ASCO Annual Meeting - Chicago, IL, May 30 –June 4, 2014 Poster #: 185B A FIRST-IN-HUMAN STUDY OF PEGYLATED RECOMBINANT HUMAN IL-10 (AM0010), DAILY ADMINISTERED FOR FOUR MONTHS IN SELECTED ADVANCED SOLID TUMORS. Todd M. Bauer1, Kyriakos P. Papadopoulos2, Karen A. Autio3, Patrick A. Ott4, Melinda Whiteside5, Martin Oft5, Jeffrey R. Infante1, F. Stephen Hodi4, Jedd D. Wolchok3 150 100 50 0 Control PEG-IL-10 ***Mann-Whitney Two-Tailed T Test: p=0.0001 IL-10 / Cytokines Signal 3 Signal 1 TCR-MHC CD8+ T cell TCR MHC Tumor cell Signal 2 Co-stim Dendritic Cell Signal 1 TCR stimulated by MHC and peptide on tumor cells Signal 2 Co-stimulatory signals stimulated by T cell activation Signal 3 Cytokine signal to induce the cytotoxic activation Preclinical rationale d. CD8+ TIL Antigen Specificity 200 1250 Tumor Re‐implant 5‐8 months after tumor rejection 1000 750 500 250 25 E L4 w an /o t iC D3 P DV 6 3 6 D EL 4 DV P w /o an AM0010 / PEG-IL-10 Mechanism of Action • Induces CD8+ T cell expansion via increased STAT3 phosphorylation (Fig. 2a,c) • Activates CD8+ T cell via STAT1 phosphorylation (Fig. 2c) • T cell activation increases Signal 2 via reduction of PD-1 expression • Induces IFN in CD8+ T cells (Fig. 2b) • IFN induces MHC in tumor cells and dendritic cells (Signal 1) and induces costimulatory molecules on dendritic cells (Signal 2) • Induces Granzymes in CD8+ T cells to kill tumor cells (Fig. 2b) Figure 3. PEG-IL-10 treatment induces tumor rejection of mouse syngeneic colon carcinoma (CT26) and melanoma (M3) 1000 Tumor volume (mm ) Vehicle Start of Dosing 50 100 50 0 G 50 Increase of intra-tumoral CD8+ T cells Increase of cytotoxic enzymes and IFN in intra-tumoral CD8+ T cells Activation of STAT1 and STAT3 in intra-tumoral CD8+ T cells Expansion of CD8+ T cells recognizing tumor cells • PEG-IL-10 increases IFN in the CD8+ T cell and MHC expression in the tumor. 10 20 30 40 Days of tumor growth 150 800 0.01 mg/kg PEG-IL-10 0.1 mg/kg PEG-IL-10 0.5 mg/kg PEG-IL-10 600 400 200 0 40 50 Figure 5. Trial Design AM0010 / PEG-IL-10 75 IFN secretion a. b. c. d. *** PE Norm. IFN + ELISPOTs Control IL- 10 100 0 • PEG-IL-10 directly activates tumor specific CD8+ T cells. • PEG-IL-10 induces tumor rejection and long lasting anti-tumor immune surveillance. 1500 0 c. Intra-tumoral CD8+ T cell activation *** b 1750 0 • Intra-tumoral memory T cells correlate with survival in cancer patients2. Figure 1. Intra-tumoral CD8+ T cells require 3 signals for full activation a 60 Start of Dosing 70 Major exclusion criteria • First-in-human, open-label, dose escalation study to evaluate the safety and tolerability of AM0010 in patients with advanced solid tumors dosed daily subcutaneously (SC) (clinicaltrials.gov identifier NCT02009449). • Induces Tumor rejection in syngeneic mouse tumor models (Fig. 3, 4) • PEG-IL-10 treated mice remain tumor free • Immune memory mediates rejection of reimplanted tumor cells (without treatment; Fig. 4b ) STUDY OBJECTIVES Primary • To assess the safety, tolerability, maximum tolerated dose (MTD), and pharmacokinetics (PK) of AM0010 Dose Escalation Phase Expansion Phase 3-6 patients per cohort (n= ~30) (selected tumors)-15 patients per cohort • Chronic inflammatory diseases of the peripheral and central nervous system • Uncontrolled systemic fungal, bacterial, viral, or other infection • Treatment with immune modulators including, but not limited to, anti-CTLA4, anti-PD1, anti-PDL1, systemic corticosteroids within 14 days • History of a bleeding diathesis Daily SC dosing Daily SC dosing Dose levels *Cohort X – 2 fold increases MTD determined Dose up