A phase Ib/II study of pacritinib, an interleukin 1 receptor associated kinase 1 (IRAK1) inhibitor, in patients (pts) with solid tumors harboring the 1q21.3 copy number amplification (CNA).

43 Background: The role of IRAK1 pathway in inflammatory and immune response is established in autoimmune diseases but less well-understood in cancer. Chromosome 1q21.3 CNA detected in plasma cell-free DNA was observed in pts with advanced solid tumors, and associated with IRAK1 upregulation. In preclinical animal models, IRAK1 upregulation promoted tumorigenesis, while its inhibition led to decreased tumor growth. Pacritinib is a JAK2/FLT3 inhibitor that is FDA approved for treatment in myelofibrosis, but also have known activity against IRAK1. We hypothesize that pacritinib may be effective in disease control of pts with plasma 1q21.3 CNA. Methods: A phase Ib/II clinical trial was designed to investigate the efficacy of pacritinib in pts with treatment (rx) refractory solid tumors harboring 1q21.3 CNA. Serial pt tumor and blood samples were collected and analyzed to elucidate the effect of IRAK1 inhibition on tumor microenvironment and systemic immune modulation. Results: 330 patients were screened, 1q21.3 CNA was detected in 30.1% of pts. Highest incidence of 1q21.3 CNA positivity was detected in breast cancer (39.8%), colorectal cancer (39.7%) and lung cancer (36.1%). 12 pts were commenced on rx over 3 dose levels (DL) (DL1: n=6, DL2: n=3, DL3: n=3). At DL1 (200mg BID), no DLTs were observed, but 2 pts had G3 transaminitis attributed to drug/disease, and 1 pt had intolerable G2 rash; decision was made for dose reduction. At DL2 (200mg OM, 100mg ON), no DLTs were observed. Reescalation to 200mg BID (DL3) was carried out with no DLT observed. Pacritinib at 200mg BD was declared the recommended phase II dose in pts with solid tumors. In the dose expansion cohort, 8 pts (4 colorectal cancer, 3 hepatobiliary HPB cancer, 1 lung cancer) have been enrolled thus far. No objective responses were observed. Within pts with HPB tumors, 1 pt with pancreatic cancer had a progression-free survival (PFS) of 25.0 weeks, and 1 pt with cholangiocarcinoma had a PFS of 15.9 weeks. Preliminary analysis of serial tumor biopsy samples suggest an expansion of CD8+ T cell population with pacritinib rx. Serial peripheral blood mononuclear cells analysis showed no significant trend in change in CD8+ T cell population, but a predominance of PD-1+ T cells with rx, and also an increase in CD4+ T cell population. In the myeloid cell population, there appears to be decrease in dendritic cell population, but no significant change in trend of macrophage was observed. Conclusions: Pacritinib at 200mg BID is safe and tolerable in pts with solid tumors. IRAK1 inhibition appears to modulate immune cell populations both in the tumor microenvironment and systemic circulation. Dose expansion is underway, with potential signal of disease control in HPB tumors. Clinical trial information: NCT04520269 .