SIRT Followed by CIS-GEM Chemotherapy Versus CIS-GEM Chemotherapy Alone as 1st Line Treatment of Patients With Unresectable Intrahepatic Cholangiocarcinoma

Study Overview
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Brief Summary
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The study will evaluate the benefit of applying Selective Internal Radiation Therapy (SIRT) using SIR-Spheres Y-90 resin microspheres prior to receiving systemic chemotherapy treatment (cisplatin-gemcitabine, or CIS-GEM) in patients with unresectable intrahepatic cholangiocarcinoma. Half of the patients will be randomized to CIS-GEM chemotherapy plus SIRT, and half of the patients will be randomized to CIS-GEM alone.

Detailed Description
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This clinical study is a prospective, multicenter, randomized, controlled study evaluating SIR-Spheres Y-90 resin microspheres followed by cisplatin-gemcitabine (CIS-GEM) chemotherapy vs. CIS-GEM chemotherapy alone as first-line treatment of patients with unresectable intrahepatic cholangiocarcinoma. Randomized patients will be followed until death, withdrawal of consent, or until end of study.

Official Title
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Prospective, Multicenter, Randomized, Controlled Study Evaluating SIR-Spheres Y-90 Resin Microspheres Preceding Cisplatin-gemcitabine (CIS-GEM) Chemotherapy Versus CIS-GEM Chemotherapy Alone as First-line Treatment of Patients With Unresectable Intrahepatic Cholangiocarcinoma

Conditions
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Intrahepatic Cholangiocarcinoma

Intervention / Treatment
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* Drug: Cisplatin-gemcitabine
* Device: Radiation: SIRT + chemotherapy (cisplatin-gemcitabine)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing, able and mentally competent to provide written informed consent. Aged 18 years or older. Histologically or cytologically confirmed unresectable and non-ablatable intrahepatic cholangiocarcinoma. Liver-only or liver predominant intrahepatic cholangiocarcinoma. Patient are permitted to have loco-regional lymph node involvement defined as: portal LN </= to 2 cm and/or para aortic LN </= to 1.5 cm in longest diameter, and/or up to 2 indeterminate lung lesions < 1 cm if these lung lesions are positron emission tomography (PET) negative. Chemotherapy naïve. Adjuvant chemotherapy is not permitted. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Adequate hematological function defined as: Hemoglobin >/= 10g/dL White Blood Cell count (WBC) >/= 3.0 x 10^9/L Absolute neutrophil count (ANC) >/= 1.5 x 10^9/L Platelet count >/= 100,000/mm^3 - Adequate liver function defined as: Total bilirubin </= 30 umol/L (1.75 mg/dL) Albumin >/= 30 g/L - Adequate renal function defined as: Serum urea and serum creatinine < 1.5 times upper limit of normal (ULN) Creatinine clearance >/= 45 ml/min (calculated with Cockcroft-Gault Equation) Life expectancy of at least 3 months without any active treatment Female patients must either be postmenopausal, sterile (surgically or radiation- or chemically-induced), or if sexually active use an acceptable method of contraception during the study. Male patients must be surgically sterile or if sexually active must use an acceptable method of contraception during the study. Considered suitable to receive either regimen in the clinical judgement of the treating investigator. Exclusion Criteria: Patients with only non-measurable lesions in the liver according to RECIST criteria Incomplete recovery from previous liver surgery, e.g. unresolved biliary tree obstruction or biliary sepsis or inadequate liver function Biliary stent in situ Main trunk Portal Vein Thrombosis (PVT) Ascites, even if controlled with diuretics. (A minor peri-hepatic rim of ascites detected at imaging is acceptable). Mixed hepatocellular carcinoma - intrahepatic cholangiocarcinoma (HCC-ICC) disease History of prior malignancy. Exceptions include in-situ carcinoma of the cervix treated by cone-biopsy/resection, non-metastatic basal and/or squamous cell carcinomas of the skin, recurrent intra-hepatic cholangiocarcinoma post local treatment or any early stage (stage 1) malignancy adequately resected with curative intent at least 5 years prior to study entry Suspicion of any bone metastasis/metastases or central nervous system metastasis/metastases on clinical or imaging examination. Prior internal or external radiation delivered to the liver. Pregnancy; breast feeding. Participation within 28 days prior to randomization, in an active part of another clinical study that would compromise any of the endpoints of the study. Evidence of ongoing active infection that may affect treatment feasibility or outcome. Prior Whipple's procedure.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Chemotherapy (Cisplatin-Gemcitabine)<br>Cisplatin 25mg/m2 in 1000ml 0.9% saline given over 1 hour followed by 500 ml 0.9% saline over 30 minutes, followed by Gemcitabine 1000 mg/m2 in 250-500 ml 0.9% saline over 30 minutes by intravenous infusions on days 1, and 8 of a 21-day cycle. | Drug: Cisplatin-gemcitabine<br>* Systemic chemotherapy<br>* Other names: CIS-GEM;|
| Experimental: Radiation: SIRT + chemotherapy (Cisplatin-Gemcitabine)<br>A single treatment of hepatic arterial injection of SIR-Spheres Y-90 resin microspheres (SIRT) followed 14-16 days later by systemic chemotherapy (ABC-02 CIS-GEM protocol) with an intention to treat with 8 cycles of cisplatin + gemcitabine, or until progression, toxicity or patient choice. Treatment may be continued beyond 8 cycles in the absence of significant disease progression, at the treating clinicians' discretion. | Drug: Cisplatin-gemcitabine<br>* Systemic chemotherapy<br>* Other names: CIS-GEM;Device: Radiation: SIRT + chemotherapy (cisplatin-gemcitabine)<br>* SIR-Spheres microspheres followed by systemic chemotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival at 18 months | Survival at 18 months is defined as the proportion of patients still alive 18 months from the date of randomization. | 18 months following the date of randomization. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Liver-specific progression free survival (PFS) |  | From date of randomization to the first documented date of progression in the liver or date of death from any cause, assessed up to 36 months.. | 
| Progression free survival (PFS) at any site |  | From date of randomization to the date of progression at any site until the first date of documented tumor progression at any site or date of death from any cause, assessed up to 36 months. | 
| Objective response rate by RECIST 1.1 and refined RECIST - liver |  | From the date of first treatment until the date of date of first documented progression in the liver, assessed up to 36 months. | 
| Objective response rate by RECIST 1.1 and refined RECIST - at any site |  | From the date of first treatment until progression at any site, assessed up to 36 months. | 
| Overall Survival |  | From date of randomization until the date of death from any cause, assessed up to 36 months. | 
| Liver surgical resection and ablation rate | To assess the number of patients in each arm who are downstaged by protocol therapy and can proceed to liver resection or ablation. The specific assessments will be the classification of resection as R0, R1 or R2, the presence of viable tumor or fibrosis, and the nearest resection margin. | 18 months following the date of randomization. | 
| Incidence of Adverse Events (Safety and tolerability) | Adverse events as assessed by CTCAE v. 4.0. | Informed consent until 28 days post last dose of protocol chemotherapy. |