A phase ΙI study of five peptides combination with oxaliplatin-based chemotherapy as a first-line therapy for advanced colorectal cancer (FXV study)

Abstract

Background: We previously conducted a phase I trial for advanced colorectal cancer (CRC) using five HLA-A*2402-restricted peptides, three derived from oncoantigens and two from vascular endothelial growth factor (VEGF) receptors, and confirmed safety and immunological responses. To evaluate clinical benefits of cancer vaccination treatment, we conducted a phase II trial using the same peptides in combination with oxaliplatin-based chemotherapy as a first-line therapy.

Methods: The primary objective of the study was the response rates (RR). Progression free survival (PFS), overall survival (OS), and immunological parameters were evaluated as secondary objective. The planned sample size was more than 40 patients for both HLA2402-matched and -unmatched groups. All patients received a cocktail of five peptides (3 mg each) mixed with 1.5 ml of IFA which was subcutaneously administered weekly for the first 12 weeks followed by biweekly administration. Presence or absence of the HLA-A*2402 genotype were used for classification of patients into two groups.

Results: Between February 2009 and November 2012, ninety-six chemotherapy naïve CRC patients were enrolled under the masking of their HLA-A status. Ninety-three patients received mFOLFOX6 and three received XELOX. Bevacizumab was added in five patients. RR was 62.0% and 60.9% in the HLA-A*2402-matched and -unmatched groups, respectively (p=0.910). The median OS was 20.7 months in the HLA-A*2402-matched group and 24.0 months in the unmatched group (log-rank, p=0.489). In subgroup with a neutrophil/lymphocyte ratio (NLR) of <3.0, patients in the HLA-matched group did not survive significantly longer than those in the unmatched group (log-rank, p=0.289) but showed a delayed response.

Conclusions: Although no significance was observed for planned statistical efficacy endpoints, a delayed response was observed in subgroup with a NLR of <3.0. Biomarkers such as NLR might be useful for selecting patients with a better treatment outcome by the vaccination.

Trial registration: Trial registration: UMIN000001791.

Figure 1

CONSORT diagram. Scheme showing an HLA-A-status double-blind, biologically-randomized phase ΙI study of five therapeutic epitope-peptides combined with oxaliplatin-based chemotherapy as a first-line therapy for advanced colorectal cancer (FXV study). CRC, colorectal cancer; FOLFOX, infusional fluorouracil, leucovorin, and oxaliplatin; XELOX, capecitabine and oxaliplatin; HLA, human leukocyte antigen.

Figure 2

Progression free survival and overall survival. A and B, comparison of progression free survival between HLA-A*2402-mached and -unmatched groups; A, all patients; B, the patients who received the vaccination for more than 12 months. C and D, comparison of overall survival between HLA-A*2402-matched and -unmatched groups; C, all patients; D, patients who received the vaccination for more than 12 months. MST, median survival time; HLA, human leukocyte antigen; M, months; *the weighted log-rank tests with the Harrington-Fleming class of weights were performed and resulted in, ρ = 0, and γ = 0.5, p = 0.186; ρ = 0, and γ = 1, ρ = 0.080; ρ = 0, and γ = 2, ρ = 0.101.

Figure 3

Biomarkers for the survival and the clinical efficacy of vaccination. Neutrophil/lymphocyte ratio (NLR) < 3.0 and Lymphocyte-% ≧ 15% were considered as indicative factors. A and B, comparison between the favorite group and others. C, comparison of the patients with a NLR of ≧ 3 or a NLR of <3 between the HLA-A*2402-matched and -unmatched groups. D, comparison of the patients with Lymphocyte-% ≧ 15% between the HLA-A*2402 positive and negative groups. Lymphocyte (Ly)-%, the percentage of lymphocytes among the peripheral leukocytes; NLR, neutrophil/lymphocyte ratio; HLA, human leukocyte antigen; L-R, log-rank test; *the weighted log-rank tests with the Harrington-Fleming class of weights were performed and resulted in, ρ = 0, and γ = 0.5, p = 0.152; ρ = 0, and γ = 1, p = 0.064; ρ = 0, and γ = 2, p = 0.035; **the Harrington-Fleming tests were resulted in, ρ = 0, and γ = 0.5, p = 0.495; ρ = 0, and γ = 1, ρ = 0.346; ρ = 0, and γ = 2, ρ = 0.251; *** the Harrington-Fleming tests were resulted in, ρ = 0, and γ = 0.5, p = 0.114; ρ = 0, and γ = 1, ρ = 0.051; ρ = 0, and γ = 2, ρ = 0.029.