545P - First-in-human (FIH) study of E7130 in patients (pts) with advanced solid tumors: Primary result of dose-escalation part

Background

E7130 is a halichondrin-class novel microtubule inhibitor with pre-clinical ameliorating effects on the tumor microenvironment (TME) featuring vascular remodeling and anticancer-associated fibroblast effects. We report the dose-escalation part of a FIH (phase 1) study of E7130 in pts with advanced solid tumors.

Methods

In this open-label study, pts with solid tumors for which no alternative standard therapy exists received E7130 IV Q2W (days 1 and 15 of a 28-day cycle) or Q3W (day 1 of a 21-day cycle). The objectives of the dose escalation part included determining tolerability and safety, pharmacokinetics (PK), pharmacodynamics (PD) and the recommended dose for a further expansion part. The maximum tolerated dose (MTD) was determined using an accelerated modified Toxicity Probability Interval design.

Results

The study enrolled 44 pts: 29 in the Q2W group (E7130 dose range: 25-400 μg/m²) and 15 in the Q3W group (E7130 dose range: 270-550 μg/m²). Median age was 67 years (24-79); 21 pts were male; 23 pts had ECOG-PS 0. In the Q2W group, E7130 dose-limiting toxicities (DLTs) were observed at 350 μg/m² in 6/13 pts (2 had grade 3 hyponatremia; 1 had grade 4 hyponatremia and a dose skip at day 15 due to toxicity; 3 others had dose skips at day 15 due to toxicity), and at 400 μg/m² in 2/6 pts (1 had grade 3 febrile neutropenia [FN]; 1 had a dose skip at day 15 due to toxicity). In the Q3W group, DLTs were observed at 550 μg/m² in 2/2 pts (1 had grade 3 FN; 1 had grade 4 neutropenia ≥ 7 days). The most common treatment-emergent adverse event was leukopenia (79.5%). The E7130 MTDs were 300 μg/m² Q2W and 480 μg/m² Q3W. Partial tumor responses were observed in 2 pts (esophageal squamous cell carcinoma, n=1; bladder urothelial carcinoma n=1). Preliminary PK analysis showed the AUC of E7130 increased with increasing dose over the assessed dose range. Preliminary PD analysis showed a change in TME-related biomarkers in plasma by E7130 at 480 μg/m² Q3W.

Conclusions

E7130 had manageable toxicity in pts with advanced solid tumors, preliminary antitumor activity, and TME-related biomarker changes. E7130 480 μg/m² Q3W was recommended for a further expansion part where safety, efficacy, PK, and biomarkers will be analyzed.

Clinical trial identification

NCT03444701.

Editorial acknowledgement

Editorial support was provided by Oxford Pharma-Genesis Inc., Newtown, PA, USA.

Legal entity responsible for the study

Eisai Co., Ltd.

Funding

Eisai Co., Ltd.

Disclosure

T. Doi: Financial Interests, Institutional, Principal Investigator: Lilly; Financial Interests, Institutional, Principal Investigator: MSD; Financial Interests, Institutional, Principal Investigator: Daiichi Sankyo; Financial Interests, Institutional, Principal Investigator: Sumitomo Dainippon; Financial Interests, Institutional, Principal Investigator: Taiho; Financial Interests, Institutional, Principal Investigator: Novartis; Financial Interests, Institutional, Principal Investigator: Merck Serono; Financial Interests, Institutional, Principal Investigator: Janssen; Financial Interests, Institutional, Principal Investigator: Boehringer Ingelheim; Financial Interests, Institutional, Principal Investigator: Pfizer; Financial Interests, Institutional, Principal Investigator: BMS; Financial Interests, Institutional, Principal Investigator: Abbvie; Financial Interests, Institutional, Principal Investigator: IQVIA; Financial Interests, Institutional, Principal Investigator: Eisai; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Abbvie; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: Astellas; Financial Interests, Personal, Advisory Board: Sumitomo Dainippon; Financial Interests, Personal, Advisory Board: Taiho; Financial Interests, Personal, Advisory Board: Takeda; Financial Interests, Personal, Advisory Board: Chugai; Financial Interests, Personal, Advisory Board: Rakuten Medical; Financial Interests, Personal, Advisory Board: Otsuka; Financial Interests, Personal, Advisory Board: Oncolys Biopharma; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: Ono; Financial Interests, Personal, Invited Speaker: Taiho. N. Matsubara: Financial Interests, Personal, Speaker’s Bureau: Janssen; Financial Interests, Personal, Speaker’s Bureau: Sanofi; Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Institutional, Research Grant: Janssen; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Takeda; Financial Interests, Institutional, Research Grant: Lilly; Financial Interests, Institutional, Research Grant: Amgen; Financial Interests, Institutional, Research Grant: Astellas; Financial Interests, Institutional, Research Grant: Chugai; Financial Interests, Institutional, Research Grant: Bayer; Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Institutional, Research Grant: Ono; Financial Interests, Institutional, Research Grant: Taiho; Financial Interests, Institutional, Research Grant: Pfizer. Y. Naito: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Invited Speaker: Chugai; Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: Chugai; Financial Interests, Personal, Speaker’s Bureau: Eisai; Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Personal, Speaker’s Bureau: Eli Lilly; Financial Interests, Personal, Invited Speaker: Fuji Film Toyama Chemistry; Financial Interests, Personal, Speaker’s Bureau: Fuji Film Toyama Chemistry; Financial Interests, Personal, Invited Speaker: Gardant; Financial Interests, Personal, Speaker’s Bureau: Gardant; Financial Interests, Personal, Invited Speaker: Nihon Kayaku; Financial Interests, Personal, Speaker’s Bureau: Nihon Kayaku; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Speaker’s Bureau: Novartis; Financial Interests, Personal, Invited Speaker: Ono; Financial Interests, Personal, Speaker’s Bureau: Ono; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Speaker’s Bureau: Pfizer; Financial Interests, Personal, Invited Speaker: Taiho; Financial Interests, Personal, Speaker’s Bureau: Taiho; Financial Interests, Personal, Invited Speaker: Takeda; Financial Interests, Personal, Speaker’s Bureau: Takeda; Financial Interests, Personal, Other, Local PI: ABBVIE; Financial Interests, Personal, Other, Local PI: Boehringer Ingelheim; Financial Interests, Personal, Other, Local PI: Chugai; Financial Interests, Personal, Other, Local PI: Daiichi Sankyo; Financial Interests, Personal, Other, Local PI: Ono; Financial Interests, Personal, Other, Local PI: Pfizer; Financial Interests, Personal, Funding: Roche; Financial Interests, Personal, Other, Local PI: Taiho; Non-Financial Interests, Principal Investigator, JCOG: Natera. Y. Kuboki: Financial Interests, Personal, Speaker’s Bureau: Taiho; Financial Interests, Personal, Speaker’s Bureau: ONO; Financial Interests, Personal, Speaker’s Bureau: Bayer; Financial Interests, Personal, Speaker’s Bureau: Sanofi; Financial Interests, Institutional, Research Grant: Daiichi-Sankyo; Financial Interests, Institutional, Principal Investigator: Taiho; Financial Interests, Institutional, Principal Investigator: Takeda; Financial Interests, Institutional, Principal Investigator: ONO; Financial Interests, Institutional, Principal Investigator: Abbie; Financial Interests, Institutional, Principal Investigator: AstraZeneca; Financial Interests, Institutional, Principal Investigator: Boehringer Ingelheim; Financial Interests, Institutional, Principal Investigator: Incyte; Financial Interests, Institutional, Principal Investigator: Amgen; Financial Interests, Institutional, Principal Investigator: Chugai; Financial Interests, Institutional, Principal Investigator: GSK; Financial Interests, Institutional, Principal Investigator: Genmab; Financial Interests, Institutional, Principal Investigator: Astelas; Financial Interests, Personal, Advisory Role: Takeda; Financial Interests, Personal, Advisory Role: Boehringer Ingelheim; Financial Interests, Personal, Advisory Role: Taiho. K. Harano: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Chugai; Financial Interests, Personal, Invited Speaker: Eizai; Financial Interests, Personal, Invited Speaker: Taiho; Financial Interests, Personal, Invited Speaker: Takeda; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Chugai; Financial Interests, Personal, Advisory Board: Taiho; Financial Interests, Personal, Advisory Board: Takeda; Financial Interests, Institutional, Research Grant: Daiichi-Sankyo; Financial Interests, Institutional, Research Grant: Merck. M. Ono: Financial Interests, Personal, Invited Speaker: Chugai; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Institutional, Research Grant: Astellas; Financial Interests, Institutional, Research Grant: Eisai; Financial Interests, Institutional, Principal Investigator: Chugai; Financial Interests, Institutional, Sponsor/Funding: Chugai. T. Hisai: Financial Interests, Personal, Full or part-time Employment: Eisai Co., Ltd. A. Mikubo: Financial Interests, Personal, Full or part-time Employment: Eisai Co., Ltd.; Financial Interests, Personal, Stocks/Shares: Eisai Co., Ltd.; Financial Interests, Personal, Sponsor/Funding: Eisai Co., Ltd. H. Ikezawa: Financial Interests, Personal, Full or part-time Employment: Eisai Co.,Ltd. S. Shiba: Financial Interests, Institutional, Full or part-time Employment: Eisai Co., Ltd. K. Ito: Financial Interests, Personal, Full or part-time Employment: Eisai, Co,. Ltd. O. Asano: Financial Interests, Institutional, Writing Engagements: Eisai Co.,Ltd; Financial Interests, Institutional, Full or part-time Employment: Eisai Co.,Ltd.; Financial Interests, Institutional, Project Lead: Eisai Co.,Ltd. S. Takahashi: Financial Interests, Personal, Invited Speaker: Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Chugai; Financial Interests, Personal, Invited Speaker: Bayer; Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Institutional, Other, Local PI: Taiho; Financial Interests, Institutional, Other, Local PI: Daiichi Sankyo; Financial Interests, Institutional, Other, Local PI: Novartis; Financial Interests, Institutional, Other, Local PI: Ono Pharmaceutical; Financial Interests, Institutional, Other, Local PI: Eisai; Financial Interests, Institutional, Other, Local PI: IQVIA; Financial Interests, Institutional, Other, Local PI: Bristrol Myers Squib; Financial Interests, Institutional, Other, Local PI: Bayer; Financial Interests, Institutional, Other, Local PI: AstraZeneca All other authors have declared no conflicts of interest.