Phase I trial of HuMax-IL8 (BMS-986253), an anti-IL-8 monoclonal antibody, in patients with metastatic or unresectable solid tumors

Marijo Bilusic, Christopher R Heery, Julie M Collins, Renee N Donahue, Claudia Palena, Ravi A Madan, Fatima Karzai, Jennifer L Marté, Julius Strauss, Margaret E Gatti-Mays, Jeffrey Schlom, James L Gulley, Marijo Bilusic, Christopher R Heery, Julie M Collins, Renee N Donahue, Claudia Palena, Ravi A Madan, Fatima Karzai, Jennifer L Marté, Julius Strauss, Margaret E Gatti-Mays, Jeffrey Schlom, James L Gulley

Abstract

Background: HuMax-IL8 (now known as BMS-986253) is a novel, fully human monoclonal antibody that inhibits interleukin-8 (IL-8), a chemokine that promotes tumor progression, immune escape, epithelial-mesenchymal transition, and recruitment of myeloid-derived suppressor cells. Studies have demonstrated that high serum IL-8 levels correlate with poor prognosis in many malignant tumors. Preclinical studies have shown that IL-8 blockade may reduce mesenchymal features in tumor cells, making them less resistant to treatment.

Methods: Fifteen patients with metastatic or unresectable locally advanced solid tumors were enrolled in this 3 + 3 dose-escalation trial at four dose levels (4, 8, 16, or 32 mg/kg). HuMax-IL8 was given IV every 2 weeks, and patients were followed for safety and immune monitoring at defined intervals up to 52 weeks.

Results: All enrolled patients (five chordoma, four colorectal, two prostate, and one each of ovarian, papillary thyroid, chondrosarcoma, and esophageal) received at least one dose of HuMax-IL8. Eight patients had received three or more prior lines of therapy and five patients had received prior immunotherapy. Treatment-related adverse events occurred in five patients (33%), mostly grade 1. Two patients receiving the 32 mg/kg dose had grade 2 fatigue, hypophosphatemia, and hypersomnia. No dose-limiting toxicities were observed, and maximum tolerated dose was not reached. Although no objective tumor responses were observed, 11 patients (73%) had stable disease with median treatment duration of 24 weeks (range, 4-54 weeks). Serum IL-8 was significantly reduced on day 3 of HuMax-IL8 treatment compared to baseline (p = 0.0004), with reductions in IL-8 seen at all dose levels.

Conclusions: HuMax-IL8 is safe and well-tolerated. Ongoing studies are evaluating the combination of IL-8 blockade and other immunotherapies.

Trial registration: NCTN, NCT02536469. Registered 23 August 2015, https://ichgcp.net/clinical-trials-registry/NCT02536469?term=NCT02536469&rank=1 .

Keywords: BMS-986253; Clinical trial; HuMax-IL8; Immune assays; Immunotherapy; Interleukin-8 (IL-8); Metastatic cancer; Monoclonal antibody; Solid tumor.

Conflict of interest statement

All National Cancer Institute authors declare that they have no competing interests.

Dr. Heery is an employee of Precision Biosciences and has no financial relationship with BMS or this product.

No writing assistance was utilized in the production of this manuscript.

Figures

Fig. 1
Fig. 1
Trial schema. Trial schema with dose-escalation strategy
Fig. 2
Fig. 2
Serum IL-8 levels pre- and post-treatment with HuMax-IL8. The human IL-8 ELISA kit was used to measure free serum IL-8 levels. Reductions in serum IL-8 levels were observed at all dose levels and were significantly reduced on day 3 compared to pre-treatment (p = 0.0004)

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Source: PubMed

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