to the MTD Cohort 5 – 20 µg/kg Cohort 4 – 10 µg/kg • Patients continue treatment for 4 months or until confirmed progression (irPD) • Patients continue treatment after confirmed irPD if clinically benefitting Cohort 3 – 5 µg/kg Cohort 2 – 2.5 µg/kg Cohort 1 – 1 µg/kg * In the absence of DLTs after 28 days escalate two-fold Figure 6. Trial Schema, Study Periods and Assessments Screening Treatment Secondary End of treatment Safety OS TRIAL STATUS • This study is open for enrollment at 4 sites in the United States • As of May 22, 2014 22 patients have been enrolled in the Dose Escalation phase. • Enrollment in Cohort 4 (10 µg/kg) has been completed without the MTD being reached. • Cohort 5 (20 µg/kg) opened to enrollment in May 2014. AM0010 SC daily • To assess the tumor response • To evaluate anti-AM0010 antibodies Week 13 Imaging then every 8 weeks Week 7 Imaging Day 1 Days Exploratory Biomarkers • Serum cytokines • T and B cell responses to tumor associated antigens • Immuno-profiling • Immuno-score T/I/B 1 2 8 15 22 29 36 43 50 P P P P P P/B P P 57 P P/B/T Safety Follow-up 200 • PEG-IL-10 increases and activates intratumoral CD8+ T cells (Fig. 2) 3. • In preclinical studies, PEG-IL-10 induces the rejection of large tumors and the development of immunological memory against the tumor cells (Fig. 4). T cell TRIAL DESIGN Long -term follow-up b. Intra-tumoral activation *** Tumor volume (mm3) Number of CD8 T cells/field a. Intra-tumoral T cells expansion CD8 IHC • AM0010 is a pegylated recombinant form of human IL-10 (PEG-rHuIL-10) that is being developed for the treatment of cancer. CD8+ Disease progression / Day 113 • Recent developments in cancer immunity have sparked the interest of scientists and clinicians, yielding novel and exciting immunotherapeutics.1 CD8+ Figure 4. PEG-IL-10 induces tumor rejection and long lasting immune memory in a syngeneic mouse skin cancer model C on tr ol Va cc -IL in e -1 0 Vc cu c. re no d im pla nt Figure 2. AM0010 activates CD8+ T cells in syngeneic mouse tumor models. t iC AM0010 - BACKGROUND Sarah Cannon Research Institute / Tennessee Oncology, PLLC., Nashville, TN; 2 START Center for Cancer Care, San Antonio, TX; 3 Memorial Sloan-Kettering Cancer Center, New York, NY; 4 Dana-Farber Cancer Institute, Boston, MA; 5 ARMO BioSciences, Redwood City CA; 6-10 fields n=three tumors 1 bi-weekly T/B P Key assessments • Tissue (T) • Imaging (I) • PK (P) • Exploratory Biomarkers (B) • Safety all visits Continue AM0010 after Day 113/DP with treatment benefit P 30 days after last dose Monthly survival subsequent therapy ACKNOWLEDGMENTS The authors would like to acknowledge the contribution of patients and their families in participating in this clinical trial. SPONSORS ENDPOINTS PATIENT ELIGIBILITY • Tumor Response will be assessed using the immune related response criteria (irRC) or the Prostate Cancer Working Group Criteria (PCWG2) for progression in bone Major inclusion criteria REFERENCES • Advanced solid tumors; limited to melanoma, prostate, ovarian, renal, colorectal, pancreas, non-small cell lung cancer 1. Hodi, O'Day et al. 2010, Topalian, Hodi et al. 2012 • Adverse Events will be graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v 4.02) • Life expectancy of >16 weeks AM0010 is being developed by ARMO BioSciences. 2. Fridman, Pages et al. 2012 3. Mumm, Emmerich et al. 2011 CONTACT INFORMATION For more information on this trial, please contact [email protected] phone: 1-650-779-5075. Poster presented at the Annual Meeting of the American Society of Clinical Oncology (ASCO), Chicago, IL, USA, May 30 –June 4, 2014