Table 3 Key clinical trials of approved and investigational PI3Kδ inhibitors for the treatment of CLL

Approved agents

 Idelalisib (second-line or later combination therapy)

NCT01539512

Phase 3 study of the efficacy and safety of idelalisib plus rituximab versus placebo plus rituximab in patients with relapsed CLL and significant coexisting medical conditions

Idelalisib plus rituximab versus placebo plus rituximab:

 Median PFS: not reached versus 5.5 months

 12-month OS: 92% versus 80%

 ORR: 81% versus 13%

 SAEs: 40% versus 35%

[56]

 Idelalisib (first-line monotherapy followed by combination therapy)

NCT02135133

Phase 2 study to evaluate idelalisib as first-line therapy; patients were treated with idelalisib monotherapy for 2 months then switched to combination therapy of idelalisib plus ofatumumab for an additional 6 months

Safety data after a median follow-up of 14.7 months:

 Hepatotoxicity was reported as a frequent, and often severe, AE

  79% of patients experienced grade ≥ 1 ALT or AST elevation

  54% of patients experienced grade ≥ 3 transaminitis (median time to development: 28 days)

  Younger age and mutated IGHV status were found to be significant risk factors for developing hepatotoxicity

 The development of idelalisib-related toxicities was reported to be associated with increased levels of inflammatory cytokines and decreased levels of regulatory T cells

[57]

 Idelalisib (second-line or later combination therapy)

NCT01659021

Phase 3 study of the efficacy and safety of idelalisib plus ofatumumab versus ofatumumab monotherapy in patients with relapsed CLL

Idelalisib plus ofatumumab versus ofatumumab monotherapy:

 Median PFS: 16.3 versus 8.0 months

 Serious infections were more common in the idelalisib plus ofatumumab group versus the ofatumumab monotherapy group

  Pneumonia: 13% versus 10%

  Sepsis: 6% versus 1%

  Pneumocystis jirovecii pneumonia: 5% versus 1%

 Treatment-related deaths: 22 versus 6

[59]

 Idelalisib (second-line or later combination followed by monotherapy)

NCT01539291

Phase 3 study of the long-term efficacy and safety of idelalisib plus rituximab followed by idelalisib monotherapy (extension of NCT01659021) in patients with relapsed CLL

 Median PFS (18-month median follow-up): 20.3 months

 Median OS: 40.6 months

 ORR: 85.5%

 Prolonged exposure to idelalisib resulted in an increased incidence of AEs including diarrhea, colitis, and pneumonitis; the incidence of elevated hepatic aminotransferases was not increased

[60]

 Idelalisib (second-line or later combination therapy)

NCT01569295

Phase 3 study of the efficacy and safety of idelalisib plus bendamustine plus rituximab versus placebo plus bendamustine plus rituximab in patients with relapsed or refractory CLL

Idelalisib plus bendamustine plus rituximab versus placebo plus bendamustine plus rituximab:

 Median PFS (14-month median follow-up): 20.8 versus 11.1 months

 All-grade AEs of infections and infestations: 69% versus 59%

 Grade ≥ 3 AEs of infections and infestations: 39% versus 25%

[61]

 Duvelisib (second-line or greater monotherapy)

DUO (NCT02004522)

Phase 3 study of the efficacy and safety of duvelisib versus ofatumumab monotherapy in patients with relapsed or refractory CLL

Duvelisib versus ofatumumab:

 Median PFS: 13.3 versus 9.9 months

 ORR: 74% versus 45%

 PFS and ORR was similar for patients with del(17p)/TP53 mutations

 Grade ≥ 3 AEs: 87% versus 48%

 Infectious AEs: 69% versus 43%

[64]

 Duvelisib (second-line or later monotherapy)

NCT02049515

Phase 3 study of the efficacy and safety of duvelisib in patients with relapsed or refractory CLL who were enrolled in the DUO trial and progressed after ofatumumab (DUO extension)

After crossover versus before crossover (to duvelisib):

 Median PFS: 15.7 and 9.4 months

 ORR: 77% versus 29%

 Median duration of response: 14.9 versus 10.4 months

 Responses were similar for patients with del(17p) and/or TP53 mutation

 73% of patients with disease refractory to ofatumumab achieved a response on duvelisib

 Safety profile was manageable

[65]

Investigational agents

 Umbralisib (second-line or later monotherapy)

NCT02742090

Phase 2 study of umbralisib in patients with CLL who are intolerant of kinase inhibitor therapy

 Median PFS: 23.5 months

12% discontinuations due to AEs

[84]

 Umbralisib (second-line or later combination therapy)

NCT02006485

Phase 1 study of triplet treatment (umbralisib, ublituximab, and ibrutinib) in patients with advanced B-cell malignancies

 ORR: 84%

Tolerable safety profile

[86]

 Umbralisib (second-line or later combination therapy)

NCT02268851

Phase 1/1b study of umbralisib plus ibrutinib in patients with CLL or mantle cell lymphoma

Interim analysis:

 Most frequent AEs were diarrhea (52%), infection (50%) and transaminitis (24%)

 SAEs occurred in 29% of patients

[85]

 ME-401 (second-line or later monotherapy or combination therapy)

NCT02914938

Phase 1 study of ME-401 alone, in combination with rituximab, or in combination with zanubrutinib in patients with relapsing or refractory CLL/SLL or B cell NHL

Interim analysis (patients with CLL/SLL [n = 10] treated with monotherapy or combination with rituximab):

 Median PFS: not reached (median follow-up: 9.7 months)

 Median duration of response: not reached

 ORR: 89% (monotherapy: 100%; combination with rituximab: 83%)

 No apparent safety differences between monotherapy or ME-401 plus rituximab treatment

[91]