Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Investigational New Drugs
Published in: Investigational New Drugs 2/2020

01-04-2020 | Heparin | PHASE I STUDIES

Phase I study of the anti-heparin-binding epidermal growth factor-like growth factor antibody U3-1565 with cetuximab in patients with cetuximab- or panitumumab-resistant metastatic colorectal cancer

Authors: Takako Eguchi Nakajima, Narikazu Boku, Ayako Doi, Hiroyuki Arai, Takuro Mizukami, Yoshiki Horie, Naoki Izawa, Mami Hirakawa, Takashi Ogura, Takashi Tsuda, Yu Sunakawa

Published in: Investigational New Drugs | Issue 2/2020

Login to get access

Summary

KRAS wild-type colorectal cancers initially responsive to anti-endothelial growth factor receptor (EGFR) antibodies [cetuximab (Cetu)/panitumumab (Pani)] develop acquired resistance. Overexpression of EGFR ligands such as heparin-binding EGF-like growth factor (HB-EGF) may be one resistance mechanism. This phase I study of U3-1565, anti-HB-EGF antibody, and Cetu combination therapy enrolled patients with KRAS wild-type metastatic colorectal cancer who had received two ≤ regimens with fluoropyrimidine, oxaliplatin, irinotecan, and Cetu/Pani and had disease progression on Cetu/Pani. Recommended dose (RD) was determined in the 1st stage, followed by evaluation of efficacy at the RD level in the 2nd-stage. Cetu was given at a loading dose of 400 mg/m2 followed by weekly infusions of 250 mg/m2 in levels 1 and 0. U3-1565 was administered at a loading dose of 24 mg/m2 followed by biweekly infusions of 16 mg/m2 in level 1 and 16–12 mg/m2 in level 0. Twenty-two patients were enrolled. No dose-limiting toxicities were observed among three patients in level 1 in the first stage, which was determined as RD. Grade 3 or higher adverse events occurred in 59.1%; those in ≥5% of patients were anemia, γ-GTP elevation, and acneiform rash. Overall response rate was 0.0% [95% confidence interval (CI): 0.0%–15.4%] and disease control was achieved in 17 patients (77.3%, 95% CI: 54.6%–92.2%). Median progression-free survival time was 85.0 days (95% CI: 54.0–91.0) and median survival time was 196 days (95% CI: 113.0–306.0). RD was determined as level 1. The efficacy of this combination therapy after progression on Cetu/Pani was negligible. Trial Registration: UMIN000013006.
Appendix
Available only for authorised users
Literature
1.
Ferlay J, Soerjomataram I, Ervik M et al (2012) GLOBOCAN 2012: estimated cancer incidence, mortality and prevalence worldwide in 2012. International Agency for Research on Cancer, Lyon
2.
Stintzing S, Modest DP, Rossius L, Lerch MM, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, al-Batran SE, Heintges T, Lerchenmüller C, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W, Held S, Giessen-Jung C, Moehler M, Jagenburg A, Kirchner T, Jung A, Heinemann V (2016) FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): a post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trial. Lancet Oncol 17:1426–1434CrossRef
3.
Yamazaki K, Nagase M, Tamagawa H, Ueda S, Tamura T, Murata K, Eguchi Nakajima T, Baba E, Tsuda M, Moriwaki T, Esaki T, Tsuji Y, Muro K, Taira K, Denda T, Funai S, Shinozaki K, Yamashita H, Sugimoto N, Okuno T, Nishina T, Umeki M, Kurimoto T, Takayama T, Tsuji A, Yoshida M, Hosokawa A, Shibata Y, Suyama K, Okabe M, Suzuki K, Seki N, Kawakami K, Sato M, Fujikawa K, Hirashima T, Shimura T, Taku K, Otsuji T, Tamura F, Shinozaki E, Nakashima K, Hara H, Tsushima T, Ando M, Morita S, Boku N, Hyodo I (2016) Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G). Ann Oncol 27:1539–1546CrossRef
