Nivolumab With or Without Ipilimumab in Treating Patients With Resectable Liver Cancer

• ClinicalTrials.gov Identifier: NCT03222076
• Recruitment Status: Completed
• First Posted: July 19, 2017
• Results First Posted: July 10, 2023
• Last Update Posted: July 10, 2023
• Sponsor: M.D. Anderson Cancer Center
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): M.D. Anderson Cancer Center

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Conditions: Hepatocellular Carcinoma; Resectable Hepatocellular Carcinoma
• Interventions: Biological: Ipilimumab; Biological: Nivolumab
• Enrollment: 30

Participant Flow

Recruitment Details
Pre-assignment Details	3 excluded: 1 did not meet inclusion criteria; 2 declined to participate The study was amended in June 2019 to remove/exclude the enrollment of Arm C .

Arm/Group Title	Arm A: Nivolumab	Arm B: Nivolumab Plus Ipilimumab	Arm C: Nivolumab Plus Ipilimumab
Arm/Group Description	Nivolumab at 240 mg IV every 2 weeks for 3 doses followed by liver imaging and hepatic resection on day 1 of week 7, followed (after 4 weeks from surgery) by nivolumab 480 mg IV every 4 weeks in the adjuvant setting until disease progression or for 2 years, whichever is sooner Nivolumab: Given IV	Nivolumab 240 mg IV every 2 weeks for 3 doses plus ipilimumab 1 mg/kg IV on day 1 of therapy (3 doses of nivolumab, 1 dose of ipilimumab) followed by hepatic resection followed (after 4 weeks from surgery) by nivolumab 480 mg IV every 4 weeks plus ipilimumab 1 mg/kg IV every 6 weeks to 4 doses in the adjuvant settingIpilimumab: Given IV Nivolumab: Given IV Ipilimumab: Given IV	Nivolumab 240 mg IV every 2 weeks for 3 doses plus ipilimumab 1 mg/kg IV on day 1 of therapy (3 doses of nivolumab, 1 dose of ipilimumab; 6 weeks) in Unresectable patients followed by post-treatment biopsy
Period Title: Overall Study
Started	13	14	0
Completed	13	14	0
Not Completed	0	0	0

Baseline Characteristics

Arm/Group Title		Arm A: Nivolumab	Arm B: Nivolumab Plus Ipilimumab	Arm C: Nivolumab Plus Ipilimumab	Total
Arm/Group Description		Nivolumab at 240 mg IV every 2 weeks for 3 doses followed by liver imaging and hepatic resection on day 1 of week 7, followed (after 4 weeks from surgery) by nivolumab 480 mg IV every 4 weeks in the adjuvant setting until disease progression or for 2 years, whichever is sooner	Nivolumab 240 mg IV every 2 weeks for 3 doses plus ipilimumab 1 mg/kg IV on day 1 of therapy (3 doses of nivolumab, 1 dose of ipilimumab) followed by hepatic resection followed (after 4 weeks from surgery) by nivolumab 480 mg IV every 4 weeks plus ipilimumab 1 mg/kg IV every 6 weeks to 4 doses in the adjuvant setting	Nivolumab 240 mg IV every 2 weeks for 3 doses plus ipilimumab 1 mg/kg IV on day 1 of therapy (3 doses of nivolumab, 1 dose of ipilimumab; 6 weeks) in Unresectable patients followed by post-treatment biopsy	Total of all reporting groups
Overall Number of Baseline Participants		13	14	0	27
Baseline Analysis Population Description		2 of the patients (1 in the Nivolumab arm and 1 in the Nivolumab + Ipilimumab arm) was not included in the analysis of PFS because their surgical cancellations were unrelated to progressive disease.
Age, Continuous; Median (Full Range); Unit of measure: Years
	Number Analyzed	13 participants	14 participants	0 participants	27 participants
		64; (56 to 68)	62; (53 to 72)		64; (53 to 72)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	13 participants	14 participants	0 participants	27 participants
	Female	2 15.4%	6 42.9%		8 29.6%
	Male	11 84.6%	8 57.1%		19 70.4%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	13 participants	14 participants	0 participants	27 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%		0 0.0%
	Asian	4 30.8%	3 21.4%		7 25.9%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%		0 0.0%
	Black or African American	3 23.1%	4 28.6%		7 25.9%
	White	6 46.2%	7 50.0%		13 48.1%
	More than one race	0 0.0%	0 0.0%		0 0.0%
	Unknown or Not Reported	0 0.0%	0 0.0%		0 0.0%
Region of Enrollment; Measure Type: Count of Participants; Unit of measure: Participants
United States	Number Analyzed	13 participants	14 participants	0 participants	27 participants
		13 100.0%	14 100.0%		27 100.0%

Outcome Measures

1. Primary Outcome

Title	Safety and Tolerability of Presurgical Nivolumab With or Without Ipilimumab, Defined as the Number of Participants With of Adverse Events.
Description	The frequency of adverse events, serious adverse events (grade ≥3), and laboratory abnormalities. Graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Safety will be recorded through the incidence of adverse events, serious adverse events and specific laboratory abnormalities (worst grade) in each treatment arm.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

Cohort C that was discontinued due to non-accrual.

