Results of a phase I study of idelalisib, a PI3Kδ inhibitor, in patients with relapsed or refractory mantle cell lymphoma (MCL)

Blood (Impact Factor: 10.45). 03/2014; 123(22). DOI: 10.1182/blood-2013-11-537555
Source: PubMed


Idelalisib, an oral inhibitor of PI3Kδ, was evaluated in a 48-week phase I study (50-350 mg qd or bid) enrolling 40 patients with relapsed/refractory mantle cell lymphoma (MCL). Primary outcome was safety and dose-limiting toxicity (DLT). Secondary outcomes were pharmacokinetic parameters, pharmacodynamic effects, overall response rate (ORR), progression-free survival (PFS), and duration of response (DOR). Patients without DLT and no evidence of disease progression after 48 weeks enrolled in the extension study. Patients had median age of 69 years (52-83) and received median of 4 prior therapies (1-14); 17/40 (43%) were refractory to their most recent treatment. Median duration of idelalisib treatment was 3.5 months (range, 0.7-30.7), with 6 (15%) continuing extension treatment. Common grade ≥3 adverse events (AEs) included (total%/grade ≥3%) diarrhea (40/18), nausea (33/5), pyrexia (28/0), fatigue (25/3), rash (23/3), decreased appetite (20/15), upper respiratory infection (20/0), pneumonia (13/10), and ALT or AST elevations (60/20). Nine (25%) patients discontinued therapy due to AEs. ORR was 16/40 (40%), with CR in 2/40 (5%) patients. Median DOR was 2.7 months, median PFS was 3.7 months, and 1-year PFS was 22%. These data provide proof of concept that targeting PI3Kδ is a viable strategy and worthy of additional study in MCL. This study is registered at, identifier: NCT00710528.


Available from: Wayne R Godfrey, Mar 15, 2016
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    • "The small sample size and the heterogeneity of the patients preclude any conclusions about the clinical activity of XC-302. The overall objective response we observed was lower than that of other PI3K p110δ inhibitors, such as Idelalisib [21, 22], perhaps because of insufficient cases, different types of disease, or the effectiveness of XC-302 itself. However, one of the nine patients with gastric mucosa-associated lymphoid tissue in 50-mg group achieved a PR in the first cycle. "
    [Show abstract] [Hide abstract] ABSTRACT: Objectives: To determine the safety of Puquitinib Mesylate (XC-302), an oral inhibitor of phosphatidylinositol 3-kinase, in treating relapsed or refractory non-Hodgkin's lymphoma (NHL). Methods: Between October 2013 and July 2015, 21 patients from Sun Yat-sen University Cancer Center were treated twice daily on each day of a 28-day cycle (median number of cycles, 2; maximum, 20) with XC-302 at a post prandial dose of 25 mg, 37.5 mg, or 50 mg. Adverse events (AEs), AUClast and Cmax, response rates, and overall survival were assessed. Results: Patients had received a median (range) of 1 (1 to 3) previous cancer treatments. At the latest follow-up, two patients were still benefitting from the study. The most common drug-related AEs were elevations in alanine transaminase (ALT, 14 of 21 patients) and aspartate transaminase (AST, 7 of 21 patients). Four patients, both in the-50-mg group, had dose-limiting toxicities, and therapy was discontinued in a fifth because of persistent abnormal liver function. The overall response rate was 2 of19. Serum concentrations of XC-302 increased in a dose-dependent pattern. Median progression-free survival in all patients was 1.9 (95% CI, 1.7 to 2.0) months. Conclusion: XC-302 has an acceptable safety profile and offers potential therapeutic value to patients with relapsed or refractory non-Hodgkin lymphoma.
    Full-text · Article · Oct 2015 · Oncotarget
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    • "and the 1-year PFS rate was 22%. The most common adverse events were diarrhoea, nausea, pyrexia, fatigue and rash, and grade 3–4 adverse events were rare (Spurgeon et al, 2013; Kahl et al, 2014). "
    [Show abstract] [Hide abstract] ABSTRACT: Mantle cell lymphoma is a heterogeneous subtype of non-Hodgkin lymphoma. Conventional treatment with immunochemotherapy followed by autologous stem cell transplantation or intensive immunochemotherapy alone has improved outcomes, but the disease remains incurable. Recent advances in basic and translational research have significantly enhanced our understanding of disease pathogenesis and have sparked the development of novel therapies. Novel agents include the proteasome inhibitor bortezomib, the immunomodulatory agent lenalidomide, the phosphatidylinositol-4,5-bisphosphate 3-kinase pathway inhibitor idelalisib and the Bruton tyrosine kinase inhibitor ibrutinib. Preliminary results from clinical trials, especially from studies of ibrutinib, have proven these agents to be effective. In ongoing studies, these agents are being integrated into conventional immunochemotherapy regimens to hopefully improve patient outcomes.
    Full-text · Article · Jun 2014 · British Journal of Haematology
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    [Show abstract] [Hide abstract] ABSTRACT: VcR-CVAD (rituximab, bortezomib, modified hyper-CVAD) induction chemoimmunotherapy and maintenance rituximab (MR) was evaluated for efficacy and safety in ECOG protocol E1405. Patients with previously untreated mantle cell lymphoma (MCL) received VcR-CVAD chemotherapy every 21 days for 6 cycles, followed by MR for 2 years. Transplant eligible patients had the option of autologous stem cell transplantation (ASCT) consolidation instead of MR. The primary end point was the complete response (CR) rate to VcR-CVAD. The secondary endpoints were overall response rate (ORR), progression-free survival (PFS), overall survival (OS) and toxicities. Seventy-five eligible patients with a median age of 62 (range 40-76) were enrolled. The ORR was 95% and a CR was achieved in 68% of patients. After a median follow-up of 4.5 years, 3-year PFS and OS were 72% and 88%, respectively. No substantial difference in PFS or OS was observed between patients treated with MR (n=44) versus ASCT (n=22). There were no unexpected toxicities. VcR-CVAD produced high ORR and CR rates in MCL. MR after VcR-CVAD induction performed similarly to ASCT and may improve response duration. Randomized clinical trials (RCTs) comparing MR against ASCT should be considered and RCTs evaluating bortezomib's contribution to conventional therapy are underway. This study was registered with (identifier NCT00433537).
    Full-text · Article · Jan 2014 · Blood
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