Background: Phosphoinositide 3-kinase (PI3K)-δ,γ isoforms are preferentially expressed in leukocytes and are central to the growth and survival of certain B and T cell malignancies. Inhibition of these isoforms by IPI-145, an oral PI3K-δ,γ inhibitor, has unique therapeutic potential in hematologic malignancies. IPI-145 has shown clinical activity and a favorable safety profile in a broad range of hematologic malignancies in an ongoing phase 1 trial (IPI-145-02). Based on these data, the DUO phase 3 trial (IPI-145-07; ClinicalTrials.gov number: NCT02004522) has been initiated to evaluate the efficacy and safety of IPI-145 compared to ofatumumab in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Methods: This open-label, two-arm trial includes adult patients with active CLL/SLL who meet at least one of the International Workshop on CLL (IWCLL) 2008 treatment criteria; have disease progression during or after previous CLL therapy; are not appropriate for purine analog-based therapy; and not refractory to ofatumumab. The trial will enroll approximately 300 patients, randomized 1:1 to IPI-145 or ofatumumab at sites in and outside the US. Patients randomized to IPI-145 will receive 25 mg IPI-145 orally, twice daily in 28-day treatment cycles for up to 18 cycles or until disease progression or unacceptable toxicity. After 18 cycles, patients may receive additional cycles of IPI-145 for up to 3 years, if they have documented evidence of response and disease requiring continued treatment. Patients randomized to ofatumumab will receive treatment consistent with the approved product label. Patients on both arms will be followed for up to 3 years from the first dose of study drug. The primary efficacy endpoint is progression-free survival. Key secondary endpoints include safety, overall survival and pharmacokinetic parameters. Patients with progressive disease during the trial may be eligible to receive the opposite study medication in a separate Infinity-sponsored extension protocol (IPI-145-12). This trial is currently enrolling patients. Clinical trial information: NCT02004522.