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

Intrahepatic Cholangiocarcinoma Clinical Trial

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05422690
• Other study ID #: U22-02-4670
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: May 15, 2024
• Est. completion date: September 30, 2028

Study information

• Verified date: April 2024
• Source: Inova Health Care Services
• Contact: Keary Janet, BS
• Phone: 571-472-0024
• Email: keary.janet[@]inova.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 16
• Est. completion date: September 30, 2028
• Est. primary completion date: September 30, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Cholangiocarcinoma
• Intrahepatic Cholangiocarcinoma

Intervention

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.

Locations

Country	Name	City	State
United States	Keary Janet	Fairfax	Virginia

Sponsors (1)

Lead Sponsor	Collaborator
Inova Health Care Services

Country where clinical trial is conducted

United States, 

References & Publications (25)

Akateh C, Ejaz AM, Pawlik TM, Cloyd JM. Neoadjuvant treatment strategies for intrahepatic cholangiocarcinoma. World J Hepatol. 2020 Oct 27;12(10):693-708. doi: 10.4254/wjh.v12.i10.693. — View Citation

Camacho JC, Kokabi N, Xing M, Prajapati HJ, El-Rayes B, Kim HS. Modified response evaluation criteria in solid tumors and European Association for The Study of the Liver criteria using delayed-phase imaging at an early time point predict survival in patie — View Citation

Cheng B, Villalobos A, Sethi I, Wagstaff W, Galt J, Brandon D, Schuster DM, Bercu Z, Majdalany B, Kokabi N. Determination of Tumor Dose Response Thresholds in Patients with Chemorefractory Intrahepatic Cholangiocarcinoma Treated with Resin and Glass-based — View Citation

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. — View Citation

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Han K, Ko HK, Kim KW, Won HJ, Shin YM, Kim PN. Radiofrequency ablation in the treatment of unresectable intrahepatic cholangiocarcinoma: systematic review and meta-analysis. J Vasc Interv Radiol. 2015 Jul;26(7):943-8. doi: 10.1016/j.jvir.2015.02.024. Epub — View Citation

Hyder O, Marsh JW, Salem R, Petre EN, Kalva S, Liapi E, Cosgrove D, Neal D, Kamel I, Zhu AX, Sofocleous CT, Geschwind JF, Pawlik TM. Intra-arterial therapy for advanced intrahepatic cholangiocarcinoma: a multi-institutional analysis. Ann Surg Oncol. 2013 — View Citation

Kuhlmann JB, Euringer W, Spangenberg HC, Breidert M, Blum HE, Harder J, Fischer R. Treatment of unresectable cholangiocarcinoma: conventional transarterial chemoembolization compared with drug eluting bead-transarterial chemoembolization and systemic chem — View Citation

Labib PL, Davidson BR, Sharma RA, Pereira SP. Locoregional therapies in cholangiocarcinoma. Hepat Oncol. 2017 Oct;4(4):99-109. doi: 10.2217/hep-2017-0014. Epub 2017 Nov 17. — View Citation

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. — View Citation

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Pillai K, Akhter J, Chua TC, Shehata M, Alzahrani N, Al-Alem I, Morris DL. Heat sink effect on tumor ablation characteristics as observed in monopolar radiofrequency, bipolar radiofrequency, and microwave, using ex vivo calf liver model. Medicine (Baltimo — View Citation

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White J, Carolan-Rees G, Dale M, Patrick HE, See TC, Bell JK, Manas DM, Crellin A, Slevin NJ, Sharma RA. Yttrium-90 Transarterial Radioembolization for Chemotherapy-Refractory Intrahepatic Cholangiocarcinoma: A Prospective, Observational Study. J Vasc Int — View Citation

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Zhen Y, Liu B, Chang Z, Ren H, Liu Z, Zheng J. A pooled analysis of transarterial radioembolization with yttrium-90 microspheres for the treatment of unresectable intrahepatic cholangiocarcinoma. Onco Targets Ther. 2019 Jun 7;12:4489-4498. doi: 10.2147/OT — View Citation

* Note: There are 25 references in all — Click here to view all references

Outcome

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