Phase I trial of UNBS5162, a novel naphthalimide in patients with advanced solid tumors or lymphoma

Abstract

Objectives UNBS5162 is a novel naphthalimide that binds to DNA by intercalation and suppresses CXCL chemokine elaboration. A Phase I study of UNBS5162 was conducted to establish pharmacokinetics (PK), maximum tolerated dose (MTD), dose-limiting toxicity, safety and anti-tumor activity in patients with advanced solid tumors or lymphoma. Methods UNBS5162 was administered in a 3 + 3 dose escalation scheme by intravenous infusion over 1 h weekly for 3 weeks of a 4-week cycle. Safety, serial serum PK and tolerability were captured throughout the study. Response Evaluation Criteria in Solid Tumors was utilized every 2 cycles to assess for anti-tumor response. Results Twenty-four patients with metastatic carcinoma and 1 patient with lymphoma were treated at eight dose levels (18–234 mg/m2). All patients were evaluable for tolerability and toxicity. Grade 3 toxicities include nausea (n = 1), fatigue (n = 1) and anorexia (n = 1). Prolongation of QTc [Hodges] was observed in 6 cases (Gr 1 = 2; Gr 2 = 2; Gr 3 = 2). Cmax and area under the curve increased linearly with dose with a t1/2 of 30–60 min. 16 patients completed 2 cycles of therapy, all with pharmacodynamics at 8 weeks. Conclusions The MTD or dose-limiting toxicity for UNBS5162 was not reached due to the magnitude of QTc prolongation at the highest dose of 234 mg/m2/week that led to study termination.

UNBS5162 inhibits proliferation of human retinoblastoma cells by promoting cell apoptosis

“…Grade 3 toxicities were observed in three cases, and QTc prolongation was observed in six cases. 20 In vivo UNBS5162 after repeat administration significantly increased survival rate in orthotopic human prostate cancer models, and in vitro exposure of the prostate cancer cell line PC3 to UNBS5162 dramatically decreased the expression of proangiogenic CXCL chemokines. 8 Chemokines are proinflammatory cytokines, which are chemotactic for immune cells and operate as cytokines through binding to transmembrane G-protein-coupled receptors.…”

UNBS5162 inhibits the proliferation of human A549 non‐small‐cell lung cancer cells by promoting apoptosis

“…Further novel amonafide analogues are still being evaluated in experimental cancer models . UNBS5162 is an improved naphthalimide; however, its effect on cancer has only been reported in regard to prostate cancer, advanced solid tumors, and lymphomas . Although the UNBS5162 prodrug UNBS3157 has been associated with increased survival in NSCLC patients, the regulatory mechanism of UNBS3157 in NSCLC is not yet known .…”

“…[23][24][25] UNBS5162 is an improved naphthalimide; however, its effect on cancer has only been reported in regard to prostate cancer, advanced solid tumors, and lymphomas. 15,26 Although the UNBS5162 prodrug UNBS3157 has been associated with increased survival in NSCLC patients, the regulatory mechanism of UNBS3157 in NSCLC is not yet known. 14 Therefore, we investigated the role of UNBS5162 in NSCLC in this study.…”

The Role of p53-Mediated Signaling in the Therapeutic Response of Colorectal Cancer to 9F, a Spermine-Modified Naphthalene Diimide Derivative

“…Previous studies have considered the evaluation of several naphthalimides in clinical trials. However, adverse side effects (e.g., dose-limiting myelosuppression) were observed, which limits the clinical application of amonafide and its derivatives [43,44]. In contrast, 9F has demonstrated lower IC 50 profiling against hepatocellular carcinoma, compared to amonafide.…”