Phase I/II trial of sequential treatment of nab-paclitaxel in combination with gemcitabine followed by modified FOLFOX chemotherapy in patients with untreated metastatic exocrine pancreatic cancer: Phase I results

Eur J Cancer. 2020 Nov:139:51-58. doi: 10.1016/j.ejca.2020.07.035. Epub 2020 Sep 22.

Abstract

Background: Although occasioned through different mechanisms, the potential neurotoxicity and also haematological toxicity of nab-paclitaxel and oxaliplatin-based chemotherapy regimen were studied in this trial, which aimed to determine the maximum-tolerated dose (MTD) and to evaluate safety and efficacy of the combination in a sequential regimen of nab-paclitaxel, gemcitabine (GEM) and modified FOLFOX (mFOLFOX) in untreated patients with metastatic pancreatic ductal adenocarcinoma (PDAC).

Materials and methods: Treatment consisted of nab-paclitaxel (125/100 mg/m2) plus GEM (1000/800 mg/m2) on days 1, 8 and 15, followed by mFOLFOX (oxaliplatin [85/75/65 mg/m2], 5-FU bolus [400/300/200 mg/m2], 5-FU infusion [2400/2000/1600 mg/m2]) on day 28, of a 42-day cycle. Patients were enrolled at the highest dose level with a subsequent 3 + 3 dose de-escalation plan.

Results: Eleven patients (median age = 61, 64% with performance status [PS] = 1) were eligible. All patients received the highest dose level. No de-escalation was needed. A dose-limiting toxicity was reported, an upper gastrointestinal haemorrhage. The MTD was nab-paclitaxel 125 mg/m2, GEM 1000 mg/m2, oxaliplatin 85 mg/m2, 5-FU bolus 400 mg/m2 and 5-FU infusion 2400 mg/m2. Common all-grade toxicities were neutropenia (73%), anaemia (55%), thrombocytopenia (55%) and asthenia (55%). Other relevant toxicities were paraesthesia (46%), nausea (36%), dysesthesia (27%) and pyrexia (27%). Objective response rate was 50% and disease control rate was 80%.

Conclusions: The regimen of nab-paclitaxel plus GEM followed by mFOLFOX showed favourable safety and tolerability profiles with significant anti-tumor activity. More data are being achieved in a randomised phase II trial, to confirm efficacy rates and dismiss long-term neurotoxicity concerns regarding the sequencing of nab-paclitaxel and oxaliplatin.

Keywords: Dose de-escalation; FOLFOX; Gemcitabine; Nab-paclitaxel; Pancreatic ductal adenocarcinoma; Phase I; Sequential treatment.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adult
  • Aged
  • Albumins / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / therapeutic use
  • Drug Administration Schedule
  • Female
  • Fluorouracil / therapeutic use
  • Gemcitabine
  • Humans
  • Leucovorin / therapeutic use
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Organoplatinum Compounds / therapeutic use
  • Paclitaxel / therapeutic use*
  • Pancreatic Neoplasms / drug therapy*

Substances

  • 130-nm albumin-bound paclitaxel
  • Albumins
  • Organoplatinum Compounds
  • Deoxycytidine
  • Paclitaxel
  • Leucovorin
  • Fluorouracil
  • Gemcitabine

Supplementary concepts

  • Folfox protocol