Radiation Therapy vs. Observation Following Gemcitabine and Cisplatin for Inoperable Localized Liver Cancer

• Sponsor: NRG Oncology (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02200042
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 1
• Locations: 34
• Arms: 2
• Actual Duration (Months): 45.1
• Patients Per Site: 0
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Stage III Intrahepatic Cholangiocarcinoma; Stage IVA Intrahepatic Cholangiocarcinoma	Radiation: Image Guided Radiation Therapy	Phase 3

Detailed Description

PRIMARY OBJECTIVES:

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

SECONDARY OBJECTIVES:

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

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

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

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

5. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Randomization ratio (Experimental:Observation) = 2:1Randomization ratio (Experimental:Observation) = 2:1
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Randomized Phase III Study of Focal Radiation Therapy for Unresectable, Localized Intrahepatic Cholangiocarcinoma
• Actual Study Start Date: Sep 29, 2014
• Actual Primary Completion Date: Jul 2, 2018
• Actual Study Completion Date: Jul 2, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Radiation therapy Liver-directed radiation therapy	Radiation: Image Guided Radiation Therapy; Patients undergo 15 fractions of image-guided radiation therapy delivered over 19-26 or 27-34 days.; Other Names: IGRT image-guided radiation therapy
No Intervention: Observation No radiation therapy

Outcome Measures

Primary Outcome Measures

1. Overall Survival [From randomization to last follow-up. Analysis occurs after all patients have been on study for at least two years.]

   Overall survival time is defined as time from randomization to the date of death from any cause. Overall survival rates are estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact.

Secondary Outcome Measures

1. Distant Metastases [From randomization to last follow-up. Analysis occurs after all patients have been on study for at least two years.]

2. Incidence of Adverse Events Evaluated Using National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 [From randomization to last follow-up. Analysis occurs after all patients have been on study for at least two years.]

3. Local Progression [From randomization to last follow-up. Analysis occurs after all patients have been on study for at least two years.]

4. Progression-free Survival (PFS) [From randomization to last follow-up. Analysis occurs after all patients have been on study for at least two years.]

5. Regional Progression Defined as Progression or Existing or Appearance of New Nodal Disease [From randomization to last follow-up. Analysis occurs after all patients have been on study for at least two years.]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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;

1. Zubrod Performance Status 0-1 at the time of study entry;

2. Age ≥ 18;

3. 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.)

1. Patient must provide study specific informed consent prior to study entry;

2. Negative Beta-Human Chorionic Gonadotropin (bHCG) prior to study entry if patient is pre or peri-menopausal.

3. 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).

1. 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;

2. Grade 3 or higher peripheral neuropathy at the time of study entry.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama	United States	35233
2	University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72205
3	Sutter Medical Center Sacramento	Sacramento	California	United States	95816
4	Emory University Hospital Midtown	Atlanta	Georgia	United States	30308
5	Piedmont Hospital	Atlanta	Georgia	United States	30309
6	Emory University Hospital/Winship Cancer Institute	Atlanta	Georgia	United States	30322
7	Queen's Medical Center	Honolulu	Hawaii	United States	96813
8	Northwestern University	Chicago	Illinois	United States	60611
9	Decatur Memorial Hospital	Decatur	Illinois	United States	62526
10	Loyola University Medical Center	Maywood	Illinois	United States	60153
11	OSF Saint Francis Medical Center	Peoria	Illinois	United States	61637
12	Northwestern Medicine Cancer Center Warrenville	Warrenville	Illinois	United States	60555
13	Indiana University/Melvin and Bren Simon Cancer Center	Indianapolis	Indiana	United States	46202
14	Maryland Proton Treatment Center	Baltimore	Maryland	United States	21201
15	Massachusetts General Hospital Cancer Center	Boston	Massachusetts	United States	02114
16	Boston Medical Center	Boston	Massachusetts	United States	02118
17	Lahey Hospital and Medical Center	Burlington	Massachusetts	United States	01805
18	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
19	Missouri Baptist Medical Center	Saint Louis	Missouri	United States	63131
20	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
21	University of New Mexico Cancer Center	Albuquerque	New Mexico	United States	87102
22	Mount Sinai Hospital	New York	New York	United States	10029
23	University of Rochester	Rochester	New York	United States	14642
24	University of Cincinnati/Barrett Cancer Center	Cincinnati	Ohio	United States	45219
25	Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210
26	Legacy Good Samaritan Hospital and Medical Center	Portland	Oregon	United States	97210
27	M D Anderson Cancer Center	Houston	Texas	United States	77030
28	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah	United States	84112
29	University of Vermont Medical Center	Burlington	Vermont	United States	05401
30	ProCure Proton Therapy Center-Seattle	Seattle	Washington	United States	98133
31	University of Washington Medical Center	Seattle	Washington	United States	98195
32	West Virginia University Healthcare	Morgantown	West Virginia	United States	26506
33	University of Wisconsin Hospital and Clinics	Madison	Wisconsin	United States	53792
34	The Research Institute of the McGill University Health Centre (MUHC)	Montreal	Quebec	Canada	H3H 2R9

Sponsors and Collaborators

• NRG Oncology
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Theodore Hong, NRG Oncology

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 20, 2017

More Information

Publications

None provided.

