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Phase 1 Dose Escalation Study of SN2310 Injectable Emulsion in Patients With Advanced Solid Tumors

ABSTRACT: This is a Phase 1 open-label study of SN2310 Injectable Emulsion in patients with advanced solid malignancies. The study is designed to determine the maximum tolerated dose and dose-limiting toxicity of SN2310 Injectable Emulsion, and to characterize the pharmacokinetics of SN2310 and SN-38 following intravenous administration of SN2310 Injectable Emulsion. Additionally, evaluation of side effects as a function of dose, and observation of any anti-tumor effects of SN2310 Injectable Emulsion will be made.

DISEASE(S): Colorectal Neoplasms,Breast Neoplasms,Pancreatic Neoplasms,Lung Neoplasms,Neoplasms,Pelvic Neoplasms

PROVIDER: 2033356 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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SN-38, an active metabolite of irinotecan, enhances anti-PD1 treatment efficacy in head and neck squamous cell carcinoma

Project description:Anti-programmed cell death 1 (PD-1) therapy shows definite but modest activity in patients with advanced/metastatic HNSCC. Preliminary evidence suggests that SN-38, an activated form of irinotecan that activates the transcription factor FoxO3a, may suppress the expression of PD-L1 in breast and ovarian tumor models. Here, we explore the efficacy of SN-38 in combination with anti-PD1 for HNSCC treatment. In vitro, SN-38 enhances FoxO3a expression and reduces the expression of PD-L1 dose-dependently in HNSCC cells. Low dose SN-38 increases interferon- excretion by natural killer (NK) cells and promotes NK cell-mediated cytotoxicity of tumor cells. In vivo studies reveal that, at non-cytotoxic drug concentrations, SN-38 significantly enhances anti-PD-1 activity in suppressing murine tumor growth. An increased infiltration of CD8+ T cells and NK cells was found in the post-treatment tumors. RNA-seq analysis confirms that SN-38 promotes the enrichment of immune cells and biological function genes related to the immune response became abundant in SN-38 and anti-PD1 treated tumors. Thus, SN-38 is a potentially beneficial adjunct to checkpoint inhibitor therapy in HNSCC. Further studies to explore its mechanism of action and possible application are mandatory.

2023-01-11 | GSE222450 | GEO

Total and phosphoproteome analysis of effects of topoisomerase 1 and ATR inhibitors in small cell lung cancer nuclei

Project description:Total and phosphoproteome analysis of effects of topoisomerase 1 (SN-38) and ATR (M1774) inhibitors in small cell lung cancer. Experiments performed in nuclear extract. See MetaData for more information.

2023-02-21 | MSV000091336 | MassIVE

Molecular characterization of irinotecan (SN-38) resistant human breast cancer cell lines

Project description:SN-38 resistant breast cancer cell lies (MCF-7 and MDA-MB-231) were established by stepwise increasing the concentration of SN-38. Gene expression profiling was performed on parental (sensitive) MCF-7 and parental (sensitive) MDA-MB-231 cell lines and their respective SN-38 resistant cell lines. For each cell line we harvested RNA from three independent passages and conducted 3 arrays.

2016-01-05 | E-MTAB-3224 | biostudies-arrayexpress

Gene expression analysis upon UGT1A_i2 knockdown

Project description:Evaluate modulation in gene expression modulation upon UGT1A_i2 knockdown in basal conditions and also under pharmacological treatment (SN-38) 6 samples in duplicate (12 samples total); HT115 colorectal cell line was infected with either UGT1A_i2 shRNA or non-target shRNA and left untreated or treated with either vehicle or SN-38 (0.5 uM)

2014-01-08 | E-GEOD-48118 | biostudies-arrayexpress

Liposomal SN-38 in Treating Patients With Metastatic Colorectal Cancer

Project description:RATIONALE: Drugs used in chemotherapy, such as liposomal SN-38, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. PURPOSE: This phase II trial is studying how well liposomal SN-38 works in treating patients with metastatic colorectal cancer.

| 2027849 | ecrin-mdr-crc

Dose-finding Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of SNB-101(SN-38) in Patients With Tumors

Project description:SNB-101 is a novel nano-particle formulation of SN-38, the active metabolite of irinotecan(CPT-11). Study SNB101P01 is a multicenter, open-label, dose escalation, phase 1 study of SNB 101 with its active ingredient SN-38, in participants with advanced solid tumors. Dose escalation will occur using a modified accelerated titration design (ATD). All participants will receive SNB 101 in different cohorts. SNB 101 will be administered intravenously to participants on day 1 and day 15 of each 28 day treatment cycle until progressive disease, unacceptable toxicity, death, or withdrawal of consent, whichever occurs first. A Safety Review Committee will determine dose escalation, de-escalation, and modification and the MTD/RP2D based on DLTs and other safety information.

| 2358597 | ecrin-mdr-crc

Gene expression analysis upon UGT1A_i2 knockdown

Project description:Evaluate modulation in gene expression modulation upon UGT1A_i2 knockdown in basal conditions and also under pharmacological treatment (SN-38)

2014-01-08 | GSE48118 | GEO

Distinct effects of sacituzumab govitecan and berzosertib on DNA damage response in ovarian cancer

Project description:Antibody–drug conjugates (ADCs) have become an important class of anticancer drugs in solid tumors including drug-resistant gynecologic malignancies. TROP2 is a cell surface antigen that is highly expressed in ovarian carcinoma (OC) but minimally expressed in normal ovarian tissues. In this study, we aimed to identify how TROP2-specific ADC, sacituzumab govitecan (SG), modulates DNA damage response pathways in drug-resistant OC. We found that SG induces G2/M arrest, increases RPA1 foci, and decreases replication fork speed, resulting in replication stress in TROP2-positive cells while these effects were less evident in TROP2-negative cells. In OC in vitro and in vivo models, SN-38 sensitivity and TROP2 expression play key roles in response to either ATR inhibitor or SG alone, or in combination. Additionally, inhibition of translesion DNA synthesis enhances SG and PARP inhibitor (PARPi) sensitivity in PARPi-resistant OC cells. These findings provide novel mechanistic insights for future clinical development of SG in drug-resistant OC

2024-10-16 | GSE278664 | GEO

Deciphering Differential Gut Bacterial Drug Metabolism with Activity-Based Protein Profiling

Project description:Gut bacterial β-glucuronidases (GUS) promote the toxic side effects of therapeutics by reactivating drugs from their inactive glucuronide conjugates. It is increasingly clear that the interindividual variability of bacterial GUS-producing species in the gut microbiota contributes to differential drug responses. Indeed, the anticancer drug irinotecan exhibits variable clinical toxicity outcomes that have been linked to interindividual differences in the composition of the gut microbiota. However, identification of the specific GUS enzymes responsible for drug metabolism in the context of the complexity of the human fecal microbiota has not been achieved. Here we pinpoint the specific bacterial GUS enzymes that reactivate SN-38, the active metabolite of irinotecan, from complex human fecal microbiota samples with activity-based protein profiling (ABPP). We identify and quantify gut bacterial GUS enzymes from human feces with ABPP-enabled proteomics and then integrate this information with ex vivo kinetics to reveal the specific GUS enzymes responsible for the reactivation of SN-38. The same ABPP approach also reveals the molecular basis for differential gut bacterial GUS inhibition between human fecal samples. Taken together, this work provides an unprecedented pipeline to identify the specific bacterial GUS enzymes responsible for drug-induced GI toxicity from the complexity of human feces, which may serve as highly precise biomarkers of clinical outcomes for irinotecan and other therapeutics.

2019-12-03 | PXD014864 | Pride

A Dose Escalation Study of Efmarodocokin Alfa (UTTR1147A) in Healthy Volunteers and Patients with Ulcerative Colitis

Project description:Background: The interleukin-22 cytokine (IL-22) has demonstrated efficacy in nonclinical colitis models with a non-immunosuppressive mechanism-of-action. Efmarodocokin alfa (UTTR1147A) is a fusion protein agonist that links IL-22 to the crystallizable fragment (Fc) of human immunoglobulin (IgG4) for improved pharmacokinetic characteristics, but with a mutation to minimize Fc effector functions. Methods: This randomized, phase 1b study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of repeat intravenous dosing of efmarodocokin alfa in healthy volunteers (HVs; n=32) and patients with ulcerative colitis (UC; n=24) at 30Ã¢Â€Â“90 Ã‚Âµg/kg doses given biweekly (Q2W) or monthly (Q4W) (6:2 active:placebo per cohort). Results: The most common adverse events (AEs) were on-target dermatological effects (dry skin, erythema, and pruritus) that were reversible. Dose-limiting non-serious dermatological AEs (severe dry skin, erythema, exfoliation, and discomfort) were seen in two HVs and one patient at 90 ug/kg Q2W. Pharmacokinetics were generally dose-proportional across the dose levels tested, but patients demonstrated lower drug exposures relative to HVs at the same dose. IL-22 serum biomarkers and IL-22 responsive genes in colon biopsies were induced with active treatment. Patients demonstrated changes in microbiota composition following active treatment, thereby reversing baseline dysbiosis. Clinical response was observed in 7/18 active- and 1/6 placebo-treated patients; clinical remission was observed in 5/18 active- and 0/6 placebo-treated patients.

| EGAS00001006172 | EGA

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