Phase 1b study with PEGylated human IL-10 (AM0010) with 5-FU and oxaliplatin (FOLFOX) in metastatic pancreatic adenocarcinoma (PDAC).

Abstract

399 Background: The benefit of adding nal-irinotecan or oxaliplatin to 5-FU in second-line therapy for PDAC is relatively small and it has been refractory to immune therapies. The success and the durability of immunotherapy is thought to depend on the activation and expansion of intratumoral, tumor specific cytotoxic CD8+ T cells which are absent in most PDACs. AM0010 stimulates the survival, expansion and cytotoxicity of intratumoral CD8+ T cells. Immune stimulation and prolonged stable disease in PDAC patients (pts) with single agent AM0010 was recently presented. Irinotecan may eliminate cytotoxic T cells. Treatment with platinum or 5-FU may activate immune responses to cancer and AM0010 has synergistic anti-tumor function with both in preclinical models. In this phase 1b clinical study, the efficacy of AM0010 with FOLFOX was explored in patients with PDAC. Methods: PDAC pts progressing on a median of 1 prior therapy (range 1-3) were treated daily with AM0010 in combination with FOLFOX (n=20). Tumor responses were monitored using irRC. Immune responses were monitored using analysis of serum cytokines, activation of blood derived T cells and peripheral T cell clonality. Pretreatment samples were analyzed by IHC for tumor infiltration by CD8+ T cells. Results: G3/4 TrAEs included thrombocytopenia (55%), anemia (45%) and neutropenia (25%). There was no significant bleeding or febrile neutropenia. 16 pts had a objective tumor response assessment; 2 had an irCR, 1 an irPR, 10 had irSD. Eight remain on treatment, 2 for > 1 year. ORR was 15%, the DCR was 65%. The mPFS was 3.9 months. AM0010 increased serum Th1 cytokines and reduced mediators of chronic inflammation IL-23 and IL-17 and the immunosuppressive cytokine TGFb. AM0010 increased the number and proliferation of PD1+ activated CD8+ T cells and induced de-novo oligoclonal expansion of T cell clones without affecting total lymphocyte counts. Conclusions: AM0010 with FOLFOX is well tolerated with moderate hematological toxicity in patients with PDAC. The observed immune activation including CD8+ T cell activation and prolonged objective responses are encouraging and will be explored in a phase 3 trial starting in 2016.