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Gemcitabine Hydrochloride and Cisplatin With or Without Radiation Therapy in Treating Patients With Localized Liver Cancer That Cannot Be Removed by Surgery

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ClinicalTrials.gov Identifier: NCT02200042
Recruitment Status : Terminated
First Posted : July 25, 2014
Last Update Posted : September 5, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
NRG Oncology

Tracking Information
First Submitted Date  ICMJE July 8, 2014
First Posted Date  ICMJE July 25, 2014
Last Update Posted Date September 5, 2018
Actual Study Start Date  ICMJE September 29, 2014
Actual Primary Completion Date July 2, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 5, 2015)
OS [ Time Frame: From the date of randomization to the date of death or last follow-up, assessed up to 8 years ]
Estimated by the Kaplan-Meier method. The distribution of OS estimates between the two arms will be compared using the log rank test. The Cox proportional hazard regression model will be used to analyze the effects of factors, in addition to treatment, which may be associated with OS.
Original Primary Outcome Measures  ICMJE
 (submitted: July 23, 2014)
Overall Survival (OS) [ Time Frame: From the date of randomization to the date of death or last follow-up, assessed up to 8 years. Analysis occurs after 102 deaths have been reported. ]
Estimated by the Kaplan-Meier method. The distribution of OS estimates between the two arms will be compared using the log rank test. The Cox proportional hazard regression model will be used to analyze the effects of factors, in addition to treatment, which may be associated with OS.
Change History Complete list of historical versions of study NCT02200042 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 29, 2016)
  • Distant metastases [ Time Frame: Up to 8 years ]
    Distant failure will be estimated by the cumulative incidence method (Kalbfleisch 1980) and the comparison of this endpoint between and experimental arm and the control arm will be done use Gray's test (Gray1988).
  • Incidence of adverse events evaluated using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 8 years ]
  • Local progression [ Time Frame: Up to 8 years ]
    Local failure will be estimated by the cumulative incidence method (Kalbfleisch 1980) and the comparison of this endpoint between and experimental arm and the control arm will be done use Gray's test (Gray1988).
  • Progression-free survival (PFS) defined as local, regional, and/or distant progression, and death due to any cause [ Time Frame: From the date of randomization to the date of death or last follow-up, assessed up to 8 years ]
    PFS will be estimated by the Kaplan-Meier method [Kaplan 1958]. The distributions of PFS estimates between the two arms will be compared using the log rank test [Mantel 1966]. The Cox proportional hazard regression model will be used to analyze the effects of factors, in addition to treatment, which may be associated with PFS.
  • Regional progression defined as progression or existing or appearance of new nodal disease [ Time Frame: Up to 8 years ]
    Regional failure will be estimated by the cumulative incidence method (Kalbfleisch 1980) and the comparison of this endpoint between and experimental arm and the control arm will be done use Gray's test (Gray1988).
Original Secondary Outcome Measures  ICMJE
 (submitted: July 23, 2014)
  • Local progression [ Time Frame: From the date of randomization to the date of first local progression failure or last follow-up, assessed up to 8 years. This endpoint will be analyzed at the time of the primary endpoint analysis. ]
    Estimated by the cumulative incidence method and the 2 arms will be compared using Gray's test.
  • Regional Progression [ Time Frame: From the date of randomization to the date of first regional progression failure or last follow-up, assessed up to 8 years. This endpoint will be analyzed at the time of the primary endpoint analysis. ]
    Estimated by the cumulative incidence method and the 2 arms will be compared using Gray's test.
  • Distant metastases [ Time Frame: From the date of randomization to the date of first distant metastases failure or last follow-up, assessed up to 8 years. This endpoint will be analyzed at the time of the primary endpoint analysis. ]
    Estimated by the cumulative incidence method and the 2 arms will be compared using Gray's test.
  • Progression-Free Survival [ Time Frame: From the date of randomization to the date of first local, regional, or distant progression failure, or death from any cause, or last follow-up, assessed up to 8 years. This endpoint will be analyzed at the time of the primary endpoint analysis. ]
    Estimated by the Kaplan-Meier method and the 2 arms will be compared using the log-rank test.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Gemcitabine Hydrochloride and Cisplatin With or Without Radiation Therapy in Treating Patients With Localized Liver Cancer That Cannot Be Removed by Surgery
Official Title  ICMJE Randomized Phase III Study of Focal Radiation Therapy for Unresectable, Localized Intrahepatic Cholangiocarcinoma
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 hydrochloride and cisplatin is more effective with or without radiation therapy in treating patients with localized liver cancer that cannot be removed by surgery.
Detailed Description

