative CR, disease progression or
unacceptable toxicity occurs.

Subjects will be monitored for MRD status in PB every 16 weeks during maintenance phase.
Subjects achieving MRD-negative CR at any time after induction will be eligible to stop
acalabrutinib and lenalidomide while continuing rituximab maintenance every 8 weeks. Subjects
on rituximab maintenance will be eligible for retreatment with acalabrutinib and lenalidomide
at time of either molecular or clinical progression, and continue until MRD-negative CR or
disease progression.

Subjects with no detectable MRD at baseline will receive 12 cycles of ALR induction followed
by up to 12 cycles of maintenance ALR. They are eligible to stop both acalabrutinib and
lenalidomide if in clinical CR, or stop lenalidomide alone if in clinical PR. These subjects
will not be eligible for retreatment.

Subjects will be followed after completing study intervention every 6 months for alternate
anti-cancer therapy and survival.

Inclusion Criteria:

- Histologically confirmed diagnosis of mantle cell lymphoma

- Age ≥ 18 years

- No prior systemic therapy for lymphoma

- Patient has measurable disease defined by a tumor mass ≥ 1.5 cm in one dimension and
measurable in two dimensions; patient with measurable spleen disease is allowed

- Treatment should be indicated according to the treating physician

- ECOG performance status ≤ 2

- Required initial laboratory parameters:

- Absolute neutrophil count (ANC) ≥ 1000 cells/mm3

- Platelet count ≥ 75,000 cells/mm3

- Calculated creatinine clearance ≥ 30 ml/min by Cockcroft-Gault formula

- Total bilirubin ≤ 2.0 x ULN

- AST/SGOT or ALT/SGPT ≤ 3.0 x ULN

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

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

- Patients of reproductive potential agree to use birth control throughout their
participation in this study, and for 28 days following study termination.

- Females of reproductive potential must adhere to the scheduled pregnancy testing as
required in the Revlimid REMS® program. Females of childbearing potential (FCBP) must
have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL
within 10 - 14 days and again within 24 hours prior to prescribing lenalidomide for
Cycle 1 (prescriptions must be filled within 7 days). FCBP must either commit to
continued abstinence from heterosexual intercourse or begin TWO acceptable methods of
birth control, one highly effective method and one additional effective method AT THE
SAME TIME, at least 28 days before and continue for at least 28 days after the last
dose of lenalidomide (or 2 days after the last dose of acalabrutinib, whichever is
longer). FCBP must also agree to ongoing pregnancy testing. Men must agree to use a
latex condom during sexual activity with a FCBP through one week post last dose even
if they have had a successful vasectomy. Men must also agree to refrain from sperm
donation during the same timeframe. See Appendix: Risks of Fetal Exposure, Pregnancy
Testing Guidelines and Acceptable Birth Control Methods.

- Understand and voluntarily sign an ICF prior to any study related assessments and
procedures are conducted.

- Able to adhere to the study visit schedule and other protocol requirements.

Exclusion Criteria:

- Patients with blastoid histology

- Patients with known or suspected CNS involvement

- Active viral infection with HIV or hepatitis type B or C. Seropositive HBV patients
are eligible if they are negative for HBV DNA by PCR and receive concomitant antiviral
therapy during treatment and for additional six months after coming off study.

- Prior history of malignancies other than MCL unless the patient has been disease free
for ≥ 5 years from the signing of the ICF. Exceptions include basal cell carcinoma or
squamous cell carcinoma of the skin; carcinoma in situ of cervix; carcinoma in situ of
breast, or localized prostate cancer

- Active uncontrolled systemic fungal, bacterial or viral infection (defined as ongoing
signs/symptoms related to the infection without improvement despite appropriate
antibiotics, antiviral therapy and/or other treatment)

- Clinically significant cardiovascular disease such as uncontrolled or symptomatic
arrhythmias, congestive heart failure, or myocardial infarction within 6 months of
screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart
Association Functional Classification.

- Malabsorption syndrome, disease significantly affecting gastrointestinal function, or
resection of the stomach or small bowel that is likely to affect absorption,
symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or
gastric restrictions and bariatric surgery, such as gastric bypass.

- Active bleeding or history of bleeding diathesis (eg, hemophilia or von Willebrand
disease).

- Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenic
purpura).

- Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer.

- Requires or receiving anticoagulation with warfarin or equivalent vitamin K
antagonists (eg, phenprocoumon) within 7 days of first dose of study drug.

- Prothrombin time (PT)/INR or aPTT (in the absence of lupus anticoagulant) >2x ULN.

- Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole,
lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving
proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible
for enrollment to this study.

- History of significant cerebrovascular disease/event, including stroke or intracranial
hemorrhage, within 6 months before the first dose of study drug.

- Major surgical procedure within 28 days of first dose of study drug. Note: If a
subject had major surgery, they must have recovered adequately from any toxicity
and/or complications from the intervention before the first dose of study drug.

- Patients with a history of toxic epidermal necrolysis or Stevens-Johnson syndrome

- Patients that are pregnant or breast feeding

- Known hypersensitivity to any study drug or excipients

- Patient on corticosteroids within two weeks prior to study entry, except for
prednisone ≤ 20 mg/day or equivalent for purposes other than treating MCL

- Use of any other experimental drug or therapy within 28 days of baseline

- Patient at high risk for deep vein thrombosis not willing to take DVT prophylaxis

- Any significant medical condition, laboratory abnormality, or psychiatric illness that
would prevent the subject from participating in the study

- Known prior exposure to BTK inhibitor