The prognosis of advanced EGAC remains poor. Triplets containing taxanes show a survival benefit but at the cost of increased toxicity. Given the favorable toxicity profile of nab-P compared to conventional taxanes we conducted a phase 1 dose escalation study to find the maximum tolerated and recommended phase 2 dose (MTD/RP2D) of the addition of nab-P to CAPOX.
Patients (pts) with metastatic or non-resectable EGAC received oxaliplatin 65 mg/m2 day 1 and 8 and capecitabine 1000 mg/m2 bid day 1-14 in a 21 day cycle, with nab-P day 1 and 8 at 4 dose levels (DL1 60, DL2 80, DL3 100 and DL4 120 mg/m2, respectively) in a standard 3 + 3 design, followed by an expansion cohort of 20 pts. Tumor response was assessed every 3 cycles (RECIST 1.1). Pts were treated until progressive disease (PD), unacceptable toxicity or a maximum of 6 cycles after which capecitabine monotherapy was continued. Ox and nab-P were reintroduced if PD occurred after more than 3 months.
We enrolled 26 pts (median age 63; 18 had esophageal cancer and 8 gastric cancer). Ten pts had received prior curative treatment. At DL1 and DL2 no dose limiting toxicity (DLT) occurred. At DL3 2 DLT’s occurred (diarrhea and dehydration due to vomiting/diarrhea). MTD was established at 80 mg/m2 and chosen for evaluation in the expansion cohort. However, because of diarrhea grade 3 in 5/12 pts (42%) in the course of treatment the nab-P dose was reduced to 60 mg/m2. Grade 3/4 toxicity of all pts treated at this DL was nausea (18%), diarrhea, vomiting, anorexia and elevated GGT (all 9%). Notable grade 1/2 toxicities were neuropathy (82%), dysgeusia, diarrhea (both 64%), nausea (55%) and vomiting (45%). Best responses were PR (13 pts), SD (9 pts) and PD (2 pts). Median follow up is 9.1 months, 22 pts completed 6 cycles and 5 pts are still on treatment of whom 4 on capecitabine monotherapy. Median PFS is 8.0 months.
MTD of nab-P in combination with CAPOX is 80 mg/m2 and RP2D 60 mg/m2 in a 3-weekly schedule. Given the manageable toxicity at RP2D and promising efficacy, further evaluation of this regimen is warranted. Biomarker research is currently ongoing.
Clinical trial identification
EudraCT: 2014-001333-88 Release date: March 25th 2014
Legal entity responsible for the study
Academic Medical Center Amsterdam
S. Schokker: Travel/accomodation funding from Roche R.A.A. Mathot: Consultant for Zeria LTD, has received unrestricted research funding from Shire, MSD and Roche, travel/accomodation funding from Shire M.F. Bijlsma: Unrestricted research funding from Celgene, travel/accommodation funding from Biouniversa M.G.H. Van Oijen: Unrestricted research grants from Amgen, Bayer, Lilly, Merck Serono, and Roche. C.J.A. Punt: Consultant for Nordic Pharma and Servier H.W.M. van Laarhoven: Consultant for Celgene, Lilly, and Nordic, unrestricted research funding from Bayer, BMS, Celgene, Lilly, Merck Serono, MSD, Nordic, and Roche All other authors have declared no conflicts of interest.