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DS-8201a in Human Epidermal Growth Factor Receptor2 (HER2)-Expressing Colorectal Cancer (DESTINY-CRC01)

ABSTRACT: The main objective of this study is to test the safety and effectiveness of DS-8201a for participants with HER2-expressing advanced colorectal cancer.

DISEASE(S): Colorectal Neoplasm,Colorectal Cancer,Colorectal Neoplasms

PROVIDER: 2262173 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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A PHASE 2, MULTICENTER, OPEN-LABEL STUDY OF DS-8201A IN SUBJECTS WITH HER2-EXPRESSING ADVANCED COLORECTAL CANCER[DESTINY-CRC01]

Project description:Primary objectives: To determine the objective response rate (ORR) of DS-8201a in HER2 - positive advanced metastatic colorectal cancer patients. (Cohort A). Primary endpoints: Objective response rate (ORR) per imaging assessment - Percentage of participants with objective response per independent central imaging facility review based on Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1

| 2553617 | ecrin-mdr-crc

Testing the Combination of Two Anti-cancer Drugs, DS-8201a and AZD6738, for The Treatment of Patients With Advanced Solid Tumors Expressing the HER2 Protein or Gene, The DASH Trial

Project description:The dose escalation phase of this trial identifies the best dose and safety of ceralasertib (AZD6738) when given in combination with trastuzumab deruxtecan (DS-8201a) in treating patients with solid tumors that have a change (mutation) in the HER2 gene or protein and have spread to other places in the body (advanced). The dose expansion phase (phase Ib) of this trial compares how colorectal and gastroesophageal cancers with HER2 mutation respond to treatment with a combination of ceralasertib and trastuzumab deruxtecan versus trastuzumab deruxtecan alone. Trastuzumab deruxtecan is a monoclonal antibody, called trastuzumab, linked to a chemotherapy drug, called deruxtecan. Trastuzumab attaches to HER2 positive cancer cells in a targeted way and delivers deruxtecan to kill them. Ceralasertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

| 2363533 | ecrin-mdr-crc

Phase 2 study of DS-8201a in subjects with colorectal cancer [DESTINY-CRC01]

Project description:Intervention name : DS-8201a INN of the intervention : trastuzumab deruxtecan Dosage And administration of the intervention : IV solution (Once every 3 weeks, 6.4 mg/kg) Control intervention name : - INN of the control intervention : - Dosage And administration of the control intervention : - Primary outcome(s): efficacy The objective response rate RECIST Version 1.1 Study Design: multi center, open-label, 3-cohort study

| 2658293 | ecrin-mdr-crc

Phase 2 study of DS-8201a in subjects with colorectal cancer [DESTINY-CRC01]

Project description:Interventions: investigational material(s) Generic name etc : DS-8201a INN of investigational material : trastuzumab deruxtecan Therapeutic category code : 42- Antineoplastic agents Dosage and Administration for Investigational material : IV solution (Once every 3 weeks, 6.4 mg/kg) control material(s) Generic name etc : - INN of investigational material : - Therapeutic category code : Dosage and Administration for Investigational material : - Primary outcome(s): efficacy The objective response rate RECIST Version 1.1 Study Design: multi center, open-label, 3-cohort study

| 102108 | ecrin-mdr-crc

Bystander killing effect of DS-8201a, a novel anti-human epidermal growth factor receptor 2 antibody-drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity.

