641P - Phase I/II clinical and pharmacokinetic study of ecubectedin in combination with irinotecan in patients with selected advanced solid tumors

Background

Ecubectedin –PM14– (ECU) is a new chemical entity that forms DNA adducts that inhibit RNA synthesis and active transcription of protein-coding genes. Antitumor activity as single agent and combined with Irinotecan (IRI) has been shown in vitro and in vivo in mice bearing xenografted human-derived tumors.

Methods

Open-label, dose-escalating, phase 1/2 trial of ECU administered as a 3-hour infusion + IRI i.v. D1 q3wk in patients (pts) with selected advanced solid tumors, adequate organ function and ECOG PS score of 0-1. 1^ry endpoint of phase 1 is to determine the maximum tolerated dose (MTD) and recommended dose (RD) of the combination, and of phase 2 is to confirm RD and evaluate efficacy (overall response rate, ORR) in selected tumor types.

Results

Phase 1: 30 pts were treated. Baseline characteristics: median age 60 years; female 70%; ECOG PS 0: 43%; median no. of prior lines (range): 4 (1-8). Most common tumor types: ovarian (n=7), NSCLC (n=5), STS (n=4). The MTD was ECU 4.5 mg/m² + IRI 50 mg/m² + 1^ry GCSF prophylaxis D1 q3wk. The RD was ECU 4.5 mg/m² + IRI 40 mg/m² + 1^ry GCSF prophylaxis D1 q3wk (dose-limiting toxicities [DLTs] at RD: G3 febrile neutropenia/ vomiting/ diarrhea in one pt, and G3 vomiting in another pt). Main treatment-related or unknown adverse events at the RD (n=15) were fatigue (80%), nausea (60%) and decreased appetite (33%). Main grade 3/4 lab abnormalities were transaminase increase (40%) and neutropenia (27%) -11 pts received 1^ry GCSF prophylaxis-. Only one pt (7%) had febrile neutropenia (without 1^ry GCSF prophylaxis). Antitumor activity comprised stable disease ≥4 months in 9 pts (30%) at all dose levels, mainly in NSCLC. Mean (CV%) plasma clearance of ECU was 4.9 L/h [56%]. PK parameters of IRI and SN-38 were similar to previously reported values. Phase 2 is ongoing, and only recruiting NSCLC patients. At cutoff, 9 pts have been treated. Safety and efficacy data of this cohort will be updated at the meeting.

Conclusions

At the RD, ECU + IRI + 1^ry GCSF prophylaxis has a manageable safety profile. Hematological abnormalities, fatigue, transaminase increase and nausea were the main toxicities. No major PK drug-drug interactions between ECU and IRI were found.

Clinical trial identification

EudraCT 2021-000415-23.

Editorial acknowledgement

Legal entity responsible for the study

PharmaMar S.A.

Funding

PharmaMar S.A.

Disclosure

A. Gil Torralvo: Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: Pfizer, Novartis, Daiichi Sankyo. M. Vieito: Financial Interests, Personal, Invited Speaker: Novocure; Financial Interests, Personal, Other, Steering committee member: BMS; Non-Financial Interests, Principal Investigator: Roche, BMS, Taiho, Hutchinson Pharma, Novartis, Mundipharma, Enterome, Debiopharm. G.F. Boggio, C. Kahatt, S. Fudio, A. Nieto: Financial Interests, Personal, Full or part-time Employment: PharmaMar; Financial Interests, Personal, Stocks/Shares: PharmaMar. C.M. Fernandéz, A. Hernandez, E. Cristoveanu: Financial Interests, Personal, Full or part-time Employment: PharmaMar. A. Redondo: Financial Interests, Personal, Invited Speaker: MSD, AstraZeneca, GSK, PharmaMar, Pharma&; Financial Interests, Personal, Advisory Board: MSD, AstraZeneca, GSK, PharmaMar, Boehringer Ingelheim; Financial Interests, Institutional, Local PI: Roche, Eisai, PharmaMar. All other authors have declared no conflicts of interest.