4.
Yoshino T, Arnold D, Taniguchi H, Pentheroudakis G, Yamazaki K, Xu RH, Kim TW, Ismail F, Tan IB, Yeh KH, Grothey A, Zhang S, Ahn JB, Mastura MY, Chong D, Chen LT, Kopetz S, Eguchi-Nakajima T, Ebi H, Ohtsu A, Cervantes A, Muro K, Tabernero J, Minami H, Ciardiello F, Douillard JY (2018) Pan-Asian adapted ESMO consensus guidelines for the management of patients with metastatic colorectal cancer: a JSMO-ESMO initiative endorsed by CSCO, KACO, MOS, SSO and TOS. Ann Oncol 29:44–70CrossRef
5.
6.
Santini D, Vincenzi B, Addeo R, Garufi C, Masi G, Scartozzi M, Mancuso A, Frezza AM, Venditti O, Imperatori M, Schiavon G, Bronte G, Cicero G, Recine F, Maiello E, Cascinu S, Russo A, Falcone A, Tonini G (2012) Cetuximab rechallenge in metastatic colorectal cancer patients: how to come away from acquired resistance. Ann Oncol 23:2313–2318CrossRef
7.
Boeckx C, Baay M, Wouters A, Specenier P, Vermorken JB, Peeters M, Lardon F (2013) Anti-epidermal growth factor receptor therapy in head and neck squamous cell carcinoma: focus on potential molecular mechanisms of drug resistance. Oncologist 18:850–864CrossRef
8.
9.
Li C, Iida M, Dunn EF, Ghia AJ, Wheeler DL (2009) Nuclear EGFR contributes to acquired resistance to cetuximab. Oncogene 28:3801–3813CrossRef
10.
Yoshida M, Shimura T, Sato M, Ebi M, Nakazawa T, Takeyama H, Joh T (2013) A novel predictive strategy by immunohistochemical analysis of four EGFR ligands in metastatic colorectal cancer treated with anti-EGFR antibodies. J Cancer Res Clin Oncol 139:367–378CrossRef
11.
Pfeil I, aus dem Siepen P, Wagner T et al. (2012) U3–1565, a fully human anti-HB-EGF monoclonal antibody, inhibits oncogenic signaling and tumor cell growth in vitro and in vivo. In: AACR 103rd Annual Meeting. Chicago
12.
13.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247CrossRef
14.
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216CrossRef
15.
Harbison CT, Horak CE, Ledeine JM, Mukhopadhyay P, Malone DP, O'Callaghan C, Jonker DJ, Karapetis CS, Khambata-Ford S, Gustafson N, Trifan OC, Chang SC, Ravetto P, IV GAG (2013) Validation of companion diagnostic for detection of mutations in codons 12 and 13 of the KRAS gene in patients with metastatic colorectal cancer: analysis of the NCIC CTG CO.17 trial. Arch Pathol Lab Med 137:820–827CrossRef
16.
Van Cutsem E, Peeters M, Siena S et al (2007) Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 25:1658–1664CrossRef
17.
Yuki S, Komatsu Y, Muranaka T, Harada K, Sugiyama J, Tsuji Y, Ando T, Hosokawa A, Hatanaka K, Naruse H, Takahata T, Sato A, Kobayashi Y, Miyagishima T, Okuda H, Kudo M, Nakamura M, Hisai H, Sakamoto N, Sakata Y (2016) Phase II trial of panitumumab monotherapy for patients with KRAS exon2 wild type colorectal cancer after progression on cetuximab. HGCSG1101. Ann Oncol 27:149–206. https://​doi.​org/​10.​1093/​annonc/​mdw370.​45 CrossRef
18.
Tsuji A, Eto T, Masuishi T, Satake H, Segawa Y, Tanioka H, Hara H, Kotaka M, Sagawa T, Watanabe T, Nakamura M, Takahashi T, Negoro Y, Manaka D, Fujita H, Suto T, Ichikawa W, Fujii M, Takeuchi M, Nakajima T (2016) Phase II study of third-line cetuximab rechallenge in patients with metastatic wild-type K-RAS colorectal cancer who achieved a clinical benefit in response to first-line cetuximab plus chemotherapy (JACCRO CC-08). Ann Oncol 27:149–206. https://​doi.​org/​10.​1093/​annonc/​mdw370.​58 CrossRef
19.
