First‐in‐human study of E7130 (a tumor microenvironment‐ameliorating microtubule inhibitor) in patients with advanced solid tumors: Primary results of the dose‐escalation part

Author:

Doi Toshihiko1ORCID,Matsubara Nobuaki2,Naito Yoichi123,Kuboki Yasutoshi1,Harano Kenichi12,Ono Makiko4,Urasaki Tetsuya4,Ohmoto Akihiro4,Kawanai Tsubasa5,Hisai Takashi6,Ikezawa Hiroki7,Shiba Sari8,Ito Ken9,Semba Taro10,Asano Osamu10,Takahashi Shunji4

Affiliation:

1. Department of Experimental Therapeutics National Cancer Center Hospital East Chiba Japan

2. Department of Medical Oncology National Cancer Center Hospital East Chiba Japan

3. Department of General Internal Medicine National Cancer Center Hospital East Chiba Japan

4. Department of Medical Oncology The Cancer Institute Hospital of Japanese Foundation for Cancer Research Tokyo Japan

5. Japan and Asia Clinical Development Department Oncology Business Group Eisai Co., Ltd. Tokyo Japan

6. Oncology Department Medical Headquarters Eisai Co., Ltd. Tokyo Japan

7. Clinical Data Science Department Medicine Development Center Eisai Co., Ltd. Tokyo Japan

8. Clinical Pharmacology Science Department Medicine Development Center Eisai Co., Ltd. Tokyo Japan

9. Oncology Tsukuba Research Development, Discovery, Medicine Creation Eisai Co., Ltd. Ibaraki Japan

10. Halichondrin Operation, Discovery, Medicine Creation Oncology Business Group Eisai Co., Ltd. Ibaraki Japan

Abstract

AbstractBackgroundE7130 is a novel anticancer agent created from a total synthetic study of norhalichondrin B. The authors report the E7130 dose‐escalation part of a first‐in‐human study of patients with advanced solid tumors (NCT03444701).MethodsJapanese patients ≥20 years of age were enrolled. E7130 was administered intravenously in two cycles: day 1 of a 21‐day cycle (Q3W) or days 1 and 15 of a 28‐day cycle (Q2W). Doses were escalated from 270 to 550 μg/m2 for the Q3W group or 25–400 μg/m2 for the Q2W group. The primary end point of the dose‐escalation phase was safety and tolerability as assessed by the incidence of dose‐limiting toxicities (DLTs) and adverse events. Other end points included determination of the maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics.ResultsForty‐four patients were enrolled: 15 in the E7130 Q3W group and 29 in the Q2W group. Treatment‐emergent adverse events (TEAEs) occurred in all patients; the most common TEAE overall was leukopenia (78.6%). Grade 3–4 TEAEs occurred in 93.3% of patients in the Q3W group and 86.2% of patients in the Q2W group. None had a TEAE resulting in study drug discontinuation, and no treatment‐related deaths were reported. Per the DLT evaluation, the MTDs were determined as 480 μg/m2 Q3W and 300 μg/m2 Q2W. Significant changes in multiple plasma biomarkers, including vascular endothelial growth factor 3 and matrix metallopeptidase 9, were dose‐dependent after initial doses of 350–480 μg/m2.ConclusionsE7130 480 μg/m2 Q3W was chosen for the dose‐expansion part over 300 μg/m2 Q2W primarily per dose‐dependent biomarker results.

Publisher

Wiley

Subject

Cancer Research,Oncology

Reference30 articles.

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2. Total synthesis of halichondrin B and norhalichondrin B

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4. In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B;Towle MJ;Cancer Res,2001

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