Abstract CT098: Anti-tumor activity of PEGylated human IL-10 (AM0010) in patients with 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 , Mumm John B. , Chan Ivan H. , Bendell Johanna C. , Bauer Todd M. , Janku Filip , Javle Milind , Colen Rivka R. , Tannir Nizar M. , Oft Martin 
Published: July 2016

Abstract
Purpose: IL-10 inhibits inflammation but stimulates cytotoxic CD8 T cells. In preclinical models, PEGylated IL-10 induces rejection of tumors and establishes CD8 T cell memory. PEG-IL-10 (AM0010) activates the anti-apoptotic STAT3 in tumor infiltrating activated CD8 T cells. This leads to the expansion of tumor reactive memory CD8 T cells both in the tumor and the blood. The primary objective of this phase 1 study is to establish tolerability and anti-tumor activity of AM0010 alone and in combination with chemotherapy and anti PD-1 immunotherapy. Here we report the results of AM0010 in the monotherapy dose escalation and one expansion cohort in renal cell cancer (RCC).
Procedures: 33 patients (pts) with advanced cancers including melanoma, RCC, non-small cell lung, colorectal, ovarian, prostate and pancreatic cancer were enrolled in cohorts of 3-6 pts each, followed by disease specific expansion cohorts at the recommended phase 2 dose (RP2D). AM0010 was self-administrated daily subcutaneously for the duration of treatment and responses were monitored following immune related response criteria (irRC). Immune responses were monitored through analysis of serum cytokines, activation of blood derived T cells, immunosequencing for peripheral T cell clonality and immunohistochemistry for the infiltration of tumors by CD8 T cells.
Results: 33 pts were enrolled in dose escalation cohorts with AM0010 monotherapy at doses from 1 to 40 μg/kg. MTD was not established. The RP2D (20μg/kg) was determined based on tolerability, single agent anti-tumor activity and immune activation. Patients were heavily pretreated with a median of 5 prior treatments. Most treatment related adverse events (TrAE) were low grade and included anemia, thrombocytopenia, rash, injection site reaction, fatigue, increased lipase, dyslipidemia and transaminitis. G3/4 non-hematopoietic TrAEs were observed in 11 of 51 pts. G3/4 anemia or thrombocytopenia TrAEs were observed in 13 pts. Most TrAEs were transient with only one patient discontinuing treatment due to a TrAE. Immune related TrAEs such as colitis, pneumonitis and endocrine disruption were not observed.
AM0010 induced a dose dependent Th1 cytokine signature (IL-18, IFNγ, IL-7) and a reduction of TGFβ in the serum of pts. AM0010 increased PD-1 positive activated CD8 T cells in the blood and the tumor and decreased proliferation of FoxP3 Tregs in the blood. AM0010 lead to an oligoclonal expansion of T cell clones in the blood without affecting the overall number of lymphocytes. Many of the expanded T cell clones were not detectable before treatment. Partial responses (PR) were observed in pts with RCC and uveal melanoma. Four of 15 RCC pts treated at RP2D (27%) had an objective response. Prolonged stable disease of 6 or more months was observed in several indications including colon cancer.
Conclusion: AM0010 is well-tolerated and leads to sustained and systemic immune stimulation. The pharmacodynamics and clinical activity observed support the further exploration of AM0010 in monotherapy and in combination regimens with checkpoint inhibitors and with 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, John B. Mumm, Ivan H. Chan, Johanna C. Bendell, Todd M. Bauer, Filip Janku, Milind Javle, Rivka R. Colen, Nizar M. Tannir, Martin Oft. Anti-tumor activity of PEGylated human IL-10 (AM0010) in patients with advanced solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT098.