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Poster Discussion – Developmental therapeutics

1831 - First in human, a phase I study of ISU104, a novel ErbB3 monoclonal antibody, in patients with advanced solid tumors

Date

28 Sep 2019

Session

Poster Discussion – Developmental therapeutics

Presenters

Sung-Bae Kim

Citation

Annals of Oncology (2019) 30 (suppl_5): v159-v193. 10.1093/annonc/mdz244

Authors

S. Kim1, B. Keam2, S. Shin3, Y.S. Chae4, T.M. Kim2, M. Kim5, J.G. Kim4, K. Park6, J.S. Ahn7, L.C. Park3, E. Lee3, J. Juhn8, S. Kim9, S. Hong10, M. Ahn11

Author affiliations

  • 1 Internal Medicine/hemato-oncology, Asan Medical Center, University of Ulsan College of Medicine, 138-931 - Seoul/KR
  • 2 Internal Medicine, Seoul National University Hospital, 110-744 - Seoul/KR
  • 3 Department Of Internal Medicine, Kosin University Gospel, 49267 - Busan/KR
  • 4 Oncology, Kyungpook National University Hospital, 700-721 - Daegu/KR
  • 5 Endocrology, University of Ulsan College of Medicine, 138-931 - Seoul/KR
  • 6 Division Of Hematology-oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul/KR
  • 7 Medicine, Samsung Medical Center Sungkyunkwan University School of Medicine, 135-710 - Seoul/KR
  • 8 Clinical Research, ISU ABXIS Co., Ltd., 13488 - Seongnam/KR
  • 9 Clinical Development, ISU Abxis, 13488 - Sungnam-si/KR
  • 10 Drug Development, ISU Abxis, 13488 - Sungnam-si/KR
  • 11 Hematology-oncology, Samsung Medical Center (SMC)-Sungkyunkwan University School of Medicine, 135-710 - Seoul/KR

Resources

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Abstract 1831

Background

ErbB3, a heterodimeric partner of EGFR or ErbB2, is activated by heregulin binding in various cancers. ISU104, blocking ErbB3 activation and dimerization, showed anti-tumor effects in various preclinical models as mono- or combination-therapy.

Methods

In the part 1, we enrolled the patients with advanced solid tumor who were refractory to standard treatments. Study was conducted with a standard 3 + 3 dose escalation scheme at 5 different doses (1, 3, 5, 10, 20 mg/kg/day). Dose-limiting toxicities (DLTs) were evaluated during the 1st Cycle of 28 days. Thereafter, ISU104 was given weekly, and tumor response was assessed every 8 weeks. Blood samples for pharmacokinetics (PK) and immunogenicity studies were performed.

Results

In the part 1, 15 patients (13 males, 2 females) were enrolled. Median age was 54 (range 36–96). No DLT was observed even at the maximum dose (20mg/kg/day). The most common drug-related adverse events (AEs) were oral mucositis (n = 3), pruritus (n = 2), diarrhea (n = 2), and fatigue (n = 2), but of which were grade 1. Only two grade 3 AEs were noted; asthenia (n = 1) and anemia (n = 1). Thirteen subjects were assessable; 7 stable diseases and 1 partial response (table). One responder lasted up to 40 weeks. Drug clearances tend to decrease (0.77±0.41 ml/h/kg at 1 mg/kg; 0.20±0.03 ml/h/kg at 20 mg/kg) and half-lives to increase (44.50±5.74 h at 1 mg/kg; 269.86±19.08 h at 20 mg/kg) as dose is increased. PK analysis and modeling suggested target-mediated clearance of ISU104 and saturation of target binding at 3 mg/kg, and the dosing regimen for the part 2 of the current study, which would be 20 mg/kg tri-weekly.Table:

454PD

Cancer typeHypopharynxHypopharynx*RectalBreastPalateRectalSubmandibularParotidColonNSCLCEsophagusTonsilEsophagus
Best responsePRSDSDSDSDSDSDSDPDPDPDPDPD
Maximum change in tumor size (target lesion) (%)-60.5-21.9-21.4-8.10.52.83.66.913.213.517.428.173.7
*

Double primary with esophagus

Conclusions

Intravenous administrations of ISU104 were well tolerated up to 20 mg/kg/day without DLT, and showed disease control rate of 60.0%. Safety and efficacy of ISU104 as mono- or combination-therapy and potential biomarkers will be further explored in head and neck, colorectal and breast cancers.

Clinical trial identification

NCT03552406.

Editorial acknowledgement

Legal entity responsible for the study

ISU Abxis.

Funding

KDDF: Korea Drug Development Fund.

Disclosure

B. Keam: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: MSD; Advisory / Consultancy: Genexin; Research grant / Funding (self): ONO; Research grant / Funding (self): MSD; Research grant / Funding (institution): AstraZeneca. T.M. Kim: Research grant / Funding (institution): AstraZeneca. K. Park: Advisory / Consultancy: Astellas Pharma; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Lilly; Advisory / Consultancy: Hanmi; Advisory / Consultancy: Kyowa Hakko Kirin; Advisory / Consultancy: Norvatis; Advisory / Consultancy: Ono Pharmaceutical; Advisory / Consultancy: Roche; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: GlaxoSmithKline; Advisory / Consultancy: MSD; Speaker Bureau / Expert testimony: AZD. J.S. Ahn: Advisory / Consultancy: Samsung Bioepis; Honoraria (institution): Menarini; Honoraria (institution): Amgen; Honoraria (institution): Pfizer; Honoraria (institution): AstraZeneca; Honoraria (institution): Roche; Honoraria (institution): Janssen; Honoraria (institution): MSD; Honoraria (institution): Bristol-Myers Squibb-Ono Pharmaceutical; Honoraria (institution): Eisai; Honoraria (institution): Boehringer Ingelheim. J. Juhn: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: ISU Abxis. S. Kim: Full / Part-time employment: ISU Abxis. S. Hong: Shareholder / Stockholder / Stock options, Full / Part-time employment: ISU ABXIS. M. Ahn: Honoraria (institution), Advisory / Consultancy: AstraZeneca; Honoraria (institution), Advisory / Consultancy: BMS; Honoraria (institution), Advisory / Consultancy: MSD; Honoraria (institution): ONO; Honoraria (institution), Advisory / Consultancy: Roche; Advisory / Consultancy: TAKEDA; Advisory / Consultancy: Novartis; Advisory / Consultancy: Alpha pharmaceutical. All other authors have declared no conflicts of interest.

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