Abstract A194: PEGylated human IL-10 (AM0010) in advanced solid tumors
Authors: Infante Jeffrey R. , Naing Aung , Papadopoulos Kyriakos P. , Autio Karen A. , Ott Patrick A. , Wong Deborah J. , Falchook Gerald S. , Patel Manish , Pant Shubham , Whiteside Melinda , Bendell Johanna C. , Bauer Todd M. , Janku Filip , Javle Milind , Colen Rivka , Tannir Nizar , Oft Martin 
Published: May 2016

Abstract
Purpose
PEGylated IL-10 induces the rejection of tumors in mice and establishes immunological memory. PEG-IL-10 induces phosphorylation and activation of the anti-apoptotic STAT3 in tumor infiltrating activated CD8 T cells. This leads to the expansion of tumor reactive CD8 T cells both within the tumor and in the periphery. The primary objective of this phase 1 study is to establish the safety, tolerability and the anti-tumor-activity of human PEGylated IL-10 (AM0010). Other objectives include pharmacokinetics, AM0010 immunogenicity and AM0010 induced immune activation.
Procedures
Patients with advanced melanoma, renal cell cancer, colorectal cancer, prostate cancer, ovarian cancer and pancreatic cancer were enrolled in escalating cohorts of 3-6 patients each followed by expansion cohorts. AM0010 was self-administrated daily subcutaneously at doses of 1 to 40 μg/kg. PK, anti-drug antibodies and immune responses were monitored.
Results
More than 90 patients were enrolled in escalation and expansion cohorts with AM0010 monotherapy at doses between 1 and 40 μg/kg. An MTD is not yet established through the planned maximally administered dose. Common treatment related adverse events (TrAE) included injection site reaction, rash, fatigue, thrombocytopenia and anemia. Most adverse events were low grade. G3 adverse events were observed including anemia, thrombocytopenia, rash, increased lipase, dyslipidemia, transaminitis. Only one patient discontinued treatment due to TrAEs. On continuous dosing the terminal half-life of AM0010 half-life is estimated to be 24 hrs. Exposures increased linearly with increasing doses. At the therapeutic dose (&gt; 20 μg/kg), AM00010 induced a characteristic immune activation signature, detectable in the serum of patients: The Th1 cytokine IL-18 was dose dependently increased in all patients; IFNg, IL-4, GM-CSF, IL-7 and FasL were elevated in every patient dosed at the therapeutic dose. AM0010 also induced a reduction of TGFβ in the serum. AM0010 treatment induced an increase of activated PD-1 positive CD8 T cells both in the tumor tissue and in circulation. The immune activation observed in patients was consistent with the CD8 mediated tumor immunity observed in preclinical models.
As monotherapy, partial responses (PR) were observed in patients with RCC, melanoma and lymphoma. In particular, 19% of RCC patients, had a PR and an additional 62% had stable disease (n = 16). In addition, prolonged stable disease with or without tumor reductions were observed in several other indications, including patients with pancreatic, lung, ovarian or colon cancer.
Conclusion
In Monotherapy, AM0010 has a well-tolerated safety profile and leads to sustained and systemic immune stimulation. The pharmacodynamics and clinical activity observed support the ongoing monotherapy expansions and combination regimens with checkpoint inhibitors as well as cytotoxic chemotherapies.
Trial registration: www.clinicaltrials.gov NCT02009449
Citation Format: Jeffrey R. Infante, Aung Naing, Kyriakos P. Papadopoulos, Karen A. Autio, Patrick A. Ott, Deborah J. Wong, Gerald S. Falchook, Manish Patel, Shubham Pant, Melinda Whiteside, Johanna C. Bendell, Todd M. Bauer, Filip Janku, Milind Javle, Rivka Colen, Nizar Tannir, Martin Oft. PEGylated human IL-10 (AM0010) in advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A194.