pilaralisib (SAR245408) / Exelixis, Sanofi - LARVOL DELTA

Pilaralisib inhibits the replication of enteroviruses by targeting the PI3K/AKT signaling pathway. (PubMed, Virol J) - "We examined the effects of PI3K inhibition on EV71 replication both in vitro and in vivo, exploring the underlying mechanisms. Our findings suggest that the PI3K/Akt signaling pathway is involved in the replication of EV71 and that its inhibition could offer a promising approach to preventing or alleviating the severity of HFMD."

Journal • CNS Disorders • Gastrointestinal Disorder • Infectious Disease

Development and validation of a UPLC-MS/MS method for the quantification of parsaclisib and its application to pharmacokinetics and metabolic stability studies. (PubMed, BMC Chem) - "Parsaclisib was detected by gradient elution on an Acquity UPLC BEH C18 column (2.1 mm × 50 mm, 1.7 μm) using acetonitrile and 0.1% formic acid as mobile phases, and pilaralisib was used as an internal standard (IS). Finally, in vitro results showed that parsaclisib had a slow intrinsic clearance (Clint) value of 2.4 µL/min/mg protein with a half-life (t1/2) value of 571.3 min. These findings theoretically supported the potential metabolism of parsaclisib in vivo."

Journal • PK/PD data • Hematological Malignancies • Oncology • PIK3CD

Apolipoprotein C1 and apoprotein E as potential therapeutic and prognostic targets for adrenocortical carcinoma. (PubMed, Cancer Biomark) - "Furthermore, anti-programmed cell death protein 1 immunotherapy strongly downregulated the expression of APOC1 in patients with ACC. Both pilaralisib and elesclomol strongly inhibited SW13 cell growth.ConclusionsThis study preliminarily clarified that APOC1 and APOE might be potential therapeutic and prognostic targets for ACC, and identified new targets and treatment strategies for ACC."

Biomarker • IO biomarker • Journal • Adrenal Cortex Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • APOC1 • APOE • CDK1 • E2F1 • MIR182 • TP53 • TYK2

Uridine Phosphorylase 1 as a Biomarker Associated with Glycolysis in Acute Lung Injury. (PubMed, Inflammation) - "Molecular docking and molecular dynamics simulations further confirmed the stability of the binding between UPP1 and the three drugs. In conclusion, this study confirms that the uridine metabolism gene UPP1 associated with glycolysis is a key biomarker of ALI and provides valuable insights into the potential application of CAY10585, XL147 and IOX2 in ALI."

Biomarker • Journal • Acute Lung Injury • Respiratory Diseases • UPP1

Establishment and characterization of human organoids derived from medullary cancer and serrated adencocarcinoma; rare histological variants of colorectal cancer (EACR 2023) - "The ClinXPro-Report revealed a potential sensitivity of the different organoids to drugs such as the ERK1/ERK2 inhibitor Ulixertinib, the PI3K inhibitor Pilaralisib, the MEK inhibitor Refametinib or the S6K1 inhibitor PF-4708671.ConclusionCRC-PDOs can be used as tools to model different histological subtypes of CRC. Notably, the less frequent subtypes SAC and MC exhibited, in our analysis, significantly greater differences in gene expression compared to CCs. Our results suggest that further characterization of less frequent subtypes is necessary and that PDOs can have potential implications in the development of personalized therapies."

Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF • KRAS • MAPK1 • NRAS

FUNCTIONAL SCREENING OF PI3K INHIBITORS STRATIFIES RESPONDERS TO IDELALISIB AND INDICATES DRUG CLASS ACTIVITY IN IDELALISIB-REFRACTORY CLL (EHA 2022) - "Aims To characterize functional responses to 10 PI3Ki in CLL To study PI3Ki drug class activity in idelalisib-refractory CLL To investigate whether ex vivo drug sensitivity can predict in vivo treatment responses Methods CLL cells from patients that were treatment naïve (n=7), idelalisib refractory (n=9), or on idelalisib treatment (longitudinal samples from n=6 patients) were screened against 10 PI3Ki (buparlisib, compound 7n, copanlisib, duvelisib, idelalisib, nemiralisib, pictilisib, pilaralisib, umbralisib, ZSTK474), both alone and in combination with the B-cell lymphoma 2 (Bcl-2) antagonist venetoclax...Ex vivo drug testing on CLL cells from a patient who presented with relapsed disease after sequential treatment with FCR, ibrutinib, idelalisib and venetoclax revealed sensitivity to PI3Ki+venetoclax treatment...Conclusion Our findings indicate PI3Ki drug class activity in idelalisib-refractory CLL, and suggest that ex vivo drug sensitivity may guide precision..."

