Phase I Dose Escalation Study with Expansion Cohort of the Addition of Nab-Paclitaxel to Capecitabine and Oxaliplatin (CapOx) as First-Line Treatment of Metastatic Esophagogastric Adenocarcinoma (ACTION Study).

Sandor Schokker,R Aarti Jibodh,Gerrit K J Hooijer,Sybren L Meijer,Ludo F M Beenen,Cynthia Waasdorp,Charlotte I Stroes,Cornelis J A Punt,Stephanie O Van Der Woude,Daan J Van Zoen,Banafsche Mearadji,Martijn G H Van Oijen,Aafke Creemers,Hanneke W M Van Laarhoven,Maarten F Bijlsma,Jessy Joy Van Kleef

doi:10.3390/cancers11060827

Sandor Schokker, R Aarti Jibodh + Show 14 more

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https://doi.org/10.3390/cancers11060827

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Abstract

First-line triplet chemotherapy including a taxane may prolong survival in patients with metastatic esophagogastric cancer. The added toxicity of the taxane might be minimized by using nab-paclitaxel. The aim of this phase I study was to determine the feasibility of combining nab-paclitaxel with the standard of care in the Netherlands, capecitabine and oxaliplatin (CapOx). Patients with metastatic esophagogastric adenocarcinoma received oxaliplatin 65 mg/m2 on days 1 and 8, and capecitabine 1000 mg/m2 bid on days 1–14 in a 21-day cycle, with nab-paclitaxel on days 1 and 8 at four dose levels (60, 80, 100, and 120 mg/m2, respectively), using a standard 3 + 3 dose escalation phase, followed by a safety expansion cohort. Baseline tissue and serum markers for activated tumor stroma were assessed as biomarkers for response and survival. Twenty-six patients were included. The first two dose-limiting toxicities (i.e., diarrhea and dehydration) occurred at dose level 3. The resulting maximum tolerable dose (MTD) of 80 mg/m2 was used in the expansion cohort, but was reduced to 60 mg/m2 after three out of eight patients experienced diarrhea grade 3. The objective response rate was 54%. The median progression-free (PFS) and overall survival were 8.0 and 12.8 months, respectively. High baseline serum ADAM12 was associated with a significantly shorter PFS (p = 0.011). In conclusion, albeit that the addition of nab-paclitaxel 60 mg/m2 to CapOx may be better tolerated than other taxane triplets, relevant toxicity was observed. There is a rationale for preserving taxanes for later-line treatment. ADAM12 is a potential biomarker to predict survival, and warrants further investigation.

Highlights

The mortality of gastric and esophageal carcinoma remains high, due to the high rate of locally advanced or metastatic disease at diagnosis, the substantial recurrence rate after treatment with curative intent, and the development of treatment resistance [1]
Twelve patients were enrolled in the dose-limiting toxicity (DLT)
We demonstrated ADAM12 and IL-6 levels to be unrelated to tumor burden, solidifying the value of these markers in assessing the activation status of stroma, as opposed to merely reflecting total tumor burden

Summary

Introduction

The mortality of gastric and esophageal carcinoma remains high, due to the high rate of locally advanced or metastatic disease at diagnosis, the substantial recurrence rate after treatment with curative intent, and the development of treatment resistance [1]. The addition of an anthracycline only marginally improves survival, while the addition of a taxane more effectively improves survival, albeit at the cost of increased toxicity [4]. Nab-paclitaxel has a favorable toxicity profile compared to conventional taxanes, and has shown non-inferiority to solvent-based paclitaxel with less toxicity in the second-line treatment of gastric carcinoma [5]. The primary aim of this study was to determine the recommended dose for phase II testing (RP2D) of nab-paclitaxel combined with capecitabine and oxaliplatin (CapOx), and to assess its feasibility in terms of toxicity

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