Symeonides, Stefan N.

PURPOSE There is growing scientific interest in incorporating patient-reported outcomes (PROs) in early phase dose-finding oncology trials (DFOTs) to assess tolerability, inform dose selection, and guide later stage trial design. However, research indicates that PRO objectives in DFOTs are often unclear. The Incorporating Patient-Reported Outcomes in Dose-Finding Trials-Research Objectives Recommendations (OPTIMISE-ROR) project was established to support trialists to effectively incorporate PROs into DFOTs. METHODS Using the Enhancing Quality and Transparency of Health Research (EQUATOR) Network's methodological framework, guideline development included the following: (1) a methodological review of published DFOTs incorporating PROs; (2) candidate item generation, refined through expert consultation; (3) a two-round international multistakeholder Delphi survey (N = 109 in Round 1 [October 2024]; N = 96 in Round 2 [December 2024]); and (4) an independently chaired virtual consensus meeting (N = 31; January 2025) where multidisciplinary, international experts reviewed and voted to finalize items for inclusion. RESULTS Consensus was reached on six recommendations emphasizing three core PRO tolerability concepts: overall side effect impact, symptomatic adverse events, and overall health-related quality of life. The integration of PROs to inform final dose recommendations in dose escalation and optimization trials should be considered, regardless of trial design. The recommendations highlight the importance of PRO data analysis over time and across dose levels, defining PRO research objectives as descriptive or statistically powered, and assessing PRO-related end points to guide end point selection for subsequent studies. CONCLUSION This foundational guidance outlines key PRO research objectives in DFOTs. By facilitating the systematic integration of PROs, this guidance supports the utilization of patient-centered evidence for the tolerability and efficacy assessment of therapies to inform dose escalation, optimization, and regulatory evaluation—ultimately contributing to the development of safer, more effective therapies.

Abstract Background: Kinases from the SRC family of kinases (SFK) are predominantly inactive in non-cancerous cells and have been shown to be highly activated in tumor tissue. The role of SFKs in cell adhesion, invasion, proliferation, survival, and angiogenesis during tumor development has been extensively described. NXP900 is a novel, selective SFK inhibitor with low nanomolar potency against YES1 (0.47nM) and SRC (2.4nM). NXP900 has a unique binding mode of action (MOA), whereby it locks its target into its native “closed” conformation (type 1.5 inhibitor), resulting in inhibition of both the kinase and the scaffolding functions of the target kinase. This MOA differentiates NXP900 from other multi-kinase inhibitors, that, among other kinases, also inhibit the kinase activity of SFK targets. These multi-kinase inhibitors lock their targets in the active “open” conformation (type 1 inhibitors), and in the case of SFK targets, while this results in inhibition of the kinase activity, it also promotes the association of SFK with pro-cancer signaling partners. In addition, NXP900 is very selective, with minimal inhibitory activity against kinases outside the SFK. Methods: Study NXP900-101 (NCT05873686) is a first-in-human, Phase 1, dose escalation and expansion clinical trial of NXP900 in patients with advanced solid tumors. The primary objective of the study is to identify a dosing regimen with an acceptable safety profile and clinically relevant pharmacokinetics and pharmacodynamics (PK/PD) for additional clinical investigations. The key safety endpoints are estimation of the incidence and intensity of adverse events and identification of the highest tolerable dose. To characterize the PK/PD profile of NXP900, serial blood samples were collected after single and multiple doses of NXP900. Results: In 26 patients with advanced solid tumors treated with 20-200 mg/day NXP900, the median age was 61 years (range: 35-88), 65% were male and the median number of prior lines of anti-cancer therapy, including surgery, was 5. The most common treatment emergent adverse events (total incidence >20%) were largely reported as Grade 1-2 and included fatigue (42%, Grade 1-2: 91%), diarrhea (35%, Grade 1-2: 89%), nausea (31%, Grade 1-2: 100%), and dyspnea (23%, Grade 1-2: 67%). NXP900 exposure was dose proportional across the evaluated range (20-200 mg); following a single 200 mg oral dose, NXP900 demonstrated rapid absorption with median peak plasma concentration and terminal half-life of approximately 3 and 12 hours, respectively. Multiple dosing (20-200 mg daily) resulted in moderate drug accumulation. PD analysis showed that NXP900 potently inhibited the phosphorylation of SRC across a range of clinically relevant doses in peripheral blood mononuclear cells. Conclusions: In its first-in-human clinical trial in patients with advanced solid tumors NXP900 was biologically active with an acceptable safety profile, supporting its continued clinical development. Citation Format: Gerald Falchook, Jordi Rodon Ahnert, Shivaani Kummar, Hani M. Babikar, Stefan Symeonides, Mitesh J. Borad, Jason Henry, J. Mark Sloan, Justin L. Hay, Megan Sardone, Udai Banerji. First in human phase 1 trial of the SRC family kinase inhibitor NXP900 in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT153.