• Responsible Party: NRG Oncology
• ClinicalTrials.gov Identifier: NCT02200042
• Other Study ID Numbers: NRG-GI001; NCI-2014-00849; PNRG-GI001_A02PAMDREVW01; PNRG-GI001_A01PAMDREVW01; NRG-GI001; NRG-GI001; U10CA180868
• First Posted: Jul 25, 2014
• Last Update Posted: Aug 28, 2019
• Last Verified: Jul 1, 2019

• Additional relevant MeSH terms: Cholangiocarcinoma

Study Results

Participant Flow

Arm/Group Title	Radiation Therapy	Observation
Arm/Group Description	Liver-directed radiation therapy Radiation Therapy: Patients undergo 15 fractions of image-guided radiation therapy delivered over 19-26 or 27-34 days.	No radiation therapy
Period Title: Overall Study
STARTED	0	1
COMPLETED	0	0
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Radiation Therapy	Observation	Total
Arm/Group Description	Liver-directed radiation therapy Radiation Therapy: Patients undergo 15 fractions of image-guided radiation therapy delivered over 19-26 or 27-34 days.	No radiation therapy	Total of all reporting groups
Overall Participants	0	1	1
Age (Count of Participants)
<=18 years	0 NaN	0 0%	0 0%
Between 18 and 65 years	0 NaN	0 0%	0 0%
>=65 years	0 NaN	1 100%	1 100%
Sex: Female, Male (Count of Participants)
Female	0 NaN	0 0%	0 0%
Male	0 NaN	1 100%	1 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 NaN	0 0%	0 0%
Not Hispanic or Latino	0 NaN	1 100%	1 100%
Unknown or Not Reported	0 NaN	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 NaN	0 0%	0 0%
Asian	0 NaN	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 NaN	0 0%	0 0%
Black or African American	0 NaN	0 0%	0 0%
White	0 NaN	1 100%	1 100%
More than one race	0 NaN	0 0%	0 0%
Unknown or Not Reported	0 NaN	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Overall Survival
Description	Overall survival time is defined as time from randomization to the date of death from any cause. Overall survival rates are estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact.
Time Frame	From randomization to last follow-up. Analysis occurs after all patients have been on study for at least two years.

Outcome Measure Data

Analysis Population Description

No patients have outcome data.

Arm/Group Title	Radiation Therapy	Observation
Arm/Group Description	Liver-directed radiation therapy Radiation Therapy: Patients undergo 15 fractions of image-guided radiation therapy delivered over 19-26 or 27-34 days.	No radiation therapy
Measure Participants	0	0

2. Secondary Outcome

Title	Distant Metastases
Time Frame	From randomization to last follow-up. Analysis occurs after all patients have been on study for at least two years.

Outcome Measure Data

Analysis Population Description

No patients have outcome data.

Arm/Group Title	Radiation Therapy	Observation
Arm/Group Description	Liver-directed radiation therapy Radiation Therapy: Patients undergo 15 fractions of image-guided radiation therapy delivered over 19-26 or 27-34 days.	No radiation therapy
Measure Participants	0	0

3. Secondary Outcome

Title	Incidence of Adverse Events Evaluated Using National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0
Time Frame	From randomization to last follow-up. Analysis occurs after all patients have been on study for at least two years.

Outcome Measure Data

Analysis Population Description

No patients have outcome data.

Arm/Group Title	Radiation Therapy	Observation
Arm/Group Description	Liver-directed radiation therapy Radiation Therapy: Patients undergo 15 fractions of image-guided radiation therapy delivered over 19-26 or 27-34 days.	No radiation therapy
Measure Participants	0	0

4. Secondary Outcome

Title	Local Progression
Time Frame	From randomization to last follow-up. Analysis occurs after all patients have been on study for at least two years.

Outcome Measure Data

Analysis Population Description

No patients have outcome data.

Arm/Group Title	Radiation Therapy	Observation
Arm/Group Description	Liver-directed radiation therapy Radiation Therapy: Patients undergo 15 fractions of image-guided radiation therapy delivered over 19-26 or 27-34 days.	No radiation therapy
Measure Participants	0	0

5. Secondary Outcome

Title	Progression-free Survival (PFS)
Time Frame	From randomization to last follow-up. Analysis occurs after all patients have been on study for at least two years.

Outcome Measure Data

Analysis Population Description

No patients have outcome data.

Arm/Group Title	Radiation Therapy	Observation
Arm/Group Description	Liver-directed radiation therapy Radiation Therapy: Patients undergo 15 fractions of image-guided radiation therapy delivered over 19-26 or 27-34 days.	No radiation therapy
Measure Participants	0	0

6. Secondary Outcome

Title	Regional Progression Defined as Progression or Existing or Appearance of New Nodal Disease
Time Frame	From randomization to last follow-up. Analysis occurs after all patients have been on study for at least two years.

Outcome Measure Data

Analysis Population Description

No patients have outcome data.

Arm/Group Title	Radiation Therapy	Observation
Arm/Group Description	Liver-directed radiation therapy Radiation Therapy: Patients undergo 15 fractions of image-guided radiation therapy delivered over 19-26 or 27-34 days.	No radiation therapy
Measure Participants	0	0

Adverse Events

Time Frame	No adverse event data was collected on this study due to early termination.
Adverse Event Reporting Description	No adverse event data was collected on this study due to early termination.
Arm/Group Title	Radiation Therapy		Observation
Arm/Group Description	Liver-directed radiation therapy Radiation Therapy: Patients undergo 15 fractions of image-guided radiation therapy delivered over 19-26 or 27-34 days.		No radiation therapy
All Cause Mortality
	Radiation Therapy		Observation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)
Serious Adverse Events
	Radiation Therapy		Observation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Radiation Therapy		Observation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)

Limitations/Caveats

This study stopped accrual early due to unmet targeted accrual goals with 1 subject accrued out of 146 planned. The registered subject withdrew consent the same day as randomization and therefore has no outcome data.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

PI's are required to abide by the sponsor's publication guidelines which require review by coauthors and subsequent review and approval by the sponsor.