IO biomarker • Chronic Lymphocytic Leukemia • Leukemia • Lymphoma • Oncology • BCL2 • CASP3

Translating in vitro CFTR rescue into small molecule correctors for cystic fibrosis using the Library of Integrated Network-based Cellular Signatures drug discovery platform. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "Of these, XL147 rescued ΔF508-CFTR function in primary CF airway epithelia, while also showing cooperativity when administered with C18. Improved CF corrector therapies are greatly needed and this integrative drug prioritization approach offers a novel method to both identify small molecules that may rescue ΔF508-CFTR function and identify gene networks underlying such rescue."

Journal • Preclinical • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • CFTR • MIR138

Study of XL147 (SAR245408) or XL765 (SAR245409) in Combination With Letrozole in Subjects With Breast Cancer (clinicaltrials.gov) - P1/2; N=72; Completed; Sponsor: Sanofi; N=99 ➔ 72

Clinical • Combination therapy • Enrollment change • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Study of XL147 (SAR245408) or XL765 (SAR245409) in Combination With Letrozole in Subjects With Breast Cancer (clinicaltrials.gov) - P1/2; N=72; Completed; Sponsor: Sanofi; Active, not recruiting ➔ Completed

Clinical • Combination therapy • Trial completion • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2

[VIRTUAL] Efficacy and Safety of Phosphoinositide 3-Kinase (PI3K) Inhibitors in Non-Hodgkin's Lymphoma: A Systematic Review and Meta-Analysis (ASH 2020) - "Twenty studies used a selective PI3K inhibitor including voxtalisib, pilaralisib, umbralisib, duvelisib, idelalisib, copanlisib, buparlisib, and parsaclisib. PI3K pathway inhibitors have shown promising efficacy. However, the therapeutic applicability is hindered by the off-target adverse events especially gastrointestinal as well as the consequences of neutropenia. Overcoming these limitations would involve exploring the selectivity of novel agents, optimizing sequencing, use in combination regimens, and varying of the doses."

Retrospective data • Review • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Gastrointestinal Disorder • Hematological Malignancies • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Thrombocytopenia

The PI3K/mTOR dual inhibitor GSK458 potently impedes ovarian cancer tumorigenesis and metastasis. (PubMed, Cell Oncol (Dordr)) - "Based on our results, we conclude that GSK458 may serve as an attractive candidate to treat ovarian cancer."

Journal • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor

Clinical achievements reached by interfering with the IGF1R-PI3K-PTEN-AKT-mTOR axis (AACR-NCI- EORTC 2011) - The development of inhibitors of the PI3K-AKT-mTOR & IGF1R axis

Review • Breast Cancer • Hematological Malignancies • Hepatocellular Cancer • Melanoma • Multiple Myeloma • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Renal Cell Carcinoma

Safety study of XL147 (SAR245408) in combination with erlotinib in adults with solid tumors (clinicaltrials.gov) - P1, N=35; Active, not recruiting -> Completed; N=65 -> 35

Enrollment • Trial completion • Non Small Cell Lung Cancer • Oncology

A phase 1/2 dose-escalation study of SAR245408 (S08) or SAR245409 (S09) in combination with letrozole (L) in subjects with hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer (BC) refractory to a nonsteroidal aromatase inhibitor (AI) (SABCS 2011) - P1/2, N=17; Arm 1 dosing data from SAR245408 400 mg qd + letrozole 2.5 mg qd dose level (maximum dose level allowed per protocol) will be completed by Aug 2011; For arm 2, the MTD was SAR245409 50 mg bid + letrozole 2.5 mg, qd; SAEs reported in arm 1 (N=2) included 2 cases of Gr1 pneumothorax and 1 Gr4 pneumonitis while in arm 2 (N=2) included Gr4 lumbar pain & Gr4 elevation of ALT & AST

P1 data • Breast Cancer • Oncology

A phase 1/2 study of SAR245408 (S08) in combination with trastuzumab (T) or paclitaxel (P) and T in patients with HER2+ metastatic breast cancer (MBC) who progressed on a previous T-based regimen (SABCS 2011) - P1/2, N=33; MTD for arm 1 is SAR245408 (S08) 300 mg PO daily & trastuzumab (T) 8/6 mg/kg D1 q3w; SAEs reported in arm 1 (3 subjects) included Gr3 dehydration (2 cases), Gr3 epigastric pain & Gr2 dyspnea, while SAEs in arm 2 (4 subjects) included Gr4 neutropenia, Gr3 anorexia, Gr3 dehydration, Gr3 epigastric pain, Gr3 thromboembolism, Gr2 nausea, Gr2 pneumonitis & Gr2 headache; Preliminary PK data did not show interactions between S08 & either T or T+paclitaxel

