A Phase 3, Open-Label, Randomized, Active-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of Pemigatinib Versus Gemcitabine Plus Cisplatin Chemotherapy in First-Line Treatment of Participants With Unresectable or Metastatic Cholangiocarcinoma With FGFR2 Rearrangement (FIGHT-302)

Pemigatinib is an inhibitor of the FGFR family of receptor tyrosine kinases
that is proposed for the treatment of cholangiocarcinoma. Aberrant signaling
through FGFR resulting from gene amplification or mutation, chromosomal
translocation, and ligand-dependent activation of the receptors has been
demonstrated in multiple types of human cancers. Fibroblast growth factor
receptor signaling contributes to the development of malignancies by promoting
tumor cell proliferation, survival, migration, and angiogenesis. Incyte is
proposing to study pemigatinib for the treatment of cholangiocarcinoma. Refer
to the IB for additional background information on pemigatinib.

This study has been transitioned to CTIS with ID 2024-513513-12-00 check the CTIS register for the current data.

Primary Objectives
Evaluate the efficacy of pemigatinib versus gemcitabine plus cisplatin in the
first-line treatment of participants with cholangiocarcinoma with FGFR2
rearrangement.

Secundary Objectives
Evaluate the efficacy of pemigatinib versus gemcitabine plus cisplatin in the
first-line treatment of participants with cholangiocarcinoma with FGFR2
rearrangement.

This is a Phase 3, open-label, randomized, active-controlled study of
pemigatinib versus gemcitabine plus cisplatin as first-line treatment of
participants with unresectable and/or metastatic cholangiocarcinoma with FGFR2
rearrangement. The study will enroll approximately 432 participants in a 1:1
randomization ratio stratified by geographic region (Western [NA and EU] vs
APAC vs ROW) and by tumor burden (locally advanced vs distant metastasis) into
1 of the following 2 treatment groups:
• Treatment Group A: Pemigatinib (13.5 mg QD) administered as continuous
therapy schedule (a cycle is 3 weeks).
• Treatment Group B: Gemcitabine (1000 mg/m2) and cisplatin (25 mg /m2)
administered as an intravenous infusion on Days 1 and 8 of every 3-week cycle
for up to 8 cycles.

Participants will be required to have documented FGFR2 rearrangement through
the sponsor's central laboratory to confirm eligibility.

• Treatment Group A: Pemigatinib (13.5 mg per day) administered as continuous
therapy schedule (a cycle is 3 weeks).
• Treatment Group B: Gemcitabine (1000 mg/m2) plus cisplatin (25 mg/m2)
administered as intravenous infusion on Days 1 and 8 of every 3-week cycle for
up to 8 cycles.

Cholangiocarcinoma continues to be a rare and lethal disease where there is a
high unmet need for new therapies. Thus, a targeted agent with a manageable
safety profile that can provide a significant DCR in a molecularly defined
population would provide a meaningful clinical benefit.
Gemcitabine-platinum combination regimens are the best evaluated first-line
treatment for cholangiocarcinoma and have been shown to extend survival.
However, the toxicities and long-term sequelae associated with chemotherapy
administration are significant and typically contribute to dose modifications
and discontinuations of treatment due to lack of tolerability.
As of 25 NOV 2018, a total of 105 participants (99.1%) who received pemigatinib
monotherapy (all doses and dose regimens combined) in Study INCB 54828-101 had
TEAEs, and, consistent with the expected pharmacological effect of FGFR
inhibition on serum phosphate levels, the most frequently reported TEAE was
hyperphosphatemia (74 participants [69.8%]; serum phosphate > 5.5 mg/dL). Other
frequently reported TEAEs included fatigue in 43 participants (40.6%), dry
mouth in 39 participants (36.8%), and alopecia in 35 participants (33.0%).
Treatment-emergent AEs occurring in >= 10% of participants who received
pemigatinib monotherapy (Parts 1 and 2 combined) are presented by dose and dose
regimen and overall in Table 8 of the protocol.
Forty-five participants (42.5%) who received pemigatinib monotherapy had at
least 1 SAE; the overall incidence of SAEs for the continuous dose regimen
(56.7%) was higher than was seen for the interval dose regimen (36.8%).
Pneumonia in 7 participants (6.6%) was the most frequently occurring SAE. Other
SAEs occurring in more than 1 participant included back pain and disease
progression in 4 participants (3.8%) each; abdominal pain, dehydration,
fatigue, hyponatremia, and acute renal failure in 3 participants (2.8%) each;
and blood bilirubin increased, cerebrovascular accident, constipation,
hypotension, pain in extremity, pleural effusion, and pyrexia in 2 participants
(1.9%) each. Within the eye disorders SOC, a single participant had an SAE of
ocular hyperemia (Grade 2), which was considered unrelated to pemigatinib by
the investigator.
A total of 11 participants (10.4%), 7 participants (9.2%) on an interval dose
regimen and 4 participants (13.3%) on a continuous dose regimen, had SAEs with
a fatal outcome: disease progression in 4 participants (3.8%) and pneumonia,
malignant neoplasm progression (ie, disease progression), cerebrovascular
accident, intracranial hemorrhage, multiorgan failure, esophageal varices
hemorrhage, pneumonia, respiratory failure, and acute respiratory failure
secondary to acute anemia (verbatim term) in 1 participant (0.9%) each. None of
these fatal events were assessed as related to pemigatinib by the investigator.
Eleven participants (10.4%) discontinued pemigatinib monotherapy due to TEAEs;
pneumonia in 3 participants (2.8%) and dehydration and small intestinal
obstruction in 2 participants (1.9%) each were the only TEAEs leading to
discontinuation of pemigatinib that occurred in more than 1 participant.