A Phase 3 Study of Duvelisib Versus Ofatumumab in Patients With Relapsed or Refractory CLL/SLL (DUO)

This is an open-label, two- arm, randomized phase 3, superiority trial designed to evaluate
the efficacy and safety of duvelisib compared to ofatumumab administered to patients who have
been diagnosed with CLL/SLL whose disease is relapsed or refractory.

Approximately 150 subjects will receive a starting dose of 25 mg duvelisib BID initially over
the course of 21-day treatment cycle followed by 28-day treatment cycles for up to 18 cycles
or until disease progression or unacceptable toxicity (whichever comes first). After 18
complete cycles of treatment, subjects may receive additional cycles of duvelisib until
disease progression or unacceptable toxicity if they, in the judgment of the Investigator,
may derive benefit from continued treatment, and if the subject meets the criteria for
additional treatment at Cycle 19 Day 1.

Approximately 150 subjects will receive a starting dose of 300 mg ofatumumab on Day 1
followed by seven weekly doses of 2000 mg. Thereafter, subjects will receive 2000 mg
ofatumumab once every month for four months. Administration of ofatumumab will not exceed the
12 doses (within 7 cycles).

Inclusion Criteria:

- Diagnosis of active CLL or SLL that meets at least one of the IWCLL 2008 criteria for
requiring treatment (Binet Stage ≥ B and/or Rai Stage ≥ I)

- Disease that has progressed during or relapsed after at least one previous CLL/SLL
therapy

- Not appropriate for treatment with a purine-based analogue regimen (per National
Comprehensive Cancer Network [NCCN] or European Society for Medical Oncology [ESMO]
guidelines), including relapse ≤ 36 months from a purine-based chemoimmunotherapy
regimen or relapse ≤ 24 months from a purine-based monotherapy regimen

- A cytogenetics or fluorescence in situ hybridization (FISH) analysis of the leukemic
cells within 24 months of randomization is required to document the presence or
absence of del(17p). Note: if a sample from within 24 months is not available, it
should be evaluated as part of the screening laboratory evaluation to inform
stratification

- Measurable disease with a lymph node or tumor mass > 1.5 cm in at least one dimension
as assessed by computed tomography (CT)

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (corresponds to
Karnofsky Performance Status [KPS] ≥ 60%)

- Willingness by subject to be randomized to receive either ofatumumab or duvelisib at
the dose and schedule defined in the protocol

- Must meet the following laboratory parameters:

1. Serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) ≤ 3 x
upper limit of normal (ULN)

2. Total bilirubin ≤ 1.5 x ULN

3. Serum creatinine ≤ 2.0 x ULN

4. Hemoglobin ≥ 8.0 g/dL with or without transfusion support

5. Platelet count ≥ 10,000 μL with or without transfusion support

- For women of childbearing potential (WCBP): negative serum β-human chorionic
gonadotropin (βhCG) pregnancy test within 1 week before randomization (WCBP defined as
a sexually mature woman who has not undergone surgical sterilization or who has not
been naturally post-menopausal for at least 24 consecutive months [women ≤ 55 years]
or 12 consecutive months [women > 55 years])

- Willingness of male and female subjects who are not surgically sterile or
postmenopausal to use medically acceptable methods of birth control from the first
dose of study drug to 30 days after the last dose of duvelisib and for 12 months after
last dose of ofatumumab. Sexually active men, and women using oral contraceptive
pills, should also use barrier contraception

- Ability to voluntarily sign consent for and adhere to the entire study visit schedule
and all protocol requirements

- Signed and dated institutional review board (IRB)/independent ethics committee
(IEC)-approved informed consent form (ICF) before any study specific screening
procedures are performed

Exclusion Criteria:

- History of Richter's transformation or prolymphocytic leukemia

- Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenia purpura
(ITP) that is uncontrolled or requiring > 20 mg once daily (QD) of prednisone (or
equivalent) to maintain hemoglobin > 8.0 g/dL or platelets > 10,000 μL without
transfusion support

- Refractory to ofatumumab (progression or relapse <12 months of receiving ofatumumab
therapy or <24 months of receiving an ofatumumab- containing regimen)

- Prior allogeneic transplant (prior autologous stem cell transplant >6 months prior to
study entry is permitted)

- Known central nervous system lymphoma or leukemia; subjects with symptoms of CNS
disease must have a negative CT scan or negative diagnostic lumbar puncture prior to
randomization

- Use of any of the following medications or procedures within the specified timeframe:

- Use of live or live attenuated vaccines within 30 days prior to randomization

- Chemotherapy, radiation therapy, or ablative therapy within 3 weeks of
randomization

- Tyrosine kinase inhibitor within 7 days of randomization

- Other investigational therapy (not included above) within 3 weeks of
randomization

- Previous treatment with a PI3K inhibitor or BTK inhibitor

- Ongoing treatment with chronic immunosuppressants (eg, cyclosporine) or systemic
steroids > 20 mg prednisone (or equivalent) QD

- History of tuberculosis treatment within the preceding two years

- Ongoing systemic bacterial, fungal, or viral infections at the time of initiation of
study treatment (defined as requiring IV antimicrobial, antifungal or antiviral
agents)

− Subjects on antimicrobial, antifungal or antiviral prophylaxis are not specifically
excluded if all other inclusion/exclusion criteria are met and there is no evidence of
active infection at randomization

- Human immunodeficiency virus (HIV) infection

- Prior, current, or chronic hepatitis B or hepatitis C infection

- History of alcohol abuse or chronic liver disease (other than metastatic disease to
the liver)

- Unable to receive prophylactic treatment for pneumocystis or herpes simplex virus
(HSV)

- Baseline QT interval corrected with Fridericia's method (QTcF) > 480 ms (average of
triplicate readings) Note: This criterion does not apply to subjects with a right or
left bundle branch block (BBB)

- Unstable or severe uncontrolled medical condition (eg, unstable cardiac function,
unstable pulmonary condition), or any important medical illness or abnormal laboratory
finding that would, in the investigator's judgment, increase the subject's risk while
participating in this study

- Concurrent active malignancy other than nonmelanoma skin cancer or carcinoma in situ
of the cervix, bladder, or prostate not requiring treatment. Subjects with previous
malignancies are eligible provided that they have been disease free for ≥2 years

- History of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia
requiring medication or mechanical control within the last 6 months

- Administration of medications or foods that are strong inhibitors or inducers of CYP3A
within 2 weeks of randomization

- Prior surgery or gastrointestinal dysfunction that may affect drug absorption (eg,
gastric bypass surgery, gastrectomy)

- Major surgery or invasive intervention within 4 weeks prior to randomization

- Pregnant or breastfeeding women

- Hypersensitivity to ofatumumab or its excipients