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A Phase Ib study of ruxolitinib + gemcitabine ± nab-paclitaxel in patients with advanced solid tumors.

Abstract：

Purpose:Aberrant activation of the Janus-associated kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is associated with increased malignant cell proliferation and survival. This Phase Ib study evaluated ruxolitinib, a potent JAK1/2 inhibitor, in combination with gemcitabine with or without nab-paclitaxel in patients with advanced solid tumors. Patients and methods:Patients received ruxolitinib + gemcitabine (regimen A) or ruxolitinib + gemcitabine + nab-paclitaxel (regimen B). The objective of the dose-finding phase was to identify the maximum tolerated doses (MTDs) of ruxolitinib plus gemcitabine with or without nab-paclitaxel. Results:Among 42 patients enrolled, the median age was 62.5 years, 81.0% had pancreatic cancer, and almost 62% had received prior systemic therapy. Regimen A was tolerated with standard doses of gemcitabine; regimen B was tolerated with reduced doses of gemcitabine/nab-paclitaxel or concomitant granulocyte colony-stimulating factor. The sponsor decided to terminate the study early due to the interim analysis results of the Phase III JANUS 1 study. Discontinuations were mainly due to radiologic or clinical disease progression (81.0% of patients). Median treatment durations were 55.5 days (cohort A0) and 150.5 days (pooled B cohorts). Four patients (pooled B cohorts) had dose-limiting toxicities: grade 3 pneumonia (n=1), grade 4 neutropenia (n=1), and grade 4 thrombocytopenia (n=2). The most common grade 3/4 hematologic adverse events (AEs) were anemia, thrombocytopenia, and neutropenia. Serious AEs occurring in ≥2 patients in cohort A0 or pooled B cohorts were abdominal pain, sepsis (cohort A0), dehydration, anemia, and asthenia (pooled B cohorts). Overall response rates (ORRs) were 12.5% in cohort A0 and 38.5% in pooled B cohorts. Among patients with pancreatic cancer, ORR was 23.5% (14.0% cohort A0 30.0% pooled B cohorts). Conclusion:The study was terminated early prior to reaching MTDs per sponsor decision; although ruxolitinib plus gemcitabine with or without nab-paclitaxel was generally safe and well tolerated in patients with advanced solid tumors, this combination will not be pursued further.

journal_name

Onco Targets Ther

journal_title

OncoTargets and therapy

authors

Bauer TM,Patel MR,Forero-Torres A,George TJ Jr,Assad A,Du Y,Hurwitz H

doi

10.2147/OTT.S157331

subject

Has Abstract

pub_date

2018-04-30 00:00:00

pages

2399-2407

issn

1178-6930

pii

ott-11-2399

journal_volume

pub_type

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A Phase Ib study of ruxolitinib + gemcitabine ± nab-paclitaxel in patients with advanced solid tumors.