A phase 1b dose escalation trial of gemcitabine and nab-paclitaxel in combination with lixumistat in patients with advanced pancreatic cancer.
Authors: Shubham Pant, Brandon George Smaglo, Ryan W Huey, Saurav Daniel Haldar, Maria Pia Morelli, Jason Willis, Lianchun Xiao, Ying Yuan, Sergio Attanasio, Rutvi Shah, Francesca Citron, Dan Zhao, Scott Kopetz, Anirban Maitra, Dean Welsch, Rahul Sheth, Priya Bhosale, Robert A. Wolff, Andrea Viale
Journal: Journal of Clinical Oncology (2025)

743 Background: Despite recent advances, there are limited effective therapeutic options for pancreatic ductal adenocarcinoma (PDAC). Conventional chemotherapy can be difficult to tolerate and offers modest survival benefits. Lixumistat is a small molecule biguanide that inhibits the first and rate-limiting step of the oxidative phosphorylation pathway, which is critical to the survival of PDAC tumor cells. A first-in-human dose escalation trial of Lixumistat in solid tumors demonstrated a favorable safety profile and a recommended phase 2 dose (RP2D) of 800 mg per day (QD) (1). Methods: A single center Phase 1b study is currently enrolling patients with treatment-naïve metastatic PDAC to evaluate the safety and tolerability of Lixumistat when combined with standard-of-care gemcitabine (Gem) plus nab- paclitaxel (NP) (NCT05497778). The initial escalation cohort received oral Lixumistat at 400 mg QD; the subsequent escalation cohort received oral Lixumistat at 800 mg QD. All patients also receive fixed doses of intravenous (IV) NP (125 mg/m 2 ) and IV Gem (1000 mg/m 2 ) on Days 1, 8, and 15 (28 day cycle). Here we report the preliminary results from the escalation phase of the trial. Results: Thirteen patients have been treated: 7 at 400 mg and 6 at 800 mg. There were no grade 4-5 toxicities. Two patients experienced a DLT at the 800 mg dose (grade 3 diarrhea and grade 3 fatigue); no DLTs were observed at the 400 mg dose. The most common Lixumistat related toxicities were Grade 1/2 nausea/vomiting (controlled with anti-emetics), skin rash, fatigue, and diarrhea. Grade 1-3 thrombocytopenia, neutropenia, and peripheral sensory neuropathy events were no more than expected with this combination and managed with Gem/NP dose reduction, omission of day 8, or therapy hold until resolved to Grade 1. Based on toxicities observed at 800 mg, 400 mg is the RP2D. Among 6 response-evaluable patients treated at the RP2D, 2 achieved an objective partial response (ORR = 33%, 95% CI: 4.3%-77.3%); 4 patients had stable disease with tumor shrinkage observed in 3 of these patients (12%, 22% and 23% reduction); and the DCR was 100% (95% CI: 54.1%-100%). Notably, a patient from the 800 mg cohort who was dose reduced to 400 mg after DLT achieved a complete response in their target lesions. Current median follow-up time is 13.2 months, and 2 patients have died. Estimated median PFS is 12.9 months (95% CI: 3.65, NA) and estimated median OS is 18 months (95% CI: 6.42, NA). Four patients remain on active treatment at the time of analysis. Conclusions: When combined with Gem and NP; a dose of 400 mg of Lixumistat QD was demonstrated to be safe, tolerable and identified as the RP2D. This trial is currently enrolling patients at the RP2D in the expansion cohort. Updated data on safety and efficacy will be presented at the meeting. 1. Janku 2022. Clinical trial information: NCT05497778 .