Nakai K, Yoneda K, Moriue T, Igarashi J, Kosaka H, Kubota Y (2009) HB-EGF-induced VEGF production and eNOS activation depend on both PI3 kinase and MAP kinase in HaCaT cells. J Dermatol Sci 55:170–178CrossRef
20.
Zhao B, Wang L, Qiu H et al (2017) Mechanisms of resistance to anti-EGFR therapy in colorectal cancer. Oncotarget 8:3980–4000PubMed
21.
Bardelli A, Corso S, Bertotti A, Hobor S, Valtorta E, Siravegna G, Sartore-Bianchi A, Scala E, Cassingena A, Zecchin D, Apicella M, Migliardi G, Galimi F, Lauricella C, Zanon C, Perera T, Veronese S, Corti G, Amatu A, Gambacorta M, Diaz LA Jr, Sausen M, Velculescu VE, Comoglio P, Trusolino L, di Nicolantonio F, Giordano S, Siena S (2013) Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer. Cancer Discov 3:658–673CrossRef
22.
Reidy DL, Vakiani E, Fakih MG, Saif MW, Hecht JR, Goodman-Davis N, Hollywood E, Shia J, Schwartz J, Chandrawansa K, Dontabhaktuni A, Youssoufian H, Solit DB, Saltz LB (2010) Randomized, phase II study of the insulin-like growth factor-1 receptor inhibitor IMC-A12, with or without cetuximab, in patients with cetuximab- or panitumumab-refractory metastatic colorectal cancer. J Clin Oncol 28:4240–4246CrossRef
23.
Montagut C, Argilés G, Ciardiello F, Poulsen TT, Dienstmann R, Kragh M, Kopetz S, Lindsted T, Ding C, Vidal J, Clausell-Tormos J, Siravegna G, Sánchez-Martín FJ, Koefoed K, Pedersen MW, Grandal MM, Dvorkin M, Wyrwicz L, Rovira A, Cubillo A, Salazar R, Desseigne F, Nadal C, Albanell J, Zagonel V, Siena S, Fumi G, Rospo G, Nadler P, Horak ID, Bardelli A, Tabernero J (2018) Efficacy of Sym004 in patients with metastatic colorectal cancer with acquired resistance to anti-EGFR therapy and molecularly selected by circulating tumor DNA analyses: a phase 2 randomized clinical trial. JAMA Oncol 4:e175245. https://​doi.​org/​10.​1001/​jamaoncol.​2017.​5245 CrossRefPubMedPubMedCentral
24.
Metadata
Title
Phase I study of the anti-heparin-binding epidermal growth factor-like growth factor antibody U3-1565 with cetuximab in patients with cetuximab- or panitumumab-resistant metastatic colorectal cancer
Authors
Takako Eguchi Nakajima
Narikazu Boku
Ayako Doi
Hiroyuki Arai
Takuro Mizukami
Yoshiki Horie
Naoki Izawa
Mami Hirakawa
Takashi Ogura
Takashi Tsuda
Yu Sunakawa
Publication date
01-04-2020
Publisher
Springer US
Published in
Investigational New Drugs / Issue 2/2020
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI
https://doi.org/10.1007/s10637-019-00782-8

Other articles of this Issue 2/2020

Investigational New Drugs 2/2020 Go to the issue

PHASE I STUDIES

A first-in-human study of the novel metabolism-based anti-cancer agent SM-88 in subjects with advanced metastatic cancer

PHASE III STUDIES

Mirtazapine, a dopamine receptor inhibitor, as a secondary prophylactic for delayed nausea and vomiting following highly emetogenic chemotherapy: an open label, randomized, multicenter phase III trial

PRECLINICAL STUDIES

Midkine silencing enhances the anti–prostate cancer stem cell activity of the flavone apigenin: cooperation on signaling pathways regulated by ERK, p38, PTEN, PARP, and NF-κB

PRECLINICAL STUDIES

A preclinical evaluation of thiostrepton, a natural antibiotic, in nasopharyngeal carcinoma

PHASE I STUDIES

Preclinical activity and a pilot phase I study of pacritinib, an oral JAK2/FLT3 inhibitor, and chemotherapy in FLT3-ITD-positive AML

PRECLINICAL STUDIES

Cardamonin, a natural chalcone, reduces 5-fluorouracil resistance of gastric cancer cells through targeting Wnt/β-catenin signal pathway
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits