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Clinical Trial
. 2020 Jan 1;6(1):60-67.
doi: 10.1001/jamaoncol.2019.3718.

Assessment of Hepatic Arterial Infusion of Floxuridine in Combination With Systemic Gemcitabine and Oxaliplatin in Patients With Unresectable Intrahepatic Cholangiocarcinoma: A Phase 2 Clinical Trial

Andrea Cercek  1 , Thomas Boerner  2 , Benjamin R Tan  3 , Joanne F Chou  4 , Mithat Gönen  4 , Taryn M Boucher  1 , Haley F Hauser  1 , Richard K G Do  5 , Maeve A Lowery  1 , James J Harding  1 , Anna M Varghese  1 , Diane Reidy-Lagunes  1 , Leonard Saltz  1 , Nikolaus Schultz  6 , T Peter Kingham  2 , Michael I D'Angelica  2 , Ronald P DeMatteo  7 , Jeffrey A Drebin  2 , Peter J Allen  8 , Vinod P Balachandran  2 , Kian-Huat Lim  3 , Francisco Sanchez-Vega  9 , Neeta Vachharajani  9 , Maria B Majella Doyle  9 , Ryan C Fields  9 , William G Hawkins  9 , Steven M Strasberg  9 , William C Chapman  9 , Luis A Diaz Jr  1 , Nancy E Kemeny  1 , William R Jarnagin  2
Affiliations
Clinical Trial

Assessment of Hepatic Arterial Infusion of Floxuridine in Combination With Systemic Gemcitabine and Oxaliplatin in Patients With Unresectable Intrahepatic Cholangiocarcinoma: A Phase 2 Clinical Trial

Andrea Cercek et al. JAMA Oncol. .

Abstract

Importance: Unresectable intrahepatic cholangiocarcinoma (IHC) carries a poor prognosis, with a median overall survival (OS) of 11 months. Hepatic arterial infusion (HAI) of high-dose chemotherapy may have potential benefit in these patients.

Objective: To evaluate clinical outcomes when HAI chemotherapy is combined with systemic chemotherapy in patients with unresectable IHC.

Design, setting, and participants: A single-institution, phase 2 clinical trial including 38 patients was conducted with HAI floxuridine plus systemic gemcitabine and oxaliplatin in patients with unresectable IHC at Memorial Sloan Kettering Cancer Center between May 20, 2013, and June 27, 2019. A confirmatory phase 1/2 study using the same therapy was conducted during the same time period at Washington University in St Louis. Patients with histologically confirmed, unresectable IHC were eligible. Resectable metastatic disease to regional lymph nodes and prior systemic therapy were permitted. Patients with distant metastatic disease were excluded.

Interventions: Hepatic arterial infusion of floxuridine and systemic administration of gemcitabine and oxaliplatin.

Main outcomes and measures: The primary outcome was progression-free survival (PFS) of 80% at 6 months.

Results: For the phase 2 clinical trial at Memorial Sloan Kettering Cancer Center, 42 patients with unresectable IHC were included and, of these, 38 patients were treated (13 [34%] men; median [range] age at diagnosis, 64 [39-81] years). The median follow-up was 30.5 months. Twenty-two patients (58%) achieved a partial radiographic response, and 32 patients (84%) achieved disease control at 6 months. Four patients had sufficient response to undergo resection, and 1 patient had a complete pathologic response. The median PFS was 11.8 months (1-sided 90% CI, 11.1) with a 6-month PFS rate of 84.1% (90% CI, 74.8%-infinity), thereby meeting the primary end point (6-month PFS rate, 80%). The median OS was 25.0 months (95% CI, 20.6-not reached), and the 1-year OS rate was 89.5% (95% CI, 80.2%-99.8%). Patients with resectable regional lymph nodes (18 [47%]) showed no difference in OS compared with patients with node-negative disease (24-month OS: lymph node negative: 60%; 95% CI, 40%-91% vs lymph node positive: 50%; 95% CI, 30%-83%; P = .66). Four patients (11%) had grade 4 toxic effects requiring removal from the study (1 portal hypertension, 2 gastroduodenal artery aneurysms, 1 infection in the pump pocket). Subgroup analysis showed significant improvement in survival in patients with IDH1/2 mutated tumors (2-year OS, 90%; 95% CI, 73%-99%) vs wild-type (2-year OS, 33%; 95% CI, 18%-63%) (P = .01). In the Washington University in St Louis confirmatory cohort, 9 patients (90%) achieved disease control at 6 months; the most common grade 3 toxic effect was elevated results of liver function tests, and median PFS was 12.8 months (1-sided 90% CI, 6.4).

Conclusions and relevance: Hepatic arterial infusion plus systemic chemotherapy appears to be highly active and tolerable in patients with unresectable IHC; further evaluation is warranted.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Cercek reported receiving research funding from AbbVie, Seattle Genetics, and serves as a paid member of the advisory boards of Bayer and Proteus. Dr Tan reported consulting or advisory roles with Roche/Genentech and receiving research funding from Bayer, Boehringer Ingelheim, Eisai, Exelixis, Lilly, Merck Serono, Pfizer, Roche/Genentech, Sillajen, and Tyrogenex. Dr Gönen has had paid consulting or advisory roles for Tesaro. Dr Lowery has had paid consulting or advisory roles for Agios and Celgene. Dr Harding has received consulting fees from Bristol Myers Squib, CytomX, Eisai, and Eli Lilly, and research support from Bristol Myers Squib. Dr Harding also reported receiving grants and personal fees from Bristol-Myers Squibb, as well as personal fees from CytomX, Eisai, QED, and Elly Lilly outside the submitted work. Dr Drebin’s spouse is an employee of American Regent Pharmaceuticals. Dr Chapman reported receiving personal fees from Novartis and Mid-America Transplant outside the submitted work; in addition, Dr Chapman had a patent to Pathfinder with royalties paid. Dr Diaz is a paid member of the board of directors of Personal Genome Diagnostics (PGDx) and Jounce Therapeutics and a paid consultant to PGDx and NeoPhore. He is an uncompensated consultant for Merck but has received research support for clinical trials from Merck. Dr Diaz is an inventor of multiple licensed patents related to technology for circulating tumor DNA analyses and mismatch repair deficiency for diagnosis and therapy from The Johns Hopkins University. Some of these licenses and relationships are associated with equity or royalty payments directly to The Johns Hopkins University. He holds equity in PGDx, Jounce Therapeutics, Thrive Earlier Detection, and NeoPhore, and his spouse holds equity in Amgen. The terms of all these arrangements are managed by Johns Hopkins University and Memorial Sloan Kettering Cancer Center in accordance with their conflict of interest policies. Dr Kemeny reported receiving funding from Amgen for research protocols not related to this study.

Figures

Figure 1.
Figure 1.. Patient Screening and Enrollment Flowchart
Abbreviation: c/w indicates consistent with; HAI, hepatic arterial infusion.
Figure 2.
Figure 2.. Hepatic Arterial Infusion Chemotherapy With Floxuridine Plus Systemic Gemcitabine and Oxaliplatin
A, Percent change from baseline in target lesion as assessed per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria in all patients (n = 38). Prior chemotherapy and resection status are noted. The squares represent patients; black indicates that the patient underwent resection or had prior chemotherapy. B, Progression-free survival. C, Overall survival.
See this image and copyright information in PMC

Comment in

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