The Purpose of This Research Study is to See if Combining Gemcitabine, Cisplatin and Nab-paclitaxel Chemotherapy Treatments With a Direct Tumor Therapy Yittrium-90 (Y-90) Will Work Better Together to Shrink Tumors and Control Cancer
Study Details
Study Description
Brief Summary
The purpose of this research is to see if combining gemcitabine, cisplatin and nab-paclitaxel chemotherapy treatments with a direct tumor therapy called Yittrium-90, will work better together to shrink the tumor and control cancer.
Condition or Disease | Intervention/Treatment | Phase |
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Phase 2 |
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Experimental: gemcitabine, cisplatin and nab-paclitaxel chemotherapy with Yittrium-90 single arm - Induction Gemcitabine, Cisplatin and Nab-Paclitaxel Triplet Chemotherapy followed by Gemcitabine, Cisplatin and yttrium-90 (Y-90) Radioembolization |
Drug: Induction Chemotherapy Triplet Therapy
Gemcitabine 1000 mg/m2, Cisplatin 25 mg/m2, Nab-paclitaxel 125 mg/m2 given on days 1 and 8 of a 21-day cycle for two cycles.
Radiation: Concurrent Y-90 treatment
One or two cycles (depending on whether or not one or two sessions of yttrium-90 are indicated as per the treating interventional radiologist) of gemcitabine 300 mg/m2 and cisplatin, 25 mg/m2 given on day 1 and 8 of a 21-day cycle. Y-90 will be administered on day 3-7 or day 10-21 of the 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 for 4-5 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.
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Outcome Measures
Primary Outcome Measures
- Assessing the objective response rate (ORR) at 6 months in patients with locally advanced, unresectable intrahepatic cholangiocarcinoma (iCCA) [6 months]
Best response in terms of tumor shrinkage (by RECIST 1.1 criteria including complete + partial responses) obtained during protocol therapy.
Secondary Outcome Measures
- Assessing Progression Free Survival (PFS) [48 months]
time from treatment initiation to disease progression, death or last patient contact
- Hepatic Progression-Free Survival (HPFS) [48 months]
time from treatment initiation to hepatic disease progression, death or last patient contact
- Overall Survival (OS) [48 months]
Time from treatment initiation to death due to any cause or last patient contact
- Disease Control Rate (DCR) [48 months]
Complete Response + Partial Response + Stable Disease (by RECIST 1.1 and mRECIST criteria) obtained during protocol therapy.
- R0 resection rate [6 months]
Rate of patients that achieve an R0 resection at 6 months.
- treatment related impact on quality of life [48 months]
Self-assessed metric of treatment-related impact on Quality of Life (QOL) as measured by the Functional Assessment of Cancer Therapy - Hepatobiliary (FACT-Hep) questionnaire with measures of Physical Well-Being, Social/Family Well-Being, Emotional Well-Being, Functional Well-Being, Hepatobiliary Cancer Subscale using a 5 point scale ((0) Not at all (1) A little bit; (2) Somewhat; (3) Quite a bit; (4) Very much). Better performance status, i.e. higher score, is associated with a higher quality of life.
- safety and toxicity rate [48 months]
Development of Treatment Toxicities (grade 3 non-hematologic toxicities persisting beyond 2 weeks despite best supportive care, any grade 3 hematologic toxicities, or any toxicity grade 4 or higher) assessed as per NCI's CTCAE v5.0 criteria.
- rate of downstaging to surgery [6 months]
Rate of downstaging to surgery that occurs during protocol therapy at 6 months.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Adult males and females at least 18 years of age
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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.
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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)
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Measurable disease per RECIST 1.1 at least 2 cm in size
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Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
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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.
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No evidence of extrahepatic disease, except for regional adenopathy that would be resected as part of a standard oncologic surgical procedure
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Adequate organ function as indicated by the following laboratory values (Table 1)
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Ability to complete testing in the protocol
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Able and willing to consent to protocol
Exclusion Criteria:
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Female patients who are pregnant or breast-feeding
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Extrahepatic or perihilar cholangiocarcinoma
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Gallbladder cancer
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Pancreatic or ampullary cancer
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Portal vein thrombosis involving the main portal vein or first order right or left portal vein branches
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Extrahepatic disease, other than regional lymph nodes that would be removed at time of surgery as part of a routine oncologic procedure for iCCA
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Previous treatment with chemotherapy, intra-arterial or radiotherapy for iCCA is exclusionary, with the exception of adjuvant therapy with capecitabine which is allowed.
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Contraindication to nab-paclitaxel, gemcitabine, or cisplatin
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Contraindication found during work-up angiography, such as 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
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75% hepatic tumor burden
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Inability to protect non-target arteries to intestines or solid organs from radioembolization
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Serum albumin < 3 g/dL
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Serum bilirubin > 2 mg/dL, serum aspartate aminotransferase or alanine aminotransferase > 5 times upper limit of normal
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Concomitant illness that would prevent adequate patient assessment or in the investigators' opinion pose an added risk for study participants.
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Life-threatening intercurrent illness
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Anticipated poor compliance
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Prisoners or subjects who are involuntarily incarcerated
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Persons with decisional incapacity/cognitive impairment
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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
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Subject is enrolled in a separate interventional clinical trial
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | Inova Schar Cancer Institute | Fairfax | Virginia | United States | 22031 |
Sponsors and Collaborators
- Inova Health Care Services
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
- De Martin E, Rayar M, Golse N, Dupeux M, Gelli M, Gnemmi V, Allard MA, Cherqui D, Sa Cunha A, Adam R, Coilly A, Antonini TM, Guettier C, Samuel D, Boudjema K, Boleslawski E, Vibert E. Analysis of Liver Resection Versus Liver Transplantation on Outcome of Small Intrahepatic Cholangiocarcinoma and Combined Hepatocellular-Cholangiocarcinoma in the Setting of Cirrhosis. Liver Transpl. 2020 Jun;26(6):785-798. doi: 10.1002/lt.25737.
- Lang H, Sotiropoulos GC, Frühauf NR, Dömland M, Paul A, Kind EM, Malagó 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.
- 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. Review.
- 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/archsurg.2012.1962.
- 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.
- 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.
- 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.
- 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.
- 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.
- U22-02-4670