Clinical trial NCT02200042: Radiation Therapy vs. Observation Following Gemcitabine and Cisplatin for Inoperable Localized Liver Cancer
Official title: Randomized Phase III Study of Focal Radiation Therapy for Unresectable, Localized Intrahepatic Cholangiocarcinoma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Stage III Intrahepatic Cholangiocarcinoma
Stage IVA Intrahepatic Cholangiocarcinoma
Lead sponsor: NRG Oncology
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2014-07-25
Enrollment: 1
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomization ratio (Experimental:Observation) = 2:1
Primary purpose: TREATMENT

Brief summary: This randomized phase III trial studies how well gemcitabine hydrochloride and cisplatin with or without radiation therapy work in treating patients with localized liver cancer that cannot be removed by surgery. Drugs used in chemotherapy, such as gemcitabine hydrochloride and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x rays to kill tumor cells. It is not yet known whether giving gemcitabine and cisplatin is more effective with or without radiation therapy in this patient population. Patients register to this study after receiving gemcitabine and cisplatin.

Detailed description: PRIMARY OBJECTIVES:

I. To evaluate the addition of liver-directed radiation therapy with respect to overall survival (OS) for patients with unresectable, localized intrahepatic cholangiocarcinoma.

SECONDARY OBJECTIVES:

I. To evaluate the addition of liver-directed radiation therapy with respect to local control for patients with unresectable, localized intrahepatic cholangiocarcinoma.

II. To evaluate the addition of liver-directed radiation therapy with respect to adverse events for patients with unresectable, localized intrahepatic cholangiocarcinoma.

III. To evaluate the addition of liver-directed radiation therapy with respect to regional control for patients with unresectable, localized intrahepatic cholangiocarcinoma.

IV. To evaluate the addition of liver-directed radiation therapy with respect to distant metastases for patients with unresectable, localized intrahepatic cholangiocarcinoma.

V. To evaluate the addition of liver-directed radiation therapy with respect to progression-free survival for patients with unresectable, localized intrahepatic cholangiocarcinoma.

After completion of study treatment, patients are followed up every 3 months for 3 years then every 6 months for 2 years.

Eligibility criteria: Inclusion Criteria:

1. Pathologically (histologically or cytologically) proven diagnosis of intrahepatic cholangiocarcinoma (IHC) without distant extrahepatic metastasis prior to study entry. Patients with an adenocarcinoma suggestive of a pancreaticobiliary primary with radiographic findings consistent with an intrahepatic cholangio-carcinoma are eligible.
2. Patient must have 1 lesion with a maximum AXIAL diameter of 12cm at the time of study entry. Up to 3 satellite lesions are permitted. Satellite lesions, are defined as lesions less than 2 cm that are within 1 cm of the periphery of the dominant lesion (gross tumor volume \[GTV\]) are permitted. The satellite lesions are NOT included in the AXIAL diameter measurement. Regional Lymph Node involvement within the porta hepatis (as medial as superior mesenteric vein \[SMV\] portal vein confluence) is permitted if nodes are deemed clinically positive (i.e. FDG \[Fluorine 18 fluorodeoxyglucose\] avid);
3. Appropriate stage for protocol entry, including no distant metastases, based upon the following minimum diagnostic workup:

   • Pre-study entry Scan (REQUIRED for All Patients to confirm no progression): computed tomography (CT) scan chest/abdomen/pelvis with multiphasic liver CT scan within 30 days prior to study entry. If CT contrast is contraindicated, CT chest without contrast and MRI of abdomen and pelvis is permitted;
4. Zubrod Performance Status 0-1 at the time of study entry;
5. Age ≥ 18;
6. Complete blood count (CBC) / differential obtained within 21 days prior to study entry, with adequate bone marrow function defined as follows:

   * Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3;
   * Platelets ≥ 75,000 cells/mm3;
   * Total bilirubin \< 2.5 mg/dl;
   * Aspartate Aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (Serum glutamic pyruvic transaminase \[SGPT\]) \< 5.0 X institutional upper limit of normal;
   * Albumin ≥ 2.5mg/dl;
   * Creatinine within normal institutional limits or creatinine clearance ≥ 60 mL/min/1.73 m2 for subject with creatinine levels above institutional normal;
   * Hemoglobin(Hgb) ≥ 9.0 g/dl. (Note: The use of transfusion or other intervention to achieve Hgb ≥ 9.0 g/dl is acceptable.)
7. Patient must provide study specific informed consent prior to study entry;
8. Negative Beta-Human Chorionic Gonadotropin (bHCG) prior to study entry if patient is pre or peri-menopausal.
9. Must have received 6 months of Gemcitabine/Cisplatin chemotherapy without progression. Disease response to chemotherapy is also permitted. If toxicity precludes 6 months of chemotherapy at least 4 months of Gemcitabine/Cisplatin must have been administered.

