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

Inclusion Criteria:

• Diagnosis of active CLL or SLL that meets at least one of the IWCLL 2008 criteria forrequiring treatment (Binet Stage ≥ B and/or Rai Stage ≥ I)
• Disease that has progressed during or relapsed after at least one previous CLL/SLLtherapy
• Not appropriate for treatment with a purine-based analogue regimen (per NationalComprehensive Cancer Network [NCCN] or European Society for Medical Oncology [ESMO]guidelines), including relapse ≤ 36 months from a purine-based chemoimmunotherapyregimen or relapse ≤ 24 months from a purine-based monotherapy regimen
• A cytogenetics or fluorescence in situ hybridization (FISH) analysis of the leukemiccells within 24 months of randomization is required to document the presence orabsence of del(17p). Note: if a sample from within 24 months is not available, itshould be evaluated as part of the screening laboratory evaluation to informstratification
• Measurable disease with a lymph node or tumor mass > 1.5 cm in at least one dimensionas assessed by computed tomography (CT)
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (corresponds toKarnofsky Performance Status [KPS] ≥ 60%)
• Willingness by subject to be randomized to receive either ofatumumab or duvelisib atthe 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 xupper 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 chorionicgonadotropin (βhCG) pregnancy test within 1 week before randomization (WCBP defined asa sexually mature woman who has not undergone surgical sterilization or who has notbeen 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 orpostmenopausal to use medically acceptable methods of birth control from the firstdose of study drug to 30 days after the last dose of duvelisib and for 12 months afterlast dose of ofatumumab. Sexually active men, and women using oral contraceptivepills, should also use barrier contraception
• Ability to voluntarily sign consent for and adhere to the entire study visit scheduleand all protocol requirements
• Signed and dated institutional review board (IRB)/independent ethics committee (IEC)-approved informed consent form (ICF) before any study specific screeningprocedures 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 (orequivalent) to maintain hemoglobin > 8.0 g/dL or platelets > 10,000 μL withouttransfusion support
• Refractory to ofatumumab (progression or relapse <12 months of receiving ofatumumabtherapy or <24 months of receiving an ofatumumab- containing regimen)
• Prior allogeneic transplant (prior autologous stem cell transplant >6 months prior tostudy entry is permitted)
• Known central nervous system lymphoma or leukemia; subjects with symptoms of CNSdisease must have a negative CT scan or negative diagnostic lumbar puncture prior torandomization
• 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 systemicsteroids > 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 ofstudy treatment (defined as requiring IV antimicrobial, antifungal or antiviralagents)
• Subjects on antimicrobial, antifungal or antiviral prophylaxis are not specificallyexcluded if all other inclusion/exclusion criteria are met and there is no evidence ofactive 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 tothe 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 oftriplicate readings) Note: This criterion does not apply to subjects with a right orleft bundle branch block (BBB)
• Unstable or severe uncontrolled medical condition (eg, unstable cardiac function,unstable pulmonary condition), or any important medical illness or abnormal laboratoryfinding that would, in the investigator's judgment, increase the subject's risk whileparticipating in this study
• Concurrent active malignancy other than nonmelanoma skin cancer or carcinoma in situof the cervix, bladder, or prostate not requiring treatment. Subjects with previousmalignancies are eligible provided that they have been disease free for ≥2 years
• History of stroke, unstable angina, myocardial infarction, or ventricular arrhythmiarequiring medication or mechanical control within the last 6 months
• Administration of medications or foods that are strong inhibitors or inducers of CYP3Awithin 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