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

From: Current and future treatment strategies in chronic lymphocytic leukemia

Agent Trial name Trial design and patients Outcomes Citation
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]
  1. AE adverse event, ALT alanine aminotransferase, AST aspartate aminotransferase, CLL chronic lymphocytic lymphoma, IGHV immunoglobulin heavy chain, ORR overall response rate, OS overall survival, PFS progression-free survival, PI3K phosphoinositide 3-kinase, SAE serious adverse event, SLL small lymphocytic lymphoma