P1/2 data • Breast Cancer • Oncology

A phase 1/2 dose-escalation study of SAR245408 (S08) or SAR245409 (S09) in combination with letrozole (L) in subjects with hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer (BC) refractory to a nonsteroidal aromatase inhibitor (AI) (SABCS 2011) - Presentation time: WEDNESDAY, DECEMBER 7, 2011, 5:00 pm - 7:00 pm; Abstract not available

Breast Cancer • Oncology

A phase 1/2 study of SAR245408 (S08) in combination with trastuzumab (T) or paclitaxel (P) and T in patients with HER2+ metastatic breast cancer (MBC) who progressed on a previous T-based regimen (SABCS 2011) - Presentation time: WEDNESDAY, DECEMBER 7, 2011, 5:00 pm - 7:00 pm; Abstract not available

Breast Cancer • Oncology

Safety study of XL147 (SAR245408), in combination with paclitaxel and carboplatin in adults with solid tumors (clinicaltrials.gov) - P1, N=74; Recruiting -> Active, not recruiting

Enrollment closed • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer

Trastuzumab-resistant cells rely on a HER2-PI3K-FoxO-survivin axis and are sensitive to PI3K inhibitors (Cancer Res) - Pubmed ID: 23204226; "Treatment with the pan-PI3K inhibitor XL147 and trastuzumab reduced proliferation and pAKT levels, triggering apoptosis of trastuzumab-resistant cells. Compared to XL147 alone, the combination exhibited a superior antitumor effect against trastuzumab-resistant tumor xenografts."

Preclinical • Oncology

Phase I dose-escalation study of pilaralisib (SAR245408, XL147) in combination with paclitaxel and carboplatin in patients with solid tumors (Oncologist) - P1, N=58; “The MTD of pilaralisib tablets in combination with paclitaxel and carboplatin was determined to be 200 mg QD. The most frequently reported adverse events (AEs) of any grade were neutropenia (67.2%) and thrombocytopenia (67.2%). PK data showed no interaction between pilaralisib and paclitaxel/carboplatin. Tumor tissue showed moderate inhibition of PI3K and mitogen-activated protein kinase (MAPK) pathways. Seven of 52 evaluable patients had a partial response (PR; 13.5%).”

P1 data

A study of the safety and pharmacokinetics of SAR245408 tablets in patients with solid tumors or lymphoma (clinicaltrials.gov) - P1, N=24; Sponsor: Sanofi; Not yet recruiting -> Recruiting.

Enrollment open • Oncology

Study of the safety and pharmacokinetics of XL147 (SAR245408) in adults with solid tumors or lymphoma (clinicaltrials.gov) - P1, N=118; Sponsor: Sanofi; Active, not recruiting -> Completed.

Trial completion • Oncology

Tumor pharmacokinetics (PK) and pharmacodynamics (PD) of SAR245409 (XL765) and SAR245408 (XL147) administered as single agents to patients with recurrent glioblastoma (GBM): An Ivy Foundation early-phase clinical trials consortium study (ASCO 2013) - Presentation time: Monday, Jun 3, 8:00 AM - 12:00 PM; Abstract #2012; P1, N=40; Sponsor: Sanofi; NCT01240460; "PK analyses revealed a mean tumor to plasma ratio of 0.38 and 0.40 in cohorts 1 and 3 and 0.27 in cohort 2. PD analysis by IHC revealed reduction compared to archived tumor in pS6K1 in 4/6 and 7/7 patients in cohorts 1 and 3 and 6/6 patients in cohort 2."

P1 data • Oncology

Safety and pharmacokinetics of SAR245408 daily oral in patients with solid tumors (clinicaltrials.gov) - P1, N=24; Recruiting -> Active, not recruiting

Enrollment closed • Oncology

Phase I trial of SAR245408 (S08), a pan-phosphatidylinositol 3 kinase (PI3K) inhibitor, in patients with chronic lymphocytic leukemia (CLL) and lymphoma (ASH 2011) - Presentation Time: Sunday, December 11, 2011, 6:00 PM-8:00 PM; P1, N=15; AEs were infrequent, those of any grade occurring in >10% of pts included diarrhea, hyperglycemia, headache & lymphopenia; Hematologic toxicity was uncommon, with grade 3-4 neutropenia observed in 4/15 pts (26.7%) & grade 3–4 thrombocytopenia observed in 1 of 15 (6.7%) pts; Follow-up to assess response is ongoing and updated data will be presented

P1 data • Oncology