The goal of this clinical trial is to learn about the safety of NEROFE and doxorubicin and how well it works in patients with advanced/unresectable or metastatic solid KRAS-mutated and ST-positive solid tumors. The main question it aims to answer is to find the recommended dose and scheduled for the combination of NEROFE and doxorubicin. Participants will receive weekly doses of NEROFE and doxorubicin.

Start Date12 Apr 2023

Sponsor / Collaborator

Georgetown University

[+1]

NCT04365179 / RecruitingPhase 1

An Open-Label Phase 1b Study of NEROFE, a Novel Hormone-Peptide in Adult Patients With Advanced Myelodysplastic Syndrome (MDS) and Acute Myelogenous Leukemia (AML)

This is an open-label Phase 1b study of NEROFE following a traditional 3+3 design to assess safety and to determine the Recommended Phase 2 Dose (RP2D) of NEROFE in patients with MDS or AML. IV NEROFE will be administered three times per week on alternate days. The exact dosage will be determined using the body surface area (BSA) measured on Day 1 of each cycle.

Start Date18 Jun 2020

Sponsor / Collaborator

Immune System Key (ISK) Ltd.

[+1]

NCT03059615 / WithdrawnPhase 2

A Phase 2a, Open-Label, Two Stage Study: Stage A: Dose-Range Finder Study to Assess the Safety and Efficacy of Two Doses of Nerofe and Two Doses of Nerofe in Combination With Doxorubicin in Subjects With Acute Myelogenous Leukemia or High Risk Myelodysplastic Syndrome (AML/High Risk MDS). Stage B: Dose Confirmation Study to Assess the Safety and Efficacy of Nerofe or Nerofe in Combination With Doxorubicin in Subjects With AML/ High Risk MDS

This is a Phase 2a, Open-label, one arm study in which the eligible patients will be treated with IV Nerofe, three times a week in 28 days cycles (up to 12 cycles).
Evaluation will include safety procedures, blood level of study drug in certain time points, immune system response and tests checking the mechanism of the drug action.

Start Date25 Oct 2018

Sponsor / Collaborator

Immune System Key (ISK) Ltd.

100 Clinical Results associated with Immune System Key (ISK) Ltd.

0 Patents (Medical) associated with Immune System Key (ISK) Ltd.

Literatures (Medical) associated with Immune System Key (ISK) Ltd.

01 Jul 2023·Oncotarget

Transformation of immunosuppressive mtKRAS tumors into immunostimulatory tumors by Nerofe and Doxorubicin.

Article

Author: Sandler, Uziel ; Devary, Orly ; Ohana, Joel ; Devary, Yoram

Members of the rat sarcoma viral oncogene (RAS) subfamily KRAS are frequently mutated oncogenes in human cancers and have been identified in pancreatic ductal, colorectal, and lung adenocarcinomas. In this study, we show that a derivative of the hormone peptide Tumor Cell Apoptosis Factor (TCApF), Nerofe^™ (dTCApFs), in combination with Doxorubicin (DOX) substantially reduces viability of tumor cells. It was observed that the combination of Nerofe and DOX downregulated KRAS signaling via miR217 upregulation, resulting in enhanced apoptosis of tumor cells. In addition, the combination of Nerofe and DOX also resulted in activation of the immune system against tumor cells, manifested by an increase in the immunostimulatory cytokines IL-2 and IFN-γ as well as the recruitment of NK cells and M1 macrophages to the tumor site.

Molecular and Clinical Oncology

dTCApFs, a derivative of a novel human hormone peptide, induces apoptosis in cancer cells through a mechanism involving loss of Golgi function

Article

Author: Sandler, Uziel ; Ohana, Joel ; Devary, Yoram ; Stemmer, Salomon M ; Kass, Gideon

dTCApFs (Nerofe™) is a 14-amino acid derivative of a longer hormone peptide, tumor-cells apoptosis factor (TCApF), which enters the cells through the T1/ST2 receptor. In the present study, the mechanism of action (MOA) of dTCApFs as an anticancer agent was investigated. Experiments were performed in pancreatic cancer cell lines, and immunofluorescent staining demonstrated that dTCApFs is located in the Golgi apparatus of treated cells. It was also demonstrated in pancreatic, breast and ovarian cell lines that dTCApFs treatment led to Golgi structural changes, loss of Golgi function, and molecular effects associated with endoplasmic reticulum (ER) stress, such as increased levels of C/EBP homologous protein, binding immunoglobulin protein (BiP), phosphorylated inositol-requiring enzyme 1 (pIRE1), and increased phosphorylation of eukaryotic translation initiation factor 2α, and to the generation of reactive oxygen species, which was attenuated by ER stress inhibitors. Moreover, in these cell lines, long-term exposure to dTCApFs led to downregulation of spliced X-box-binding protein 1, which is an ER stress repair mechanism gene, downregulation of the Golgi anti-apoptotic protein, and reduced cell viability. In vivo studies using murine xenograft models of human pancreatic cancer verified the cell culture findings by demonstrating structural changes in the ER/Golgi and increased levels of pIRE1and BiP in dTCApFs-treated mice vs. the controls. Finally, human tissue samples from a patient who received dTCApFs for 11 months in a clinical trial were analyzed, and an increase was observed in the number of cells expressing pIRE1 and BiP post-treatment. In conclusion, we herein report a novel MOA for an anticancer agent involving triggering of apoptosis through induction of opposite effects: ER stress and downregulation of the ER stress repair mechanism. These findings provide the framework for the clinical evaluation of dTCApFs.

Molecular and Clinical Oncology

A phase I clinical trial of dTCApFs, a derivative of a novel human hormone peptide, for the treatment of advanced/metastatic solid tumors

Article

Author: Ohana, Joel ; Oren-Apoteker, Pnina ; Purim, Ofer ; Stemmer, Salomon M ; Sender, Naomi ; Silverman, Michael H ; Benjaminov, Ofer ; Meir, Chen ; Sandler, Uziel ; Devary, Yoram

The aim of the present phase I first-in-human study was to investigate the safety/efficacy of dTCApFs (a novel hormone peptide that enters cells through the T1/ST2 receptor), in advanced/metastatic solid tumors. The primary objective of this open-label dose-escalation study was to determine the safety profile of dTCApFs. The study enrolled patients (aged ≥18 years) with pathologically confirmed locally advanced/metastatic solid malignancies, who experienced treatment failure or were unable to tolerate previous standard therapy. The study included 17 patients (64% male; median age, 65 years; 47% colorectal cancer, 29% pancreatic cancer). The patients received 1-3 cycles of escalating dTCApFs doses (6-96 mg/m²). The mean number ± standard deviation of treatment cycles/patient was 3.2±1.4; no dose-limiting toxicities were observed up to a dose of 96 mg/m², and the maximum tolerated dose was not reached. Half-life, maximal plasma concentration, and dTCApFs exposure were found to be linearly correlated with dose. Five patients were treated for ≥3 months (12, 24, 48 mg/m²) and experienced stable disease throughout the treatment period, and 1 experienced pathological complete response. Analysis of serum biomarkers revealed decreased levels of angiogenic factors at dTCApFs concentrations of 12-48 mg/m², increased levels of anticancer cytokines, and induction of the endoplasmic reticulum (ER) stress biomarker GRP78/BiP. Efficacy and biomarker data suggest that patients whose tumors were T1/ST2-positive exhibited a better response to dTCApFs. In conclusion, dTCApFs was found to be safe/well-tolerated, and potentially efficacious, with linear pharmacokinetics. Consistent with preclinical studies, the mechanism through which dTCApFs exerts anticancer effects appears to involve induction of ER stress, suppression of angiogenesis, and activation of the innate immune response. However, further studies are warranted.

100 Deals associated with Immune System Key (ISK) Ltd.

100 Translational Medicine associated with Immune System Key (ISK) Ltd.

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Tumour cells apoptosis factor (Immune System Key) ( IL-33R )	Acute Myeloid Leukemia More	Phase 2 Clinical
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