Parsaclisib in Japanese patients with relapsed or refractory B‐cell lymphoma (CITADEL‐111): A phase Ib study

Abstract

Parsaclisib, a potent, selective, next‐generation PI3Kδ inhibitor, has shown clinical benefit in patients with relapsed or refractory B‐cell lymphoma. We undertook a phase Ib study (CITADEL‐111) evaluating safety, pharmacokinetics, and efficacy of parsaclisib in Japanese patients with relapsed or refractory B‐cell malignancies. Patients received oral parsaclisib daily for 8 weeks then once weekly (10‐mg dose, n = 3; 20‐mg dose, n = 14). Pharmacokinetic samples were collected on days 1, 8, and 15, and efficacy was monitored according to Lugano criteria. At data cut‐off (August 14, 2020), 6 patients (35.3%) remained on study treatment and 11 (64.7%) discontinued due to progressive disease (9 [52.9%]) or adverse events (2 [11.8%]). Median duration of treatment was 8.3 (range, 0.3–24.4) months. The most commonly reported nonhematologic adverse events were constipation (6 [35.3%]), nausea, and pyrexia (each 4 [23.5%]). Five patients (29.4%) experienced treatment‐emergent new or worsening decreased neutrophils to grade 3 or 4. No treatment‐emergent worsening in aminotransferase elevations to grade 3 or 4 were observed. Ten patients (58.8%) required dose interruption and 5 (29.4%) dose reduction. Body weight–normalized parsaclisib exposure was comparable between Japanese and Western patients. Objective response rate was 100% in follicular lymphoma (9 of 9 patients, including complete response in 2 patients [22.2%]) and marginal zone lymphoma (2 of 2 patients), and 16.7% in diffuse large B‐cell lymphoma (1 of 6 patients). Results observed in Japanese patients with relapsed or refractory follicular or marginal zone lymphoma support further clinical development of parsaclisib in these patient populations.

Safety and efficacy of parsaclisib in combination with obinutuzumab and bendamustine in patients with relapsed or refractory follicular lymphoma (CITADEL‐102): A phase 1 study

“…A set of DEP were identified, with significant fold‐changes generally maintained across multiple time points (from cycle 2 day one, cycle 4 day one, and cycle 8 day one) (Supplemental Figure 3). Changes were observed in various proteins previously described as parsaclisib‐responsive 23 including B‐cell markers, cytokines involved in B‐cell trafficking, and proteins elevated in B‐cell lymphomas (CXCL13/BCA1, TNFRSF9, FCRL2, CD79B, and TNFRSF13B).…”

“…Changes were observed in various proteins previously described as parsaclisib-responsive 23 including B-cell markers, cytokines involved in B-cell trafficking, and proteins elevated in B-cell lymphomas (CXCL13/BCA1, TNFRSF9, FCRL2, CD79B, and TNFRSF13B).…”

3,4-Diaminopyrazolo[3,4-d]pyrimidines: a new three-component microwave-assisted synthesis and anti-leukemic properties

“…1), targeting phosphoinositide 3-kinase δ, has entered phase II clinical trials for relapsed B-cell malignancies (NCT02018861, NCT02998476 and NCT03314922). 21–23 CGP57380, a potent inhibitor of MAPK-interacting kinase 1, 24 demonstrated synergism with mTOR inhibitors and activity against adult T-cell acute lymphoblastic leukaemia (Jurkat cells) 24 and acute myeloid leukaemia (U937 cells). 25 CGP57380 was found to inhibit leukaemia stem cell function in blast crisis chronic myeloid leukaemia cells 26 and overcome imatinib resistance in chronic myelogenous leukaemia.…”