PRIMARY OBJECTIVES:

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

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

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

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

V. To evaluate the addition of liver-directed radiation therapy to chemotherapy 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 5 years.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Stage III Intrahepatic Cholangiocarcinoma
  • Stage IVA Intrahepatic Cholangiocarcinoma
Intervention  ICMJE
  • Drug: Cisplatin
    Given IV
    Other Names:
    • Abiplatin
    • Blastolem
    • Briplatin
    • CDDP
    • Cis-diammine-dichloroplatinum
    • Cis-diamminedichloridoplatinum
    • Cis-diamminedichloro Platinum (II)
    • Cis-diamminedichloroplatinum
    • Cis-dichloroammine Platinum (II)
    • Cis-platinous Diamine Dichloride
    • Cis-platinum
    • Cis-platinum II
    • Cis-platinum II Diamine Dichloride
    • Cismaplat
    • Cisplatina
    • Cisplatinum
    • Cisplatyl
    • Citoplatino
    • Citosin
    • Cysplatyna
    • DDP
    • Lederplatin
    • Metaplatin
    • Neoplatin
    • Peyrone's Chloride
    • Peyrone's Salt
    • Placis
    • Plastistil
    • Platamine
    • Platiblastin
    • Platiblastin-S
    • Platinex
    • Platinol
    • Platinol- AQ
    • Platinol-AQ
    • Platinol-AQ VHA Plus
    • Platinoxan
    • Platinum
    • Platinum Diamminodichloride
    • Platiran
    • Platistin
    • Platosin
  • Drug: Gemcitabine Hydrochloride
    Given IV
    Other Names:
    • dFdCyd
    • Difluorodeoxycytidine Hydrochloride
    • Gemzar
    • LY-188011
  • Radiation: Image Guided Radiation Therapy
    Undergo image-guided radiation therapy
    Other Names:
    • IGRT
    • image-guided radiation therapy
  • Other: Laboratory Biomarker Analysis
    Correlative studies
Study Arms  ICMJE
  • Experimental: Arm I (gemcitabine, cisplatin, radiation therapy)
    Patients receive gemcitabine hydrochloride IV over 30 minutes and cisplatin IV over 60 minutes on days 1 and 8 for 1 course. Beginning 7-21 days from the last dose of chemotherapy, patients undergo 15 fractions of image-guided radiation therapy delivered over 19-26 or 27-34 days. Beginning 7 days after completion of radiation therapy, patients continue treatment with gemcitabine hydrochloride and cisplatin. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: Cisplatin
    • Drug: Gemcitabine Hydrochloride
    • Radiation: Image Guided Radiation Therapy
    • Other: Laboratory Biomarker Analysis
  • Active Comparator: Arm II (gemcitabine hydrochloride, cisplatin)
    Patients receive gemcitabine hydrochloride IV and cisplatin IV as in Arm I. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. Patients may continue gemcitabine hydrochloride at the discretion of the treating physician.
    Interventions:
    • Drug: Cisplatin
    • Drug: Gemcitabine Hydrochloride
    • Other: Laboratory Biomarker Analysis
Publications * 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. Erratum in: J Clin Oncol. 2019 Apr 10;37(11):942.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: September 4, 2018)
1
Original Estimated Enrollment  ICMJE
 (submitted: July 23, 2014)
182
Actual Study Completion Date  ICMJE July 2, 2018
Actual Primary Completion Date July 2, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Pathologically (histologically or cytologically) proven diagnosis of intrahepatic cholangiocarcinoma (IHC) without distant extrahepatic metastasis within 90 days of registration; patients with an adenocarcinoma suggestive of a pancreaticobiliary primary with radiographic findings consistent with an intrahepatic cholangio-carcinoma are eligible
  • Patient must have 1 lesion with a maximum AXIAL diameter of 12 cm; 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 (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. fludeoxyglucose F 18 [FDG] avid)
  • Appropriate stage for protocol entry, including no distant metastases, based upon the following minimum diagnostic workup:

