A Phase I, Open-Label Study Evaluating the Safety, Tolerability, and Pharmacokinetics of Escalating Doses of DHES0815A in Patients With HER2-Positive Breast Cancer

This first-in-human, Phase 1, open-label, multicenter, dose-escalation study will evaluate the safety, tolerability, and PK of DHES0815A as a single agent in participants with advanced and/or metastatic HER2-positive breast cancer for whom established treatment has proven ineffective or intolerable or is unavailable. The study may include a dose-expansion cohort (based on an ongoing assessment of the totality of data obtained in this study) to further assess safety, tolerability, PK, and preliminary anti-tumor activity.

Start Date17 Apr 2018

Sponsor / Collaborator

Genentech, Inc.

100 Clinical Results associated with RG-6148

100 Translational Medicine associated with RG-6148

100 Patents (Medical) associated with RG-6148

Literatures (Medical) associated with RG-6148

01 Nov 2021·Gynecologic OncologyQ2 · MEDICINE

DHES0815A, a novel antibody-drug conjugate targeting HER2/neu, is highly active against uterine serous carcinomas in vitro and in vivo

Q2 · MEDICINE

Article

Author: Pei Hui ; Natalia Buza ; Paola Manara ; Masoud Azodi ; Burak Zeybek ; Gulden Menderes ; Silvia Pelligra ; Vaagn Andikyan ; Justin Harold ; Nupur Nagarkatti ; Dennis Mauricio ; Aranzazu Manzano ; Elena Ratner ; Gloria S. Huang ; Adele Guglielmi ; Gary Altwerger ; Stefania Bellone ; Luca Zammataro ; Elena Bonazzoli ; Peter E. Schwartz ; Alessandro D. Santin ; Joan Tymon-Rosario ; Barbara Gnutti ; Mitchell Clark ; Dan-Arin Silasi

OBJECTIVEUterine serous carcinoma (USC) is an aggressive histologic variant of endometrial cancer which portends a poor prognosis. DHES0815A is a novel antibody-drug-conjugate (ADC) which binds specifically to HER2 overexpressing tumors at a distinct epitope from that bound by trastuzumab and pertuzumab after which it delivers the toxic payload, PBD-MA, a DNA mono-alkylating agent. The objective of this study was to evaluate the preclinical activity of DHES0815A against primary USC cell lines and xenografts.METHODSTwelve primary USC cell lines were assessed by immunohistochemistry (IHC) for HER2 protein expression and for C-erbB2 gene amplification using fluorescent in situ hybridization (FISH) analysis. Cell viability and bystander killing in USC cell lines after exposure to DHES0815A, the non-targeted ADC, and the unconjugated antibody (i.e. MHES0488A) were evaluated using flow cytometry-based-assays. In vivo activity of DHES0815A was tested against HER2/neu overexpressing USC xenografts.RESULTSHigh HER2/neu protein expression was seen in 25% (3/12) of the primary USC cell lines. USC cell lines overexpressing HER2/neu were significantly more sensitive to DHES0815A when compared to the non-targeted control ADC (p < 0.001). DHES0815A did not induce significant bystander killing of HER2/neu negative tumors when admixed with HER2/neu positive tumors. DHES0815A caused growth-inhibition and increased survival in USC HER2/neu overexpressing xenografts when compared to controls (p < 0.01).CONCLUSIONSDHES0815A is both highly selective and toxic to USC tumors overexpressing HER2/neu both in vitro and in vivo. HER2-directed ADCs, alone or in combination with other HER2/neu targeted agents may represent a novel treatment option for patients with tumors harboring HER2/neu overexpression refractory to trastuzumab and traditional chemotherapy.

