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)

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.

Serum-based measurements of stromal activation through ADAM12 associate with poor prognosis in colorectal cancer

“…ADAM12 levels were measured by ELISA in all available serum samples from the CAIRO2 cohort ( n = 235 (31%)). ADAM12 levels were high with a median of 603 (IQR 1351) pg/mL, compared to previously published healthy controls (median 153 (IQR 169) pg/mL [ 21 ]), and higher compared to metastatic esophagogastric adenocarcinoma (median 242.5 pg/mL) [ 43 ] and esophageal adenocarcinoma (median 108.7 pg/mL) [ 44 ], but lower than metastatic pancreatic ductal adenocarcinoma patients (median 2293 pg/mL) [ 21 ].…”

“…CMS4 tumors harbor more stroma, explaining the association in bulk tumor measurements. We take this to imply that ADAM12 is a purely stromal activation marker, as also shown for pancreatic and esophageal cancer [ 21 , 43 , 44 ]. There was however a clear prognostic signal for ADAM12 within the mesenchymal subtype.…”

Circulating tumor DNA predicts outcome in metastatic gastroesophageal cancer

“…Baseline CT scans were used to measure three dimensional tumor volume as previously described [ 24 ]. In short semi-automated software (MM oncology, Syngo Via, Siemens Healthineers, Forchheim, Germany) was used for volume calculations (in milliliters) under the supervision of an experienced radiologist blinded for outcome.…”

Preoperative serum ADAM12 levels as a stromal marker for overall survival and benefit of adjuvant therapy in patients with resected pancreatic and periampullary cancer

“…Serum is stored at −80 C. ADAM12 levels were determined in mono in 80 ml of serum, using a commercially available ADAM12 DuoSet ELISA kit (R&D Systems, Minneapolis, MN), according to the manufacturer's instructions and as previously described. 4 The analyses were performed by a technician, blinded for outcomes. Carbohydrate antigen (CA) 19-9 and bilirubin levels were measured in 50 ml serum using an immunochemical assay on the Roche e602 (Roche Diagnostics, Almere, The Netherlands) integrated in a Cobas c8000 system (Roche Diagnostics).…”

“…3 In subsequent studies, serum ADAM12 levels showed prognostic value in patients with gastrointestinal adenocarcinomas. 4 In metastatic PDAC, it was shown that only patients with low circulating ADAM12 levels benefited from the addition of nab-paclitaxel to the standard of care gemcitabine. 3 This could possibly be explained by the mechanical barrier function of stroma preventing delivery of nabpaclitaxel, but needs to be explored further.…”