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 Overview
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Brief Summary
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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.

Official Title
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A Phase II Trial of Induction Gemcitabine, Cisplatin and Nab-Paclitaxel Triplet Chemotherapy Followed by Gemcitabine, Cisplatin and Radioembolization for the Treatment of Locally Advanced Unresectable Intrahepatic Cholangiocarcinoma

Conditions
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Intrahepatic Cholangiocarcinoma

Intervention / Treatment
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* Drug: Induction Chemotherapy Triplet Therapy
* Radiation: Concurrent Y-90 treatment
* Drug: Consolidation Doublet Therapy:


Participation Criteria
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Eligibility Criteria
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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 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 nab-paclitaxel, gemcitabine, or cisplatin 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 > 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Treatments are repeated every 21 days. Chemotherapy will be administered on days 1 and 8 of the 21 day cycle. For the first two cycles, treatment will consist of three drugs, gemcitabine, cisplatin and nab-paclitaxel. After these two cycles, the nab-paclitaxel will be removed from the treatment plan and participants will continue on trial with gemcitabine and cisplatin alone for 6 additional cycles (8 total cycles, or 6 months total of treatment). During the 3rd and possibly the 4th cycle, these drugs will be given at a reduced dose as y-90 treatment to the tumors in your liver will also be given. The interventional team will administer y-90 during these cycles as either one dose during cycle 3, or two doses, one during cycle 3 and one during cycle 4 if there is too much cancer to treat all at once. The remaining cycles of treatment will be with gemcitabine and cisplatin by themselves.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: gemcitabine, cisplatin and nab-paclitaxel chemotherapy with Yittrium-90<br>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<br>* 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.<br>Radiation: Concurrent Y-90 treatment<br>* 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.<br>Drug: Consolidation Doublet Therapy:<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessing the objective response rate (ORR) at 6 months in patients with locally advanced, unresectable intrahepatic cholangiocarcinoma (iCCA) | Best response in terms of tumor shrinkage (by RECIST 1.1 criteria including complete + partial responses) obtained during protocol therapy. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessing Progression Free Survival (PFS) | time from treatment initiation to disease progression, death or last patient contact | 48 months | 
| Hepatic Progression-Free Survival (HPFS) | time from treatment initiation to hepatic disease progression, death or last patient contact | 48 months | 
| Overall Survival (OS) | Time from treatment initiation to death due to any cause or last patient contact | 48 months | 
| Disease Control Rate (DCR) | Complete Response + Partial Response + Stable Disease (by RECIST 1.1 and mRECIST criteria) obtained during protocol therapy. | 48 months | 
| R0 resection rate | Rate of patients that achieve an R0 resection at 6 months. | 6 months | 
| treatment related impact on quality of life | 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. | 48 months | 
| safety and toxicity rate | 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. | 48 months | 
| rate of downstaging to surgery | Rate of downstaging to surgery that occurs during protocol therapy at 6 months. | 6 months |