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First in human, a phase I study of ISU104, a novel ErbB3 monoclonal antibody, in patients with advanced solid tumours
abstracts
Annals of Oncology
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): BristolMyers Squibb-Ono Pharmaceutical; Honoraria (institution): Eisai; Honoraria (institution): Boehringer Ingelheim. J. Juhn: Leadership role, Shareholder / Stockholder / Stock options, Full / Parttime 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.
454PD
First in human, a phase I study of ISU104, a novel ErbB3 monoclonal antibody, in patients with advanced solid tumours
S.-B. Kim1, B. Keam2, S. Shin3, Y.S. Chae4, T.M. Kim2, M.-S. Kim5, J.G. Kim4, K. Park6, J.S. Ahn7, L.C. Park3, E. Lee3, J. Juhn8, S. Kim9, S.-B. Hong10, M.-J. Ahn11 1 Internal Medicine/Hemato-oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea, 2Internal medicine, Seoul National University Hospital, Seoul, Republic of Korea, 3Department of Internal Medicine, Kosin University Gospel, Busan, Republic of Korea, 4Oncology, Kyungpook National University Hospital, Daegu, Republic of Korea, 5Endocrology, University of Ulsan College of Medicine, Seoul, Republic of Korea, 6Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea, 7Medicine, Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul, Republic of Korea, 8Clinical Research, ISU ABXIS Co., Ltd., Seongnam, Republic of Korea, 9Clinical Development, ISU Abxis, Sungnam-si, Republic of Korea, 10Drug Development, ISU Abxis, Sungnam-si, Republic of Korea, 11Hematology-Oncology, Samsung Medical Center (SMC)-Sungkyunkwan University School of Medicine, Seoul, Republic of Korea 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 combinationtherapy.
Table: 454PD Cancer type
Hypopharynx Hypopharynx* Rectal Breast Palate Rectal Submandibular Parotid Colon NSCLC Esophagus Tonsil Esophagus
Best response PR Maximum change in -60.5 tumor size (target lesion) (%)
SD -21.9
SD SD -21.4 -8.1
SD 0.5
SD 2.8
SD 3.6
SD 6.9
PD 13.2
PD 13.5
PD 17.4
PD 28.1
PD 73.7
*Double primary with esophagus
v168 | Developmental Therapeutics
Volume 30 | Supplement 5 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz244.016/5578166 by guest on 26 October 2019
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 þ 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 ¼ 3), pruritus (n ¼ 2), diarrhea (n ¼ 2), and fatigue (n ¼ 2), but of which were grade 1. Only two grade 3 AEs were noted; asthenia (n ¼ 1) and anemia (n ¼ 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 (0.7760.41 ml/h/kg at 1 mg/kg; 0.2060.03 ml/h/kg at 20 mg/ kg) and half-lives to increase (44.5065.74 h at 1 mg/kg; 269.86619.08 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. 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. Legal entity responsible for the study: ISU Abxis. Funding: KDDF: Korea Drug Development Fund. Disclosure: B. Keam: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: MSD;
Annals of Oncology
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): BristolMyers Squibb-Ono Pharmaceutical; Honoraria (institution): Eisai; Honoraria (institution): Boehringer Ingelheim. J. Juhn: Leadership role, Shareholder / Stockholder / Stock options, Full / Parttime 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.
454PD
First in human, a phase I study of ISU104, a novel ErbB3 monoclonal antibody, in patients with advanced solid tumours
S.-B. Kim1, B. Keam2, S. Shin3, Y.S. Chae4, T.M. Kim2, M.-S. Kim5, J.G. Kim4, K. Park6, J.S. Ahn7, L.C. Park3, E. Lee3, J. Juhn8, S. Kim9, S.-B. Hong10, M.-J. Ahn11 1 Internal Medicine/Hemato-oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea, 2Internal medicine, Seoul National University Hospital, Seoul, Republic of Korea, 3Department of Internal Medicine, Kosin University Gospel, Busan, Republic of Korea, 4Oncology, Kyungpook National University Hospital, Daegu, Republic of Korea, 5Endocrology, University of Ulsan College of Medicine, Seoul, Republic of Korea, 6Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea, 7Medicine, Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul, Republic of Korea, 8Clinical Research, ISU ABXIS Co., Ltd., Seongnam, Republic of Korea, 9Clinical Development, ISU Abxis, Sungnam-si, Republic of Korea, 10Drug Development, ISU Abxis, Sungnam-si, Republic of Korea, 11Hematology-Oncology, Samsung Medical Center (SMC)-Sungkyunkwan University School of Medicine, Seoul, Republic of Korea 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 combinationtherapy.
Table: 454PD Cancer type
Hypopharynx Hypopharynx* Rectal Breast Palate Rectal Submandibular Parotid Colon NSCLC Esophagus Tonsil Esophagus
Best response PR Maximum change in -60.5 tumor size (target lesion) (%)
SD -21.9
SD SD -21.4 -8.1
SD 0.5
SD 2.8
SD 3.6
SD 6.9
PD 13.2
PD 13.5
PD 17.4
PD 28.1
PD 73.7
*Double primary with esophagus
v168 | Developmental Therapeutics
Volume 30 | Supplement 5 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz244.016/5578166 by guest on 26 October 2019
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 þ 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 ¼ 3), pruritus (n ¼ 2), diarrhea (n ¼ 2), and fatigue (n ¼ 2), but of which were grade 1. Only two grade 3 AEs were noted; asthenia (n ¼ 1) and anemia (n ¼ 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 (0.7760.41 ml/h/kg at 1 mg/kg; 0.2060.03 ml/h/kg at 20 mg/ kg) and half-lives to increase (44.5065.74 h at 1 mg/kg; 269.86619.08 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. 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. Legal entity responsible for the study: ISU Abxis. Funding: KDDF: Korea Drug Development Fund. Disclosure: B. Keam: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: MSD;