Phase I study of envafolimab (KN035), a novel subcutaneous single-domain anti-PD-L1 monoclonal antibody, in Japanese patients with advanced solid tumors
AbstractEnvafolimab is the first and only globally approved subcutaneously injectable PD-L1 antibody. This open-label, multicenter Phase 1 trial assessed the safety, tolerability, pharmacokinetic (PK) profile, and efficacy of envafolimab as a single agent in Japanese patients with advanced solid tumors. In the dose-escalation phase, 10 patients received subcutaneous (SC) envafolimab QW at 1.0 mg/kg, 2.5 mg/kg and 5.0 mg/kg. In the dose-expansion phase, 16 patients were treated at 2.5 or 5.0 mg/kg Q2W in part-1 and 9 patients received SC envafolimab 300 mg Q4W in part-2. No dose-limiting toxicities (DLTs) were reporte...
Source: Investigational New Drugs - August 6, 2022 Category: Drugs & Pharmacology Source Type: research
A phase Ib dose escalation study of oral monotherapy with KX2-391 in elderly patients with acute myeloid leukemia
SummaryPoor tolerance to standard therapies and multi-drug resistance complicate treatment of elderly patients with acute myeloid leukemia (AML). It is therefore imperative to explore novel tolerable agents and target alternative pathways. KX2-391 is an oral non-ATP-competitive inhibitor of Src kinase and tubulin polymerization. This multi-center phase Ib open-label safety and activity study involved elderly patients with relapsed or refractory AML, or who declined standard chemotherapy. Twenty-four patients averaging 74 years of age were enrolled. The majority previously received hypomethylating agents. Five doses were ...
Source: Investigational New Drugs - July 16, 2022 Category: Drugs & Pharmacology Source Type: research
Selinexor synergizes with azacitidine to eliminate myelodysplastic syndrome cells through p53 nuclear accumulation
AbstractMyelodysplastic syndromes (MDS) are clonal malignancies of multipotent hematopoietic stem cells, characterized by ineffective hematopoiesis leading to cytopenia. Hypomethylating agents, including azacitidine, have been used for treating MDS with some success; however, the overall survival rate remains poor and, therefore, finding new therapies is necessary. Selinexor, which exerts anticancer effects against some hematologic tumors, is a nuclear export protein inhibitor that blocks cell proliferation and induces apoptosis in various cancer cell lines. We investigated the effects of combined selinexor and azacitidine...
Source: Investigational New Drugs - July 16, 2022 Category: Drugs & Pharmacology Source Type: research
Antitumor activity of mianserin (a tetracyclic antidepressant) primarily driven by the inhibition of SLC1A5-mediated glutamine transport
SummaryTargeting tumor metabolic vulnerabilities such as “glutamine addiction” has become an attractive approach for the discovery of novel antitumor agents. Among various mechanisms explored, SLC1A5, a membrane transporter that plays an important role in glutamine cellular uptake, represents a viable target to interfere with tumor’s ability to acqu ire critical nutrients during proliferation. In the present study, a stably transfected HEK293 cell line with human SLC1A5 (HEK293-SLC1A5) was established for the screening and identification of small molecule SLC1A5 inhibitors. This in vitro system, in conjunction with d...
Source: Investigational New Drugs - July 14, 2022 Category: Drugs & Pharmacology Source Type: research
Real-world data on efficacy and safety of azacitidine therapy in chronic myelomonocytic leukemia in China: results from a multicenter, retrospective study
This study provides valuable real-life data in China on the treatment schedules, efficacy and safety of AZA in the treatment of CMML. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 14, 2022 Category: Drugs & Pharmacology Source Type: research
Improved delivery of Mcl-1 and survivin siRNA combination in breast cancer cells with additive siRNA complexes
This study aimed at investigating the influence of commercial transfection reagents (Prime-Fect, Leu-Fect A, and Leu-Fect C) complexed with different siRNAs (CDC20, HSP90, Mcl-1 and Survivin) in MDA-MB-436 breast cancer cells and the impact of incorporating an anionic additive, Trans-Booster, into siRNA formulations for improving in vitro gene silencing and delivery efficiency. Gene silencing was quantitatively analyzed by real-time RT-PCR while cell proliferation and siRNA uptake were evaluated by the MTT assay and flow cytometry, respectively. Amongst the investigated siRNAs and transfection reagents, Mcl-1/Prime-Fect co...
Source: Investigational New Drugs - July 14, 2022 Category: Drugs & Pharmacology Source Type: research
Brain pharmacokinetics and metabolism of the AMP-activated protein kinase selective inhibitor SBI-0206965, an investigational agent for the treatment of glioblastoma
Conclusion. SBI-0206965 has adequate brain permeability but low relative oral bioavailability which may be due to rapid hepatic metabolism, likely catalyzed by CYP3A enzymes. Our observations will facilitate further development of SBI-0206965, and/or other structurally related molecules, for the treatment of GBM and other brain tumors. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 8, 2022 Category: Drugs & Pharmacology Source Type: research
First-in-human study of IM156, a novel potent biguanide oxidative phosphorylation (OXPHOS) inhibitor, in patients with advanced solid tumors
AbstractPreclinical models suggest anticancer activity of IM156, a novel biguanide mitochondrial protein complex 1 inhibitor of oxidative phosphorylation (OXPHOS). This first-in-human dose-escalation study enrolled patients with refractory advanced solid tumors to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Eligible patients received oral IM156 every other day (QOD) or daily (QD) and were assessed for safety, dose-limiting toxicities (DLTs), pharmacokinetics, and preliminary signals of efficacy. 22 patients with advanced cancers (gastric, n = 8; colorectal, n = 3; ovarian, n =...
