Phase 1 dose-escalation study of momelotinib, a Janus kinase 1/2 inhibitor, combined with gemcitabine and nab-paclitaxel in patients with previously untreated metastatic pancreatic ductal adenocarcinoma

Abstract

Purpose Preclinical evidence suggests the importance of Janus activating kinase (JAK) and TANK-binding kinase 1 (TBK1) in pancreatic ductal adenocarcinoma (PDAC). We evaluated the safety and efficacy of momelotinib (MMB), a JAK1/2 inhibitor with additional activity against TBK1, plus albumin-bound paclitaxel + gemcitabine (nab-P + G), in patients with previously untreated metastatic PDAC. Experimental Design Patients were enrolled into five cohorts of increasing doses of MMB between 100 and 200 mg administered once or twice daily in combination with nab-P + G in 28-day cycles to determine maximum tolerated dose (MTD). Safety, efficacy, pharmacokinetics, and pharmacodynamics were assessed for all patients. Results Twenty-five patients were enrolled. Dose-limiting toxicities of Grade 3 diarrhea occurred in 1 patient each in the 100 and 200 mg MMB once-daily dose groups. MTD was not reached. The 200 mg MMB twice-daily was the maximum administered dose. Objective response rate was 28% (all partial responses), and 13 (52%) patients had a best response of stable disease. The most common adverse events (AEs) were fatigue (80%), nausea (76%), and anemia (68%). Grade 3 or 4 AEs, most commonly neutropenia (32%), were reported by 88% of patients, of which 44% were considered related to MMB. Pharmacokinetic analyses showed MMB concentrations were too low for TBK1 inhibition. Conclusions MMB was safe and well tolerated in combination with nab-P + G. As no OS or PFS benefit vs nab-P + G was apparent in context of suboptimal engagement of the target TBK1, this study does not support further development of MMB as a first-line therapy in pancreatic cancer.

Discovery and Targeting of the Signaling Controls of PNPLA3 to Effectively Reduce Transcription, Expression, and Function in Pre-Clinical NAFLD/NASH Settings

“…Over the course of an 18 h treatment, PNPLA3 mRNA was reduced up to 80% at 10 μM, without affecting cell viability ( Figure 1 a). Of note, 10 μM is roughly five-fold lower than the peak plasma concentration achieved with a single 150 mg oral dose of momelotinib in a dose escalation study in metastatic cancer patients [ 21 ].…”

Targeting the JAK/STAT pathway in solid tumors

“…Its impact in solid tumors is under active clinical investigation. In a Phase I doseescalation study in patients with untreated metastatic pancreatic cancer, momelotinib in combination with gemcitabine and nab-paclitaxel was well-tolerated; however, limited efficacy and no apparent association between efficacy and increasing dose led to the termination of this trial prior to the initiation of planned Phase III studies (NCT02101021) [122] . A Phase Ib study of momelotinib combined with trametinib in KRAS-mutated NSCLC showed no improvement in response compared with historic data with trametinib monotherapy (NCT02258607) [123] .…”

Emerging roles for the IL-6 family of cytokines in pancreatic cancer

“…Application of another JAK1/2 inhibitor, momelotinib, in combination with gemcitabine and nab-paclitaxel for patients with previously untreated metastatic pancreatic cancer demonstrated that the combination was well tolerated but exhibited no clinical benefit compared with gemcitabine/nab-paclitaxel dual treatment [264]. Ongoing studies trialling the combination of STAT3 inhibitor napabucasin with gemcitabine/nab-paclitaxel in patients with metastatic pancreatic cancer demonstrated that the treatment is well tolerated, though conclusive results regarding efficacy are pending [265,266].…”