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the trial after results from JANUS 1 showed no benefit of ruxolitinib and capecitabine compared to placebo
[98]
and capecitabine . In a Phase II trial of ruxolitinib in metastatic prostate cancer, there was no significant
clinical response and the trial was terminated (NCT00638378). There is currently a rollover study that is
providing continued access to ruxolitinib for patients with pancreatic, colorectal, lung, and breast cancers
enrolled in previous trials (NCT02955940).

Several ongoing early-stage clinical trials are investigating ruxolitinib as monotherapy. There are two
current window-of-opportunity trials: one testing neoadjuvant ruxolitinib in HNC (NCT03153982) and
one examining ruxolitinib in premalignant breast disease (NCT02928978). Some trials are also investigating
ruxolitinib in combination other agents. Among these are a Phase I study testing ruxolitinib in combination
with temozolomide in patients with high-grade gliomas (NCT03514069), a Phase Ib study of ruxolitinib
and trametinib (MEK inhibitor) in colon and pancreatic cancers with RAS mutations (NCT04303403), a
Phase I study testing ruxolitinib with pembrolizumab (PD-L1 inhibitor) in triple-negative breast cancer
(NCT03012230), two Phase II studies investigating ruxolitinib with chemotherapy in inflammatory breast
cancer (NCT02876302, NCT02041429), a Phase I/II trial evaluating ruxolitinib with trastuzumab (HER2
inhibitor) in HER2+ breast cancer (NCT02066532), and a Phase I/II study of ruxolitinib with paclitaxel
and carboplatin in ovarian, fallopian tube, and peritoneal cancers (NCT02713386). Ruxolitinib is one of
75 approved agents being tested in a trial that uses the Co-eXpression ExtrapolatioN (COXEN) model to
identify biomarkers and to predict which drugs would provide the most benefit to patients with urothelial
cancer (NCT02788201).

Tofacitinib
Tofacitinib is a JAK1/3 inhibitor that is FDA approved for treatment of rheumatoid arthritis and ulcerative
colitis [99-102] . Tofacitinib treatment of breast cancer cells prevented activation and nuclear localization of
STAT3 [103] . In prostate cancer preclinical models, tofacitinib decreased STAT5 activation and epithelial-
to-mesenchymal transition [104] . This JAK inhibitor is currently being tested in patients with solid tumors
(mainly pancreatic adenocarcinoma and cholangiocarcinoma) in a Phase I trial (NCT04034238).

AZD1480
AZD1480 is a selective ATP-competitive JAK1/2 inhibitor that showed promising activity against many
solid tumor preclinical models. AZD1480 treatment of cell lines and murine models, including but not
limited to GBM [105] , breast cancer [106,107] , HNC [108] , and ovarian cancer [109] , inhibited STAT3 activation, cell
viability, and tumor growth. Despite these encouraging preclinical findings, neurotoxicity was observed in
a Phase I clinical trial of AZD1480 in solid tumors and halted the development of this agent, leading to the
termination of this trial (NCT01112397) and a parallel Phase I study in patients with HCC, NSCLC, and
gastric cancer (NCT01219543) [110] .

AZD4205
AZD4205 is a selective JAK1 inhibitor [111] . In a preclinical NSCLC in vivo model, AZD4205 treatment
inhibited tumor growth and STAT3 activation; these findings were more significant when AZD4205 was
administered in combination with the EGFR inhibitor osimertinib. A Phase I/II clinical trial investigating
AZD4205 combined with osimertinib was initiated in patients with NSCLC (NCT03450330).

INCB047986 and INCB052793
INCB047986 and INCB052793 are selective inhibitors of JAK1. INCB047986 was studied in a Phase I
clinical trial in breast and pancreatic cancers, among other solid tumors, but the trial was terminated early
(NCT01929941). INCB052793 has been studied in multiple myeloma (MM) preclinical models, but there
are no reports using this agent in solid tumors. In combination with other anti-MM agents, INCB052793
decreased cell viability and inhibited tumor growth [112] . A Phase I/II trial was initiated investigating this
agent in solid tumors but was terminated due to lack of efficacy (NCT02265510).