Exclusion Criteria:

1. Multiple lesions that don't meet the criteria as satellite lesions as defined in protocol;
2. Extrahepatic metastases or malignant nodes beyond the periportal region. Celiac, pancreaticoduodenal and para-aortic nodes\> 2 cm are ineligible. Note that benign non-enhancing periportal lymphadenopathy is not unusual in the presence of hepatitis and is permitted, even if the sum of enlarged nodes is \> 2.0 cm;
3. Hepatic insufficiency resulting in clinical jaundice, encephalopathy and/or variceal bleed at the time of study entry;
4. Prior radiotherapy to the region of the liver that would result in overlap of radiation therapy fields;
5. Prior selective internal radiotherapy/hepatic arterial Yttrium therapy, at any time;
6. Direct tumor extension into the stomach, duodenum, small bowel or large bowel;
7. Prior invasive malignancy, excluding the current diagnosis, (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years. (Note: carcinoma in situ of the breast, oral cavity, or cervix is all permissible);
8. Prior systemic chemotherapy for the study cancer other than gemcitabine/cisplatin; note that prior chemotherapy for a different cancer is allowable;
9. Currently receiving other anti-cancer agents;
10. Participants who require anticoagulation should receive low-molecular weight or standard heparin and not warfarin;
11. Prior surgery for the IHC. (Liver resection is not allowed);
12. Severe, active co-morbidity, defined as follows:

    * Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months of study entry;
    * Transmural myocardial infarction within the last 6 months of study entry;
    * Acute bacterial or fungal infection requiring intravenous antibiotics at the time of study entry;
    * Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days prior to study entry;
    * HIV positive with CD4 (cluster of differentiation 4) count \< 200 cells/microliter. Note that patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count ≥ 200 cells/microliter at the time of study entry. Note also that HIV testing is not required for eligibility for this protocol;
    * End-stage renal disease (ie, on dialysis or dialysis has been recommended).
13. Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic;
14. Grade 3 or higher peripheral neuropathy at the time of study entry.

Primary outcomes:
measure: Overall Survival
timeFrame: From randomization to last follow-up. Analysis occurs after all patients have been on study for at least two years.
Secondary outcomes:
measure: Distant Metastases
timeFrame: From randomization to last follow-up. Analysis occurs after all patients have been on study for at least two years.
measure: Incidence of Adverse Events Evaluated Using National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0
timeFrame: From randomization to last follow-up. Analysis occurs after all patients have been on study for at least two years.
measure: Local Progression
timeFrame: From randomization to last follow-up. Analysis occurs after all patients have been on study for at least two years.
measure: Progression-free Survival (PFS)
timeFrame: From randomization to last follow-up. Analysis occurs after all patients have been on study for at least two years.
measure: Regional Progression Defined as Progression or Existing or Appearance of New Nodal Disease
timeFrame: From randomization to last follow-up. Analysis occurs after all patients have been on study for at least two years.
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham Cancer Center
state: Alabama
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences
state: Arkansas
city: Sacramento
country: United States
facility: Sutter Medical Center Sacramento
state: California
city: Atlanta
country: United States
facility: Emory University Hospital Midtown
state: Georgia
city: Atlanta
country: United States
facility: Piedmont Hospital
state: Georgia
city: Atlanta
country: United States
facility: Emory University Hospital/Winship Cancer Institute
state: Georgia
city: Honolulu
country: United States
facility: Queen's Medical Center
state: Hawaii
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Decatur
country: United States
facility: Decatur Memorial Hospital
state: Illinois
city: Maywood
country: United States
facility: Loyola University Medical Center
state: Illinois
city: Peoria
country: United States
facility: OSF Saint Francis Medical Center
state: Illinois
city: Warrenville
country: United States
facility: Northwestern Medicine Cancer Center Warrenville
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University/Melvin and Bren Simon Cancer Center
state: Indiana
city: Baltimore
country: United States
facility: Maryland Proton Treatment Center
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital Cancer Center
state: Massachusetts
city: Boston
country: United States
facility: Boston Medical Center
state: Massachusetts
city: Burlington
country: United States
facility: Lahey Hospital and Medical Center
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Saint Louis
country: United States
facility: Missouri Baptist Medical Center
state: Missouri
city: Lebanon
country: United States
facility: Dartmouth Hitchcock Medical Center
state: New Hampshire
city: Albuquerque
country: United States
facility: University of New Mexico Cancer Center
state: New Mexico
city: New York
country: United States
facility: Mount Sinai Hospital
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Cincinnati
country: United States
facility: University of Cincinnati/Barrett Cancer Center
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center
state: Ohio
city: Portland
country: United States
facility: Legacy Good Samaritan Hospital and Medical Center
state: Oregon
city: Houston
country: United States
facility: M D Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute/University of Utah
state: Utah
city: Burlington
country: United States
facility: University of Vermont Medical Center
state: Vermont
city: Seattle
country: United States
facility: ProCure Proton Therapy Center-Seattle
state: Washington
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
city: Morgantown
country: United States
facility: West Virginia University Healthcare
state: West Virginia
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics
state: Wisconsin
city: Montreal
country: Canada
facility: The Research Institute of the McGill University Health Centre (MUHC)
state: Quebec
Study officials:
affiliation: NRG Oncology
name: Theodore Hong
role: PRINCIPAL_INVESTIGATOR
References:
citation: Tao R, Krishnan S, Bhosale PR, Javle MM, Aloia TA, Shroff RT, Kaseb AO, Bishop AJ, Swanick CW, Koay EJ, Thames HD, Hong TS, Das P, Crane CH. Ablative Radiotherapy Doses Lead to a Substantial Prolongation of Survival in Patients With Inoperable Intrahepatic Cholangiocarcinoma: A Retrospective Dose Response Analysis. J Clin Oncol. 2016 Jan 20;34(3):219-26. doi: 10.1200/JCO.2015.61.3778. Epub 2015 Oct 26.