    • History/physical examination within 30 days prior to registration
    • Assessment by medical oncologist who specializes in treatment of IHC within 30 days of registration
    • Pre-randomization scan (REQUIRED for all patients): computed tomography (CT) scan chest/abdomen/pelvis with multiphasic liver CT scan within 30 days prior to registration; if CT contrast is contraindicated, CT chest without contrast and magnetic resonance imaging (MRI) of abdomen and pelvis is permitted
  • Zubrod performance status 0-1 within 30 days prior to registration
  • Absolute neutrophil count (ANC) >= 1,500 cells/m^3
  • Platelets >= 100,000 cells/mm^3
  • Total bilirubin < 2.5 mg/dl
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 5.0 X institutional upper limit of normal
  • Albumin >= 2.5 mg/dl
  • Creatinine within normal institutional limits or creatinine clearance >= 60mL/min/1.73 m^2 for subject with creatinine levels above institutional normal
  • Hemoglobin >= 9.0 g/dl; (note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 9.0 g/dl is acceptable)
  • Patient must provide study specific informed consent prior to study entry
  • Negative beta human chorionic gonadotropin (bHCG) within 14 days prior to study entry if patient is pre or perimenopausal

Exclusion Criteria:

  • Multiple lesions that don't meet the criteria as satellite lesions
  • 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
  • Maximum diameter exceeding 12 cm (maximum diameter does not include satellite lesion)
  • Hepatic insufficiency resulting in clinical jaundice, encephalopathy and/or variceal bleed within 60 days prior to study entry
  • Prior radiotherapy to the region of the liver that would result in overlap of radiation therapy fields
  • Prior selective internal radiotherapy/hepatic arterial yttrium therapy, at any time
  • Direct tumor extension into the stomach, duodenum, small bowel or large bowel
  • Prior invasive malignancy (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)
  • Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable
  • Currently receiving other anti-cancer agents
  • Participants who require anticoagulation should receive low-molecular weight or standard heparin and not warfarin
  • Prior surgery for the IHC; (liver resection is not allowed)
  • Prior allergic reactions attributed to compounds of similar chemical or biologic composition to gemcitabine (gemcitabine hydrochloride) or cisplatin
  • Severe, active co-morbidity, defined as follows:

    • Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
    • Transmural myocardial infarction within the last 6 months
    • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
    • Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days before registration
    • Human immunodeficiency virus (HIV) positive with cluster of differentiation (CD)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 within 30 days prior to registration; note also that HIV testing is not required for eligibility for this protocol
    • End-stage renal disease (i.e., on dialysis or dialysis has been recommended)
  • Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception
  • Grade 3 or higher peripheral neuropathy
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02200042
Other Study ID Numbers  ICMJE NRG-GI001
NCI-2014-00849 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
PNRG-GI001_A02PAMDREVW01
PNRG-GI001_A01PAMDREVW01
NRG-GI001 ( Other Identifier: NRG Oncology )
NRG-GI001 ( Other Identifier: CTEP )
U10CA180868 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party NRG Oncology
Study Sponsor  ICMJE NRG Oncology
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Theodore Hong NRG Oncology
PRS Account NRG Oncology
Verification Date September 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP