Article

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
ABSTRACT
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 Clinicaltrials.gov, identifier: NCT00710528.
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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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    • "This has the interesting biological implication of p85-mediated regulation of p110 being unique and selectively affected by loss of PIK3R1 exon 11. Given these findings and the predominantly immunological clinical disease in these patients, specific targeting of p110 using inhibitors such as those currently in clinical trials for hematological malignancy (Lannutti et al., 2011; Brown et al., 2014; Flinn et al., 2014; Gilbert, 2014; Kahl et al., 2014) offers a potentially safe and effective treatment option to restore immune homeostasis while limiting unwanted effects in nonimmune cells that do not express p110. "
    [Show abstract] [Hide abstract] ABSTRACT: Class IA phosphatidylinositol 3-kinases (PI3K), which generate PIP3 as a signal for cell growth and proliferation, exist as an intracellular complex of a catalytic subunit bound to a regulatory subunit. We and others have previously reported that heterozygous mutations in PIK3CD encoding the p110δ catalytic PI3K subunit cause a unique disorder termed p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency (PASLI) disease. We report four patients from three families with a similar disease who harbor a recently reported heterozygous splice site mutation in PIK3R1, which encodes the p85α, p55α, and p50α regulatory PI3K subunits. These patients suffer from recurrent sinopulmonary infections and lymphoproliferation, exhibit hyperactive PI3K signaling, and have prominent expansion and skewing of peripheral blood CD8(+) T cells toward terminally differentiated senescent effector cells with short telomeres. The PIK3R1 splice site mutation causes skipping of an exon, corresponding to loss of amino acid residues 434-475 in the inter-SH2 domain. The mutant p85α protein is expressed at low levels in patient cells and activates PI3K signaling when overexpressed in T cells from healthy subjects due to qualitative and quantitative binding changes in the p85α-p110δ complex and failure of the C-terminal region to properly inhibit p110δ catalytic activity.
    Full-text · Article · Dec 2014 · Journal of Experimental Medicine
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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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