A phase I trial investigating pulsatile erlotinib in combination with gemcitabine and oxaliplatin in advanced biliary tract cancers

Invest New Drugs. 2017 Feb;35(1):95-104. doi: 10.1007/s10637-016-0406-z. Epub 2016 Nov 16.

Abstract

Advanced biliary tract cancers (ABTC) are among the deadliest malignancies with limited treatment options after progression on standard-of-care chemotherapy, which includes gemcitabine (GEM) and oxaliplatin (OX). The epidermal growth factor receptor inhibitor erlotinib has been explored in ABTC with modest efficacy. Erlotinib given continuously may antagonize the action of chemotherapy against cycling tumor cells, but pulsatile dosing of erlotinib with chemotherapy may improve efficacy. The purpose of this study was to assess the safety of pulsatile erlotinib with GEMOX. This was a single-institution phase Ib study that enrolled adult patients with unresectable or metastatic biliary tract, pancreas, duodenal, or ampullary carcinomas that have not received any prior treatment for their disease. Dose escalation followed a standard 3 + 3 design, and dose-limiting toxicities (DLTs) were any treatment-related, first course non-hematologic grade ≥ 3 toxicity, except nausea/vomiting, or grade 4 hematologic toxicity. A dose expansion cohort in ABTC was treated at the MTD. Twenty-eight patients were enrolled and 4 dose levels were explored. The MTD was erlotinib 150 mg + GEM 800 mg/m2 + OX 85 mg/m2. DLTs were diarrhea and anemia. Most frequent toxicities were nausea (78 %), fatigue (71 %), neuropathy (68 %), and diarrhea (61 %), predominantly grade 1-2. In the ABTC patients, the objective response and disease control rates were 29 % and 94 %, respectively, and median overall survival was 18 months. Erlotinib plus GEMOX was well tolerated. Encouraging anti-tumor activity was seen as evidenced by a high disease control rate and longer median OS than standard chemotherapy in the patients with ABTC.

Keywords: Biliary tract cancers; Gemcitabine and oxaliplatin; Phase Ib trial; Pulsatile erlotinib.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antigens, CD
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Biliary Tract Neoplasms / drug therapy*
  • Biliary Tract Neoplasms / genetics
  • Biliary Tract Neoplasms / metabolism
  • Cadherins / metabolism
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / adverse effects
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / therapeutic use
  • Drug Administration Schedule
  • ErbB Receptors / genetics
  • Erlotinib Hydrochloride / administration & dosage*
  • Erlotinib Hydrochloride / adverse effects
  • Erlotinib Hydrochloride / therapeutic use
  • Female
  • Gemcitabine
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Mutation
  • Organoplatinum Compounds / administration & dosage*
  • Organoplatinum Compounds / adverse effects
  • Organoplatinum Compounds / therapeutic use
  • Oxaliplatin
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Treatment Outcome
  • Vimentin / metabolism

Substances

  • Antigens, CD
  • Antineoplastic Agents
  • CDH1 protein, human
  • Cadherins
  • KRAS protein, human
  • Organoplatinum Compounds
  • Vimentin
  • Oxaliplatin
  • Deoxycytidine
  • Erlotinib Hydrochloride
  • EGFR protein, human
  • ErbB Receptors
  • Proto-Oncogene Proteins p21(ras)
  • Gemcitabine