Project description:Antibody-drug conjugates deliver anticancer agents selectively and efficiently to tumor tissue and have significant antitumor efficacy with a wide therapeutic window. DS-8201a is a human epidermal growth factor receptor 2 (HER2)-targeting antibody-drug conjugate prepared using a novel linker-payload system with a potent topoisomerase I inhibitor, exatecan derivative (DX-8951 derivative, DXd). It was effective against trastuzumab emtansine (T-DM1)-insensitive patient-derived xenograft models with both high and low HER2 expression. In this study, the bystander killing effect of DS-8201a was evaluated and compared with that of T-DM1. We confirmed that the payload of DS-8201a, DXd (1), was highly membrane-permeable whereas that of T-DM1, Lys-SMCC-DM1, had a low level of permeability. Under a coculture condition of HER2-positive KPL-4 cells and negative MDA-MB-468 cells in vitro, DS-8201a killed both cells, whereas T-DM1 and an antibody-drug conjugate with a low permeable payload, anti-HER2-DXd (2), did not. In vivo evaluation was carried out using mice inoculated with a mixture of HER2-positive NCI-N87 cells and HER2-negative MDA-MB-468-Luc cells by using an in vivo imaging system. In vivo, DS-8201a reduced the luciferase signal of the mice, indicating suppression of the MDA-MB-468-Luc population; however, T-DM1 and anti-HER2-DXd (2) did not. Furthermore, it was confirmed that DS-8201a was not effective against MDA-MB-468-Luc tumors inoculated at the opposite side of the NCI-N87 tumor, suggesting that the bystander killing effect of DS-8201a is observed only in cells neighboring HER2-positive cells, indicating low concern in terms of systemic toxicity. These results indicated that DS-8201a has a potent bystander effect due to a highly membrane-permeable payload and is beneficial in treating tumors with HER2 heterogeneity that are unresponsive to T-DM1.

| S-EPMC4946713 | biostudies-literature

ACE1702 in Subjects With Advanced or Metastatic HER2-expressing Solid Tumors

Project description:ACE1702 (anti-HER2 oNK cells) is an off-the-shelf Natural Killer (NK) cell product that targets human HER2-expressing solid tumors. The ACE1702-001 phase I study aims to evaluate the safety and tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of ACE1702 in patients with advanced or metastatic HER2-expressing tumors, and to determine the phase Ib/II starting dose for ACE1702.

| 2333964 | ecrin-mdr-crc

MCF10A cells expressing HER2 and HER3 and grown in three-dimensional cultures

Project description:The tyrosine kinase receptors HER2 and HER3 play an important role in breast cancer. The HER2/HER3 heterodimer is a critical oncogenic unit associated with reduced relapse-free and decreased overall survival. We provide gene expression profile of the mammary epithelial cells MCF10A expressing HER2, HER3 or HER2/HER3 and grown in three-dimensional cultures for 15 days in the presence of heregulin, a known HER3-ligand that stabilizes and activates the HER2/HER3 heterodimer. The mammary epithelial cells MCF10A were transduced with retroviral vectors expressing HER2, HER3 or both. Cells from each group were grown for 15 days in three-dimensional cultures. At the end of the experiment, RNA was extracted for gene expression analysis.

2012-09-01 | E-GEOD-37009 | biostudies-arrayexpress

MCF10A cells expressing HER2 and HER3 and grown in three-dimensional cultures

2012-09-01 | GSE37009 | GEO

Pembrolizumab and Disitamab Vedotin in HER2-expressing Metastatic Colorectal Cancer

Project description:This is an open-label, multi-center, phase Ⅱ study. This study will evaluate the efficacy and safety of pembrolizumab in combination with disitamab vedotin in subject with HER2-expressing metastatic Colorectal Cancer (mCRC).

| 2719190 | ecrin-mdr-crc

Transcription profiling by array of human mammary epithelial cells infected with a recombinant adenoviral vector expressing a mutated HER2 inactivated for kinase function or wild type HER2

Project description:As an oncogene, use of HER2 vaccines in humans requires the development of HER2 immunotherapies with maximal immunologic potential, but minimal oncologic potential. To address these issues, we developed a recombinant adenoviral vector expressing a mutated HER2 inactivated for kinase function (Ad-HER2-ki). Ad-HER2-ki was highly expressed, but non-phosphorylated and elicited minimal transcription dysregulation in primary cells. In contrast, Ad-HER2-wt elicited a strong oncogenic signature associated with tumorigenesis. Experiment Overall Design: Early Passage Human Mammary Epithelial cells (HMECs) were serum starved for 36hrs. and infected at a MOI of 150 with either Ad-GFP, Ad-HER2-wt, or Ad-HER2-ki vectors. At 18 hpi, RNA was extracted and transcriptomes evaluated by microarray. Five samples were infected per virus treatment, each a completely separate biologic replicate.

2008-11-22 | E-GEOD-13274 | biostudies-arrayexpress

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