Safety, Antitumor Activity, and Immune Activation of Pegylated Recombinant Human Interleukin-10 (AM0010) in Patients With Advanced Solid Tumors

Abstract

Purpose Interleukin-10 (IL-10) stimulates the expansion and cytotoxicity of tumor-infiltrating CD8+ T cells and inhibits inflammatory CD4+ T cells. Pegylation prolongs the serum concentration of IL-10 without changing the immunologic profile. This phase I study sought to determine the safety and antitumor activity of AM0010. Patients and Methods Patients with selected advanced solid tumors were treated with AM0010 in a dose-escalation study, which was followed by a renal cell cancer (RCC) dose-expansion cohort. AM0010 was self-administered subcutaneously at doses of 1 to 40 μg/kg once per day. Primary end points were safety and tolerability; clinical activity and immune activation were secondary end points. Results In the dose-escalation and -expansion cohorts, 33 and 18 patients, respectively, were treated with daily subcutaneous injection of AM0010. AM0010 was tolerated in a heavily pretreated patient population. Treatment-related adverse events (AEs) included anemia, fatigue, thrombocytopenia, fever, and injection site reactions. Grade 3 to 4 nonhematopoietic treatment-related AEs, including rash (n = 2) and transaminitis (n = 1), were observed in five of 33 patients. Grade 3 to 4 anemia or thrombocytopenia was observed in five patients. Most treatment-related AEs were transient or reversible. AM0010 led to systemic immune activation with elevated immune-stimulatory cytokines and reduced transforming growth factor beta in the serum. Partial responses were observed in one patient with uveal melanoma and four of 15 evaluable patients with RCC treated at 20 μg/kg (overall response rate, 27%). Prolonged stable disease of at least 4 months was observed in four patients, including one with colorectal cancer with disease stabilization for 20 months. Conclusion AM0010 has an acceptable toxicity profile with early evidence of antitumor activity, particularly in RCC. These data support the further evaluation of AM0010 both alone and in combination with other immune therapies and chemotherapies.

Trial registration: ClinicalTrials.gov NCT02009449.

Fig 1.

Spider plots indicating the change in tumor burden (according to immune-related response criteria) in (A) all patients in the dose-escalation cohorts, (B) patients with renal cell cancer (RCC) or melanoma in the dose-escalation cohorts, and (C) all patients with RCC treated at 20 μg/kg (arrows indicate ongoing response at data cutoff). (D) Tumor response in a patient with RCC and (E) delayed tumor response in a patient with RCC (arrows indicate tumors). CRC, colorectal cancer; NSCLC, non–small-cell lung cancer; PDAC, pancreatic ductal adenocarcinoma. (*) Mixed response (some lesions reduced).

Fig 2.

Average serum values of cytokines for all available patients in escalation cohorts (predose serum of days 1 and 29 analyzed). (A) AM0010 serum trough (C_min); (B) interleukin-18 (IL-18); (C) Spearman correlation between AM0010 C_min and IL-18 (R² = 0.5; P < .001); (D) latency-associated peptide (LAP) transforming growth factor beta (TGF-β); (E) average serum values of interferon-gamma (IFN-γ; left) and IL-4 (right) in patients in the dose-escalation cohorts treated at 20 to 40 μg/kg (predose serum analyzed on days 1 and 29). (*) P < .01. (†) P < .05. (‡) P < .001.