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Allen et al. Hepatoma Res 2021;7:73 https://dx.doi.org/10.20517/2394-5079.2021.98 Page 9 of 15

Ongoing neoadjuvant and downstaging clinical trials
Currently, there are ten ongoing clinical trials identified investigating neoadjuvant and downstaging
chemotherapy in biliary tract cancers, with these listed in Table 4. Four trials investigate outcomes in
resectable intrahepatic CCA. NCT04546828 is a phase II study investigating cisplatin plus gemcitabine plus
nab-paclitaxel, with the primary outcome the R0 rate. NCT04669496 is a phase II-III trial investigating
GEMOX plus lenvatinib plus toripalimab, a PD-1 monoclonal antibody, with all patients receiving adjuvant
capecitabine following resection. This is yet to commence recruitment. NCT04727541 is a phase II study
investigating bintrafusp-alfa, a bivalent PD-L1/TGFβ trap fusion protein, with the primary outcome
pathological response rate. NCT04523402 is a phase II study investigating GEMOX in intrahepatic CCA
with high-risk lymph node metastases, with the primary outcome DFS. NCT03603834 is investigating
modified FOLFOXIRI in resectable or potentially resectable CCA with ORR as the primary outcome.

There are three phase III trials currently underway. NCT04559139 is a global trial comparing neoadjuvant
cisplatin plus gemcitabine prior to re-resection in patients with an incidentally identified GBC following
cholecystectomy to adjuvant cisplatin plus gemcitabine. GAIN (NCT03673072/EudraCT 2017-004444-38) is
a phase III trial comparing perioperative cisplatin plus gemcitabine prior to re-resection of incidentally
diagnosed GBC following cholecystectomy or in patients with CCA, to surgery, with all patients receiving
[56]
adjuvant chemotherapy (investigators choice) .
There are two clinical trials underway investigating downstaging chemoradiotherapy in upfront
unresectable disease. POLCAGB (CTRI/2016/08/007199/NCT02867865) is a phase II-III clinical trial
comparing neoadjuvant cisplatin plus gemcitabine to five weeks of chemoradiotherapy (45 Gy EBRT plus
[57]
gemcitabine) followed by two cycles of cisplatin plus gemcitabine . In addition, NCT04378023 is
investigating chemoradiotherapy (50-54 Gy EBRT plus capecitabine) followed by cisplatin plus gemcitabine
until liver transplant in unresectable hilar CCA.

There is currently one phase II trial (NCT04308174) investigating the addition of durvalumab, a PD-L1
monoclonal antibody, to cisplatin plus gemcitabine in patients with localized CCA or GBC.

DISCUSSION
Cancers of the biliary tract are relatively rare, and consequently, it has been a challenge to perform phase III
clinical trials investigating adjuvant and neoadjuvant therapy. Of the five phase III trials assessing the
efficacy of adjuvant chemotherapy, four were considered negative. Both ESPAC-3 and the early phase III
clinical trial by Takada et al. investigating mitomycin C and fluorouracil were underpowered to draw
[39]
significant conclusions regarding adjuvant therapy, specifically in biliary tract cancers. BCAT did not
demonstrate a benefit with adjuvant gemcitabine in perihilar or distal CCA despite efficacy in metastatic
biliary tract cancers. One explanation is that treatment completion was approximately 50%, with an average
dose-intensity of 80%. Additionally, despite retrospective analyses and metanalyses suggesting a definite
benefit in R1 and N+ cancers, this was not observed in BCAT, although the trial was not powered to
demonstrate significance in this subgroup analysis. PRODIGE 12-ACCORD 18 has been the only phase III
clinical trial to investigate a combination of gemcitabine and platinum chemotherapy as adjuvant treatment.
With ABC-02 and BT22 demonstrating that combination gemcitabine and cisplatin improved ORR,
progression-free survival, and OS in metastatic disease, the theory was that GEMOX would result in
improved outcomes. Despite a numerically improved DFS and OS of 12 and 25 months, respectively,
neither met statistical significance. The calculated HR for DFS was 0.88, well above the pre-planned 0.6, and
the OS HR was greater than 1. This supports the argument that this was a truly negative trial as opposed to
being underpowered. It is concerning that this randomized trial evaluating a chemotherapy dose intensity