PIVOT-02: A phase 1/2, open-label, multicenter, dose escalation and dose expansion study of NKTR-214 and nivolumab in patients with select, locally advanced or metastatic solid tumor malignancies

Abstract

Background: Abundance and functional quality of tumor infiltrating lymphocytes are positively linked with tumor response and improved survival with checkpoint inhibitors. NKTR-214 is a CD122-biased agonist that targets the IL2 pathway and is designed to provide sustained signaling through the heterodimeric IL2 receptor pathway (IL2Rβγ) to preferentially activate and expand NK and effector CD8+ T cells over CD4+ T regulatory cells within the tumor microenvironment. NKTR-214 has been administered to 28 patients with advanced cancers. NKTR-214 as a single agent demonstrated a substantial increase in both CD8+ T and NK cells within the tumor microenvironment in patients with prior immune checkpoint therapy (Bernatchez et al 2016). Given the favorable safety profile and strong biomarker data, a trial combining NKTR-214 and nivolumab was initiated. Trial design: PIVOT-02 is a phase 1/2 open-label trial in patients (pts) with locally advanced or metastatic melanoma (mM), non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), urothelial carcinoma, or triple-negative breast cancer (TNBC). The primary objectives are to evaluate safety and tolerability, determine the recommended phase 2 dose (RP2D), and assess tumor response by RECIST 1.1. In an outpatient setting, NKTR-214 is administered at dose levels of 0.003, 0.006 and 0.009 mg/kg in combination with nivolumab at two flat dose schedules of either 240 mg @ q2w or 360 mg @ q3w. As of May 8, 17 pts (7 mM, 8 RCC, and 2 NSCLC) have been enrolled into 4 cohorts in the dose-escalation phase. In the dose-expansion phase, approximately 250 pts will be enrolled in five tumor types and eight indications; immunotherapy naïve patients and patients who are relapsed/refractory to checkpoint therapy are being studied separately. Extensive blood and tumor tissue samples are being collected to measure immune activation using immunophenotyping including flow cytometry, immunohistochemistry (IHC), T cell clonality and gene expression analyses. Enrollment is ongoing.