Nature CommunicationsQ1 · CROSS-FIELD

The HER2-directed antibody-drug conjugate DHES0815A in advanced and/or metastatic breast cancer: preclinical characterization and phase 1 trial results

Q1 · CROSS-FIELD

ArticleOA

Author: Zhang, Donglu ; Saad, Ola ; Leipold, Douglas ; Wei, BinQing ; Commerford, Renee ; Modi, Shanu ; Yu, Shang-Fan ; Cho, Eunpi ; Wilson, Tim ; Kamath, Amrita ; Hamilton, Erika ; Choeurng, Voleak ; Lee, Genee ; Sliwkowski, Mark X ; LoRusso, Patricia ; Li, Guangmin ; Fields, Carter T ; Lewis, Gail D ; Crocker, Lisa ; Guo, Jun ; Mamounas, Michael ; Krop, Ian ; Pillow, Thomas ; Kalinsky, Kevin ; Lee, M Violet ; Schutten, Melissa M ; Jung, Kyung Hae ; Monemi, Sharareh ; Ungewickell, Alexander ; Sadowsky, Jack ; Dragovich, Peter S

AbstractApproved antibody-drug conjugates (ADCs) for HER2-positive breast cancer include trastuzumab emtansine and trastuzumab deruxtecan. To develop a differentiated HER2 ADC, we chose an antibody that does not compete with trastuzumab or pertuzumab for binding, conjugated to a reduced potency PBD (pyrrolobenzodiazepine) dimer payload. PBDs are potent cytotoxic agents that alkylate and cross-link DNA. In our study, the PBD dimer is modified to alkylate, but not cross-link DNA. This HER2 ADC, DHES0815A, demonstrates in vivo efficacy in models of HER2-positive and HER2-low cancers and is well-tolerated in cynomolgus monkey safety studies. Mechanisms of action include induction of DNA damage and apoptosis, activity in non-dividing cells, and bystander activity. A dose-escalation study (ClinicalTrials.gov: NCT03451162) in patients with HER2-positive metastatic breast cancer, with the primary objective of evaluating the safety and tolerability of DHES0815A and secondary objectives of characterizing the pharmacokinetics, objective response rate, duration of response, and formation of anti-DHES0815A antibodies, is reported herein. Despite early signs of anti-tumor activity, patients at higher doses develop persistent, non-resolvable dermal, ocular, and pulmonary toxicities, which led to early termination of the phase 1 trial.

International Journal of Molecular SciencesQ2 · BIOLOGY

HER2 Directed Antibody-Drug-Conjugates beyond T-DM1 in Breast Cancer

Q2 · BIOLOGY

ReviewOA

Author: Gampenrieder, Simon Peter ; Greil, Richard ; Rinnerthaler, Gabriel

Since the discovery of the human epidermal growth factor receptor 2 (HER2) as an oncogenic driver in a subset of breast cancers and the development of HER2 directed therapies, the prognosis of HER2 amplified breast cancers has improved meaningfully. Next to monoclonal anti-HER2 antibodies and tyrosine kinase inhibitors, the antibody-drug conjugate T-DM1 is a pillar of targeted treatment of advanced HER2-positive breast cancers. Currently, several HER2 directed antibody-drug conjugates are under clinical investigation for HER2 amplified but also HER2 expressing but not amplified breast tumors. In this article, we review the current preclinical and clinical evidence of the investigational drugs A166, ALT-P7, ARX788, DHES0815A, DS-8201a, RC48, SYD985, MEDI4276 and XMT-1522.

100 Deals associated with RG-6148

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
HER2 Positive Breast Cancer	Phase 1	US	Genentech, Inc.	17 Apr 2018
HER2 Positive Breast Cancer	Phase 1	KR	Genentech, Inc.	17 Apr 2018

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03451162 (CTgov)	Phase 1	HER2 Positive Breast Cancer	14	DHES0815A (Dose Escalation Cohort: DHES0815A 0.6 mg/kg)	(sgrhzrywcx) = aqhoyfpkzq aeoycdrbmy (iztkvznkkn, mqtdhoumwk - dggmtvnesm) View more	-	05 Aug 2024
				DHES0815A (Dose Escalation Cohort: DHES0815A 1.2 mg/kg)	(sgrhzrywcx) = ufvhequggt aeoycdrbmy (iztkvznkkn, sjmielqqar - pxmhzgtpwb) View more

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis

RG-6148

Overview

Basic Info

Structure

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation