A Phase Ib Study of Single-Agent Idelalisib Followed by Idelalisib in Combination with Chemotherapy in Patients with Metastatic Pancreatic Ductal Adenocarcinoma

Abstract

Lessons Learned Although this study of idelalisib in patients with PDAC was limited in size and duration because of early termination, idelalisib exposure resulted in an overall safety profile consistent with studies in hematological malignancies, except that the incidences of diarrhea and colitis were reduced in patients with PDAC. Preclinical studies of the PI3K pathway in PDAC and positive clinical results of PI3K inhibition in other cancers support the continued development of PI3K inhibitors in PDAC. Background Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal solid tumors and is often refractory to treatment. Phosphatidylinositol‐3 kinase (PI3K) δ inhibition influences regulatory immune cell function and improves survival in preclinical PDAC models. Here, idelalisib, an inhibitor of PI3Kδ, was investigated as treatment for metastatic PDAC. Methods This was an open‐label, multicenter, phase Ib, nonrandomized, dose‐escalation study. Study aims were to investigate the maximum tolerated dose, safety, pharmacokinetics/pharmacodynamics, and efficacy of idelalisib alone and in combination with chemotherapeutics—nab‐paclitaxel and modified (m)FOLFOX6. Results Because of early termination, only 16 patients were enrolled in the single‐agent idelalisib arm, 12 of whom received at least one dose of idelalisib. The most common treatment‐emergent adverse events (≥25%) related to idelalisib (n = 12) were increased aspartate aminotransferase, pyrexia, and maculopapular rash. One patient presented with diarrhea; no cases of colitis were reported. One patient discontinued treatment because of pyrexia and maculopapular rash; two patients died because of disease progression. Conclusion This study was terminated because factors contributing to safety concerns in phase III studies of idelalisib for hematological malignancies were not fully understood. In this small sample of patients with metastatic PDAC, exposure to idelalisib resulted in safety findings consistent with previous studies, with reduced diarrhea/colitis.

FOXO transcriptional activity is associated with response to chemoradiation in EAC

“…Graph shows Spearman correlation of surviving fraction after CRT versus quantified p-S6K corrected to α-tubulin as in ( A ). C Cells were treated for 7 days with the CRT regimen, including a concentration range of 0, 62.5, 125, 250, 500 and 1000 nM Alpelisib, Idelalisib, Pictilisib or LY3023414 [ 26 – 31 ]. Percentage viable cells were measured on day 8 and plotted normalized to CRT.…”

Targeting T regulatory (Treg) cells in immunotherapy-resistant cancers

“…The tumor responses were minor and transient, most likely because the treatment was relatively short. These adenosine triphosphate (ATP)-competitive and designated PI3K-δ inhibitors, such as AMG-319 or idelalisib, have limitations due to their toxicity profile in patients with solid malignancies [ 180 ] . By contrast, the non-ATP, allosteric modulator and highly selective PI3K-δ inhibitor, roginolisib (IOA-244), has a lower rate of severe toxicity, which allows for treatments lasting greater than 6 months [ 75 , 181 , 182 ] .…”

Targeting KRAS for the potential treatment of pancreatic ductal adenocarcinoma: Recent advancements provide hope (Review)

“…In a phase I study of patients with refractory solid tumors including PDAC, buparlisib combination with mFOLFOX6 caused an increase in toxicity and one patient with stage IV PDAC exhibited a 47% decrease in measurable disease from baseline (80). A phase Ib study of PI3K inhibitor idelalisib alone or in combination with nab-paclitaxel or mFOLFOX6 in patients with PDAC was terminated prematurely due to severe toxicity issues observed in a phase III clinical study of idelalisib for hematological malignancies (81).…”