Preliminary results of STELLAR-001, a dose escalation phase I study of the anti-C5aR, IPH5401, in combination with durvalumab in advanced solid tumours

Abstract

Background Anaphylatoxin C5a is released in the cancer microenvironment and binds to the C5aR receptor, which in turns promotes protumoral inflammation and immune suppression through recruitment and activation of myeloid derived suppressor cells (MDSC) and neutrophils. Overexpression of C5aR has been reported in several tumor types and correlates with aggressive tumor features and poor prognosis. Additionally, C5aR was found to be upregulated in NSCLC patients in progression after an initial response to an anti-PD-(L)1 therapy (aPD1). IPH5401, a fully human anti-C5aR1 antibody, inhibits the C5a mediated effects on MDSC and neutrophils. Preclinical data suggest that the combined blockade of C5aR1 and aPD1 synergistically reduce tumor growth and delay tumor progression. These data suggest that combining IPH5401 with aPD1 may improve efficacy and overcome secondary resistance to aPD1. Methods This is an ongoing phase I to evaluate the safety of IPH5401 + durvalumab (durva) in advanced solid tumors. In the 3 + 3 dose-escalation, patients (pts) receive IPH5401 at 4 dose levels (DL) (DL1, DL2, DL3 [Q1w] and DL4 [Q2w]) single agent during the first 2 weeks (w) then in combination with durva 1500 mg Q4w. Blood samples are collected at various time points for characterization of pharmacokinetics, pharmacodynamics and immunogenicity. Upon completion of the phase I part and determination of a recommended phase II dose, expansion cohorts in NSCLC and HCC will be activated. Results As of April, 30th 2019, 12 pts have been enrolled (4 HCC, 2 UCC, 5 NSCLC, 1 RCC). No DLT was seen to date. DL3 and DL4 are ongoing. A total of 11 treatment related AEs (TRAEs) were reported in 5 patients: G2 diarrhea with lymphocytic colitis (n = 1), G1 diarrhea (n = 1), G1 skin rashes (n = 2), G1 White blood cell decrease (n = 1), G1 pneumopathy (n = 1), G1 lung disorder (n = 1), G1 fatigue (n = 1), G1 arthralgia (n = 1), G1 back pain (n = 1), G1 musculoskeletal chest pain (n = 1). There were no grade 3/4 TRAEs and no TRAEs that led to study discontinuation. Conclusions Preliminary results of this combination of IPH5401 plus durva suggest a manageable toxicity profile. Results of dose escalation including PK/PD data will be presented.