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Itacitinib
Preclinical studies of the JAK1 inhibitor itacitinib have mostly been conducted in preclinical models of
hematological malignancies. In conjunction with INCB054329, an inhibitor of bromodomain and extra-
terminal motif proteins, itacitinib inhibited STAT3 activation and tumor growth in MM cell lines and
murine models [113] . Given this effect of JAK1 inhibition on STAT3 activity, clinical studies with this agent
were initiated in solid tumors. In a Phase Ib/II study of itacitinib in combination with nab-paclitaxel
and gemcitabine in solid tumors (84% of which had pancreatic cancer), 24% of patients responded (all
partial response) (NCT01858883). The therapeutic combination was well-tolerated after dose reduction of
itacitinib; however, this study was terminated due to another Phase III clinical trial reporting no impact of
the JAK1/2 inhibitor ruxolitinib on overall survival in pancreatic cancer [114] . Other ongoing clinical trials
are studying itacitinib in patients with HCC (NCT04358185), NSCLC (NCT03425006 and NCT02917993),
and a variety of advanced solid tumors (NCT02646748). A Phase II study in soft tissue sarcoma is currently
suspended (NCT03670069); a Phase II study in NSCLC (NCT02257619) and a Phase Ib study in other solid
tumors (NCT02559492) were terminated, with no published findings.

Momelotinib
Momelotinib is a JAK1/2 inhibitor that also has activity against TANK-binding kinase 1 (TBK1) [115,116] .
Several preclinical studies in solid tumor models have investigated the impact of momelotinib on the JAK/
STAT pathway. Momelotinib has been shown to increase sensitivity of ovarian cancer to chemotherapy in
in vitro and in vivo preclinical models [117,118] . In combination with paclitaxel, momelotinib inhibited tumor
growth, suppressed STAT3 activation, reduced expression of the stem cell marker OCT4, significantly
increased the time to recurrence, and decreased tumor burden [117,118] . Similarly, in GBM preclinical models,
momelotinib in combination with temozolomide inhibited STAT3 activation, decreased cell growth,
[119]
increased apoptosis, and inhibited tumor growth compared to temozolomide monotherapy . In colorectal
cancer cells, momelotinib inhibited STAT5 activation, decreased cell growth, and increased cell death [120] .
These promising preclinical results across several types of solid tumors support further investigation of
momelotinib as a therapeutic agent.

Clinical use of momelotinib has been studied extensively in myeloproliferative diseases: in myelofibrosis,
treatment with this agent was associated with a reduction in splenic volume that was non-inferior
to ruxolitinib [121] . Its impact in solid tumors is under active clinical investigation. In a Phase I dose-
escalation 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] . In a Phase Ib study of momelotinib in combination with erlotinib in
EGFR-mutated, metastatic NSCLC, patients experienced neutropenia as an adverse effect of this drug
combination, and the trial was halted (NCT02206763) [124] . Another Phase Ib clinical trial of momelotinib
with chemotherapeutic agents, capecitabine and oxaliplatin, in pancreatic adenocarcinoma was terminated
(NCT02244489).

Pacritinib
Pacritinib is a selective JAK2 inhibitor currently being studied in a Phase III clinical trial for treatment of
myelofibrosis (NCT02055781) [125,126] . In GBM cell lines, pacritinib, alone or in combination with afatinib,
inhibited STAT3 activation, cell viability, and spheroid formation [127-129] . Pacritinib plus afatinib was also
shown to decrease tumor burden in mice with GBM tumors [129] . Similar to momelotinib, pacritinib reduced
resistance to temozolomide in GBM in vivo models [127,128] . Pacritinib has been shown to inhibit liver fibrosis
and thus may be effective in preventing HCC [130] . A Phase II trial of pacritinib in refractory colorectal