The Purpose of This Research Study is to See if Combining Gemcitabine, Cisplatin and Durvalumab Chemotherapy Treatments With a Direct Tumor Therapy Yittrium-90 (Y-90) Will Work Better Together to Shrink Tumors and Control Cancer

Official title

A Phase II Single-center, Open-label, Single Arm Study of Induction Gemcitabine, Cisplatin and Durvalumab Followed by Gemcitabine, Cisplatin and Yttrium-90 (Y-90) Radioembolization for the Treatment of Locally Advanced Unresectable Intrahepatic Cholangiocarcinoma

Overview

The purpose of this research is to see if combining gemcitabine, cisplatin and Durvalumab chemotherapy treatments with a direct tumor therapy called Yittrium-90, will work better together to shrink the tumor and control cancer.

Interventions

• Drug Induction Chemotherapy Triplet Therapy
  Gemcitabine 1000 mg/m2, Cisplatin 25 mg/m2 infused on both day 1 and day 8 of a 21-day cycle. Durvalumab 1500 mg will be given on day 1 of each cycle.
• Radiation Concurrent Y-90 treatment
  Patients will undergo a Y-90 treatment planning consultation by the treating interventional radiologist during cycle 1. One or two cycles (depending on tumor size) of cisplatin, 25 mg/m2 and gemcitabine 300 mg/m2 given on day 1 and day 8 in combination with Yttrium-90 (Y-90) microspheres which will be given on day 3-7 or day 10-21 at the discretion of the interventional radiologist, separated in time by at least 2 days from a chemo infusion during that cycle
• Drug Consolidation Doublet Therapy:
  Gemcitabine 1000 mg/m2 and Cisplatin 25 mg/m2 given on days 1 and 8 of a 21-day cycle with durvalumab 1500 mg given on day 1 of each cycle for 3-5 additional cycles. For the cycle directly after Y-90, gemcitabine will be kept at a dose of 300 mg/m2 to minimize risk of toxicity.

Primary outcome measures

• Assessing the objective response rate (ORR) at 6 months in patients with locally advanced, unresectable intrahepatic cholangiocarcinoma (iCCA) [Time frame: 6 months]

Secondary outcome measures (8)

• Assessing Progression Free Survival (PFS) [Time frame: 48 months]
• Hepatic Progression-Free Survival (HPFS) [Time frame: 48 months]
• Overall Survival (OS) [Time frame: 48 months]
• Disease Control Rate (DCR) [Time frame: 48 months]
• R0 resection rate [Time frame: 6 months]
• treatment related impact on quality of life [Time frame: 48 months]
• safety and toxicity rate [Time frame: 48 months]
• rate of downstaging to surgery [Time frame: 6 months]

Eligibility criteria

Inclusion criteria

• Adult males and females at least 18 years of age
• Histologically and/or cytologically confirmed iCCA that is previously untreated or, if systemic therapy has been rendered for prior disease, has been administered at least 6 months before the development of recurrent or de novo new sites of disease.
• Unresectable disease, as deemed by the Inova multidisciplinary tumor board (i.e. disease that cannot be safely resected with negative margins, leaving 2 adjacent segments of liver with intact portal venous and hepatic arterial inflow and intact biliary and hepatic venous outflow with the future liver remnant of sufficient volume to avoid postoperative liver insufficiency)
• Measurable disease per RECIST 1.1 at least 2 cm in size
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
• Noncirrhotic liver - patients should not have a preexisting diagnosis of cirrhosis either diagnosed via biopsy or with features consistent with cirrhosis on imaging (e.g. shrunken liver with nodularity consistent with cirrhosis). Child-Pugh score must be less than 5.
• No evidence of extrahepatic disease, except for regional adenopathy that would be resected as part of a standard oncologic surgical procedure
• Adequate organ function as indicated by the following laboratory values (Table 1)
• Ability to complete testing in the protocol
• Able and willing to consent to protocol

Exclusion criteria

• Female patients who are pregnant or breast-feeding
• History of allogeneic organ transplantation.
• Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions:

• Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study.
• Patients with controlled type 1 diabetes on an insulin regimen are eligible for the study.
• Patients with vitiligo or alopecia.
• Any chronic skin condition that does not require systemic therapy.
• Patients without an active autoimmune disease in the last 5 years may be included but only after consultation with the study physician.
• Patients with diet controlled celiac disease.
• Current or recent use of immunosuppressive medication within 14 days before durvalumab initiation except if:

• Intranasal, inhaled, topical or local steroid injections
• Systemic corticosteroids at physiologic doses that do not exceed 10 mg/day of prednisone or its equivalent.
• Steroids as premedication for hypersensitivity reactions, (i.e. CT scan premedication).
• Child-Pugh B7 or greater cirrhosis
• Extrahepatic or perihilar cholangiocarcinoma
• Gallbladder cancer
• Pancreatic or ampullary cancer
• Portal vein thrombosis involving the main portal vein or first order right or left portal vein branches
• Extrahepatic disease, other than regional lymph nodes that would be removed at time of surgery as part of a routine oncologic procedure for iCCA
• Previous treatment with chemotherapy, intra-arterial or radiotherapy for iCCA is exclusionary, with the exception of adjuvant therapy with capecitabine which is allowed.
• Contraindication to durvalumab, gemcitabine, or cisplatin
• Active hepatitis B or C for which patients refuse treatment. Patients who are newly diagnosed with active disease as part of protocol screening and are agreeable to initiate on antiviral treatment are allowed to enroll.
• Contraindication found during work-up angiography, including significant lung shunting (lung dose >30 Gy for a single treatment or >50 Gy cumulative), or non-manageable extrahepatic deposition of technetium Tc 99m macroaggregated albumin on scintigraphy performed after planning angiography
• > 75% hepatic tumor burden
• Inability to protect non-target arteries to intestines or solid organs from radioembolization
• Serum albumin < 3 g/dL
• Serum bilirubin > 2 mg/dL, serum aspartate aminotransferase or alanine aminotransferase > 5 times upper limit of normal
• Concomitant illness that would prevent adequate patient assessment or in the investigators' opinion pose an added risk for study participants.
• Life-threatening intercurrent illness
• Anticipated poor compliance
• Prisoners or subjects who are involuntarily incarcerated
• Persons with decisional incapacity/cognitive impairment
• Any history or evidence of severe illness or any other condition that would make the patient, in the opinion of the investigator unsuitable for the study
• Subject is enrolled in a separate interventional clinical trial

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Keary Janet — Fairfax

Publications

• Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209-249. doi: 10.3322/caac.21660. Epub 2021 Feb 4. PMID 33538338
• Saha SK, Zhu AX, Fuchs CS, Brooks GA. Forty-Year Trends in Cholangiocarcinoma Incidence in the U.S.: Intrahepatic Disease on the Rise. Oncologist. 2016 May;21(5):594-9. doi: 10.1634/theoncologist.2015-0446. Epub 2016 Mar 21. PMID 27000463
• Ribero D, Pinna AD, Guglielmi A, Ponti A, Nuzzo G, Giulini SM, Aldrighetti L, Calise F, Gerunda GE, Tomatis M, Amisano M, Berloco P, Torzilli G, Capussotti L; Italian Intrahepatic Cholangiocarcinoma Study Group. Surgical Approach for Long-term Survival of Patients With Intrahepatic Cholangiocarcinoma: A Multi-institutional Analysis of 434 Patients. Arch Surg. 2012 Dec;147(12):1107-13. doi: 10.1001 PMID 22910846
• Si A, Li J, Xiang H, Zhang S, Bai S, Yang P, Zhang X, Xia Y, Wang K, Yan Z, Lau WY, Shi L, Shen F. Actual over 10-year survival after liver resection for patients with intrahepatic cholangiocarcinoma. Oncotarget. 2017 Jul 4;8(27):44521-44532. doi: 10.18632/oncotarget.17815. PMID 28562348
• Tarchi P, Tabrizian P, Prigoff J, Schwartz M. Outcomes of resection for solitary </=5 cm intrahepatic cholangiocarcinoma. Surgery. 2018 Apr;163(4):698-702. doi: 10.1016/j.surg.2017.09.058. Epub 2017 Dec 23. PMID 29277385
• Yeh CN, Hsieh FJ, Chiang KC, Chen JS, Yeh TS, Jan YY, Chen MF. Clinical effect of a positive surgical margin after hepatectomy on survival of patients with intrahepatic cholangiocarcinoma. Drug Des Devel Ther. 2014 Dec 17;9:163-74. doi: 10.2147/DDDT.S74940. eCollection 2015. PMID 25552905
• Lang H, Sotiropoulos GC, Fruhauf NR, Domland M, Paul A, Kind EM, Malago M, Broelsch CE. Extended hepatectomy for intrahepatic cholangiocellular carcinoma (ICC): when is it worthwhile? Single center experience with 27 resections in 50 patients over a 5-year period. Ann Surg. 2005 Jan;241(1):134-43. doi: 10.1097/01.sla.0000149426.08580.a1. PMID 15622001
• Mazzaferro V, Gorgen A, Roayaie S, Droz Dit Busset M, Sapisochin G. Liver resection and transplantation for intrahepatic cholangiocarcinoma. J Hepatol. 2020 Feb;72(2):364-377. doi: 10.1016/j.jhep.2019.11.020. PMID 31954498

Identifiers

NCT: NCT05422690 · U22-02-4670

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