Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer (TeloVac): an open-label, randomised, phase 3 trial

Lancet Oncol. 2014 Jul;15(8):829-40. doi: 10.1016/S1470-2045(14)70236-0. Epub 2014 Jun 19.

Abstract

Background: We aimed to assess the efficacy and safety of sequential or simultaneous telomerase vaccination (GV1001) in combination with chemotherapy in patients with locally advanced or metastatic pancreatic cancer.

Methods: TeloVac was a three-group, open-label, randomised phase 3 trial. We recruited patients from 51 UK hospitals. Eligible patients were treatment naive, aged older than 18 years, with locally advanced or metastatic pancreatic ductal adenocarcinoma, and Eastern Cooperative Oncology Group performance status of 0-2. Patients were randomly assigned (1:1:1) to receive either chemotherapy alone, chemotherapy with sequential GV1001 (sequential chemoimmunotherapy), or chemotherapy with concurrent GV1001 (concurrent chemoimmunotherapy). Treatments were allocated with equal probability by means of computer-generated random permuted blocks of sizes 3 and 6 in equal proportion. Chemotherapy included six cycles of gemcitabine (1000 mg/m(2), 30 min intravenous infusion, at days 1, 8, and 15) and capecitabine (830 mg/m(2) orally twice daily for 21 days, repeated every 28 days). Sequential chemoimmunotherapy included two cycles of combination chemotherapy, then an intradermal lower abdominal injection of granulocyte-macrophage colony-stimulating factor (GM-CSF; 75 μg) and GV1001 (0·56 mg; days 1, 3, and 5, once on weeks 2-4, and six monthly thereafter). Concurrent chemoimmunotherapy included giving GV1001 from the start of chemotherapy with GM-CSF as an adjuvant. The primary endpoint was overall survival; analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN4382138.

Findings: The first patient was randomly assigned to treatment on March 29, 2007, and the trial was terminated on March 27, 2011. Of 1572 patients screened, 1062 were randomly assigned to treatment (358 patients were allocated to the chemotherapy group, 350 to the sequential chemoimmunotherapy group, and 354 to the concurrent chemoimmunotherapy group). We recorded 772 deaths; the 290 patients still alive were followed up for a median of 6·0 months (IQR 2·4-12·2). Median overall survival was not significantly different in the chemotherapy group than in the sequential chemoimmunotherapy group (7·9 months [95% CI 7·1-8·8] vs 6·9 months [6·4-7·6]; hazard ratio [HR] 1·19, 98·25% CI 0·97-1·48, p=0·05), or in the concurrent chemoimmunotherapy group (8·4 months [95% CI 7·3-9·7], HR 1·05, 98·25% CI 0·85-1·29, p=0·64; overall log-rank of χ(2)2df=4·3; p=0·11). The commonest grade 3-4 toxic effects were neutropenia (68 [19%] patients in the chemotherapy group, 58 [17%] patients in the sequential chemoimmunotherapy group, and 79 [22%] patients in the concurrent chemoimmunotherapy group; fatigue (27 [8%] in the chemotherapy group, 35 [10%] in the sequential chemoimmunotherapy group, and 44 [12%] in the concurrent chemoimmunotherapy group); and pain (34 [9%] patients in the chemotherapy group, 39 [11%] in the sequential chemoimmunotherapy group, and 41 [12%] in the concurrent chemoimmunotherapy group).

Interpretation: Adding GV1001 vaccination to chemotherapy did not improve overall survival. New strategies to enhance the immune response effect of telomerase vaccination during chemotherapy are required for clinical efficacy.

Funding: Cancer Research UK and KAEL-GemVax.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / secondary
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Cancer Vaccines / administration & dosage*
  • Cancer Vaccines / adverse effects
  • Capecitabine
  • Cell Proliferation
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives
  • Disease-Free Survival
  • Fatigue / chemically induced
  • Female
  • Fluorouracil / administration & dosage
  • Fluorouracil / analogs & derivatives
  • Granulocyte-Macrophage Colony-Stimulating Factor / administration & dosage
  • Humans
  • Immunologic Factors / administration & dosage
  • Intention to Treat Analysis
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Neutropenia / chemically induced
  • Pain / chemically induced
  • Pancreatic Ducts*
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / pathology
  • Peptide Fragments / administration & dosage*
  • Peptide Fragments / adverse effects
  • T-Lymphocytes / immunology
  • Telomerase / administration & dosage*
  • Telomerase / adverse effects

Substances

  • Cancer Vaccines
  • Immunologic Factors
  • Peptide Fragments
  • Deoxycytidine
  • Capecitabine
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • gemcitabine
  • GV1001 peptide
  • Telomerase
  • Fluorouracil