Source: Investigational New Drugs - July 8, 2022 Category: Drugs & Pharmacology Source Type: research
3D cell cultures, as a surrogate for animal models, enhance the diagnostic value of preclinical in vitro investigations by adding information on the tumour microenvironment: a comparative study of new dual-mode HDAC inhibitors
AbstractAnchorage-independent 3D-cultures of multicellular tumour spheroids (MCTS) and in vitro microtumours of cancer cells can provide upfront information on the effects of anticancer drug candidates, tantamount to that obtained from animal xenograft studies. Unlike 2D cancer cell cultures, 3D-models take into account the influence of the tumour microenvironment and the location dependence of drug effects and accumulation. We exemplified this by comparison of the effects of two new dual-mode anticancer agents, Troxbam and Troxham, and their monomodal congeners SAHA (suberoylanilide hydroxamic acid) and CA-4 (combretastat...
Source: Investigational New Drugs - July 7, 2022 Category: Drugs & Pharmacology Source Type: research
Combination of TACE and Lenvatinib as a promising option for downstaging to surgery of initially unresectable intrahepatic cholangiocarcinoma
ConclusionsTACE-L proves to be a safe and efficacious conversion therapy modality that allows for secondary resectability in patients with initially unresectable ICC. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 6, 2022 Category: Drugs & Pharmacology Source Type: research
Two novel piperidones induce apoptosis and antiproliferative effects on human prostate and lymphoma cancer cell lines
SummaryCancer remains the second most common cause of death in the US. Due to a recurrent problem with anticancer drug resistance, there is a current need for anticancer drugs with distinct modes of action for combination drug therapy We have tested two novel piperidone compounds, named 2608 (1-dichloroacetyl − 3,5-bis(3,4-difluorobenzylidene)-4-piperidone) and 2610 (1-dichloroacetyl-3,5-bis(3,4-dichlorobenzylidene)-4-piperidone), for their potential cytotoxicity on numerous human cancer cell lines. We found that both compounds were cytotoxic for breast, pancreatic, leukemia, lymphoma, colon, and fib roblast cell lines...
Source: Investigational New Drugs - July 6, 2022 Category: Drugs & Pharmacology Source Type: research
Anlotinib plus etoposide and cisplatin/carboplatin as first-line therapy for extensive-stage small cell lung cancer (ES-SCLC): a single-arm, phase II study
AbstractPatients with extensive-stage small-cell lung cancer (ES-SCLC) have high relapse rates and poor prognosis. Anlotinib monotherapy has shown promising efficacy for patients with ES-SCLC and has a non-overlapping toxicity profile with chemotherapy. Therefore, the study aims to assess the efficacy and safety of the addition of anlotinib to platinum-chemotherapy as first-line therapy for patients with ES-SCLC. ES-SCLC patients without systemic chemotherapy and immunotherapy were recruited. Eligible patients received anlotinib (12 mg/day, on day 1–14) of a 21-day cycle, with concomitant etoposide (100 mg/m2, on day ...
Source: Investigational New Drugs - July 5, 2022 Category: Drugs & Pharmacology Source Type: research
Author Correction: The 45-month therapy outcomes of permanent seed implantation and radical prostatectomy for prostate cancer patients
(Source: Investigational New Drugs)
Source: Investigational New Drugs - July 5, 2022 Category: Drugs & Pharmacology Source Type: research
Phase I study of aflibercept in combination with docetaxel in Japanese patients with advanced solid malignancies
This study sought to determine the recommended dose of aflibercept, a recombinant fusion protein targeting VEGF-A, VEGF-B and placental growth factor (PlGF), combined with docetaxel in Japanese patients with advanced solid malignancies. This phase I study was planned to include 12 patients following a 3 + 3 algorithm to determine the maximum tolerated dose of aflibercept combined with docetaxel in patients with metastatic or unresectable solid tumors (trial registration: NCT00545246). Docetaxel (75 mg/m2 every 3 weeks or 60 mg/m2 after protocol amendment) was combined with escalating doses of aflibercept (2, 4 an...
Source: Investigational New Drugs - June 30, 2022 Category: Drugs & Pharmacology Source Type: research
First-in-human phase 1/1b study to evaluate sitravatinib in patients with advanced solid tumors
AbstractSitravatinib (MGCD516), a spectrum-selective receptor tyrosine kinase inhibitor targetingTAM (TYRO3,AXL,MERTK) and split kinase family receptors, has demonstrated preclinical anti-tumor activity and modulation of tumor microenvironment. This first-in-human phase 1/1b study included sitravatinib dose exploration and anti-tumor activity evaluation in selected patients with advanced solid tumors. Primary objectives included assessment of safety, pharmacokinetics and clinical activity of sitravatinib. Secondary objectives included identifying doses for further investigation and exploring molecular markers for patient s...
Source: Investigational New Drugs - June 29, 2022 Category: Drugs & Pharmacology Source Type: research