Arm/Group Title	Arm A: Nivolumab	Arm B: Nivolumab Plus Ipilimumab	Arm C: Nivolumab Plus Ipilimumab
Arm/Group Description:	Nivolumab at 240 mg IV every 2 weeks for 3 doses followed by liver imaging and hepatic resection on day 1 of week 7, followed (after 4 weeks from surgery) by nivolumab 480 mg IV every 4 weeks in the adjuvant setting until disease progression or for 2 years, whichever is sooner	Nivolumab 240 mg IV every 2 weeks for 3 doses plus ipilimumab 1 mg/kg IV on day 1 of therapy (3 doses of nivolumab, 1 dose of ipilimumab) followed by hepatic resection followed (after 4 weeks from surgery) by nivolumab 480 mg IV every 4 weeks plus ipilimumab 1 mg/kg IV every 6 weeks to 4 doses in the adjuvant setting	Nivolumab 240 mg IV every 2 weeks for 3 doses plus ipilimumab 1 mg/kg IV on day 1 of therapy (3 doses of nivolumab, 1 dose of ipilimumab; 6 weeks) in Unresectable patients followed by post-treatment biopsy
Overall Number of Participants Analyzed	13	14	0
Measure Type: Count of Participants; Unit of Measure: Participants
	13 100.0%	14 100.0%	0

2. Secondary Outcome

Title	Objective Response Rate
Description	Overall response rate, defined as the proportion of patients with a complete response or partial response after 6 weeks of therapy by RECIST 1.1 criteria divided by the number of randomly assigned patients.
Time Frame	After 6 weeks of therapy, up to 5 years

Outcome Measure Data

Analysis Population Description

Cohort C that was discontinued due to non-accrual.

Arm/Group Title	Arm A (Nivolumab)	Arm B (Ipilimumab, Nivolumab)	Arm C (Ipilimumab, Nivolumab)
Arm/Group Description:	Patients receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 2 weeks for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo liver surgery on day 1 of week 7. Beginning 4 weeks after surgery, patients continue nivolumab IV over 30 minutes every 4 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. Nivolumab: Given IV	Patients receive ipilimumab IV over 90 minutes on day 1 and nivolumab as Arm A. Treatment repeats every 2 weeks for up to 3 cycles for nivolumab in the absence of disease progression or unacceptable toxicity. Patients undergo liver surgery on day 1 of week 7. Beginning 4 weeks after surgery, patients receive ipilimumab IV over 90 minutes every 6 weeks and nivolumab IV over 30 minutes every 4 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. Ipilimumab: Given IV Nivolumab: Given IV	Patients receive ipilimumab and nivolumab as in Arm B. Patients undergo post-treatment biopsy on day 1 of week 7, then receive ipilimumab IV over 90 minutes every 6 weeks and nivolumab IV over 30 minutes every 4 weeks for up to 3 additional cycles in the absence of disease progression or unacceptable toxicity. Beginning 4 weeks after surgery, patients receive ipilimumab IV over 90 minutes every 6 weeks and nivolumab IV over 30 minutes every 4 weeks up to 2 years in the absence of disease progression or unacceptable toxicity. Ipilimumab: Given IV Nivolumab: Given IV
Overall Number of Participants Analyzed	13	14	0
Measure Type: Number; Unit of Measure: participants
	3	0

3. Secondary Outcome

Title	Time to Progression
Description	Time to progression defined as the time from the start of the study drug to the first documented tumor progression or recurrence of the tumor as determined by the investigator by RECIST 1.1 or immune-related response criteria.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

2 of the patients (1 in the Nivolumab arm and 1 in the Nivolumab + Ipilimumab arm) was not included in the analysis of PFS because their surgical cancellations were unrelated to progressive disease.

Upper limit of 95% Confidence Interval is not estimable due to insufficient number of participants and number of events.

Arm/Group Title	Arm A (Nivolumab)	Arm B (Ipilimumab, Nivolumab)	Arm C (Ipilimumab, Nivolumab)
Arm/Group Description:	Patients receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 2 weeks for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo liver surgery on day 1 of week 7. Beginning 4 weeks after surgery, patients continue nivolumab IV over 30 minutes every 4 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. Nivolumab: Given IV	Patients receive ipilimumab IV over 90 minutes on day 1 and nivolumab as Arm A. Treatment repeats every 2 weeks for up to 3 cycles for nivolumab in the absence of disease progression or unacceptable toxicity. Patients undergo liver surgery on day 1 of week 7. Beginning 4 weeks after surgery, patients receive ipilimumab IV over 90 minutes every 6 weeks and nivolumab IV over 30 minutes every 4 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. Ipilimumab: Given IV Nivolumab: Given IV	Patients receive ipilimumab and nivolumab as in Arm B. Patients undergo post-treatment biopsy on day 1 of week 7, then receive ipilimumab IV over 90 minutes every 6 weeks and nivolumab IV over 30 minutes every 4 weeks for up to 3 additional cycles in the absence of disease progression or unacceptable toxicity. Beginning 4 weeks after surgery, patients receive ipilimumab IV over 90 minutes every 6 weeks and nivolumab IV over 30 minutes every 4 weeks up to 2 years in the absence of disease progression or unacceptable toxicity. Ipilimumab: Given IV Nivolumab: Given IV
Overall Number of Participants Analyzed	12	13	0
Median (95% Confidence Interval); Unit of Measure: months
	9.4 [1]; (1.47 to NA)	19.53 [1]; (2.33 to NA)

[1]

2 of the patients (1 in the Nivolumab arm and 1 in the Nivolumab + Ipilimumab arm) was not included in the analysis of PFS because their surgical cancellations were unrelated to progressive disease.

4. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	Progression free survival, defined as the time from the start of treatment to the date of progessive disease, recurrence, or death, whichever occurred first. The Kaplan-Meier method will be used to estimate probability of PFS for each treatment arm.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

2 of the patients (1 in the Nivolumab arm and 1 in the Nivolumab + Ipilimumab arm) was not included in the analysis of PFS because their surgical cancellations were unrelated to progressive disease.

Upper limit of 95% Confidence Interval is not estimable due to insufficient number of participants and number of events.

Arm/Group Title	Arm A (Nivolumab)	Arm B (Ipilimumab, Nivolumab)	Arm C (Ipilimumab, Nivolumab)
Arm/Group Description:	Patients receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 2 weeks for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo liver surgery on day 1 of week 7. Beginning 4 weeks after surgery, patients continue nivolumab IV over 30 minutes every 4 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. Nivolumab: Given IV	Patients receive ipilimumab IV over 90 minutes on day 1 and nivolumab as Arm A. Treatment repeats every 2 weeks for up to 3 cycles for nivolumab in the absence of disease progression or unacceptable toxicity. Patients undergo liver surgery on day 1 of week 7. Beginning 4 weeks after surgery, patients receive ipilimumab IV over 90 minutes every 6 weeks and nivolumab IV over 30 minutes every 4 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. Ipilimumab: Given IV Nivolumab: Given IV	Patients receive ipilimumab and nivolumab as in Arm B. Patients undergo post-treatment biopsy on day 1 of week 7, then receive ipilimumab IV over 90 minutes every 6 weeks and nivolumab IV over 30 minutes every 4 weeks for up to 3 additional cycles in the absence of disease progression or unacceptable toxicity. Beginning 4 weeks after surgery, patients receive ipilimumab IV over 90 minutes every 6 weeks and nivolumab IV over 30 minutes every 4 weeks up to 2 years in the absence of disease progression or unacceptable toxicity. Ipilimumab: Given IV Nivolumab: Given IV
Overall Number of Participants Analyzed	12	13	0
Median (95% Confidence Interval); Unit of Measure: months
	9.4 [1]; (1.47 to NA)	19.53 [1]; (2.33 to NA)

[1]

2 of the patients (1 in the Nivolumab arm and 1 in the Nivolumab + Ipilimumab arm) was not included in the analysis of PFS because their surgical cancellations were unrelated to progressive disease.

Adverse Events

Time Frame	Overall Study (Up to 5 years)
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Nivolumab		Nivolumab Plus Ipilimumab
Arm/Group Description	Nivolumab at 240 mg IV every 2 weeks for 3 doses followed by liver imaging and hepatic resection on day 1 of week 7, followed (after 4 weeks from surgery) by nivolumab 480 mg IV every 4 weeks in the adjuvant setting until disease progression or for 2 years, whichever is sooner Nivolumab: Given IV		Nivolumab 240 mg IV every 2 weeks for 3 doses plus ipilimumab 1 mg/kg IV on day 1 of therapy (3 doses of nivolumab, 1 dose of ipilimumab) followed by hepatic resection followed (after 4 weeks from surgery) by nivolumab 480 mg IV every 4 weeks plus ipilimumab 1 mg/kg IV every 6 weeks to 4 doses in the adjuvant settingIpilimumab: Given IV Nivolumab: Given IV Ipilimumab: Given IV
All-Cause Mortality
	Nivolumab		Nivolumab Plus Ipilimumab
	Affected / at Risk (%)		Affected / at Risk (%)
Total	0/13 (0.00%)		4/14 (28.57%)
Serious Adverse Events
	Nivolumab		Nivolumab Plus Ipilimumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0.00%)		0/14 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	1%
	Nivolumab		Nivolumab Plus Ipilimumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/13 (76.92%)		12/14 (85.71%)
Endocrine disorders
Hypothyroidism †	2/13 (15.38%)	2	2/14 (14.29%)	2
Gastrointestinal disorders
Nausea †	3/13 (23.08%)	3	3/14 (21.43%)	3
Constipation †	2/13 (15.38%)	2	1/14 (7.14%)	1
General disorders
Fatigue †	1/13 (7.69%)	1	6/14 (42.86%)	6
Investigations
Anaemia †	2/13 (15.38%)	2	3/14 (21.43%)	3
Increased alanine aminotransferase †	3/13 (23.08%)	3	7/14 (50.00%)	7
Increased aspartate aminotransferase †	3/13 (23.08%)	3	7/14 (50.00%)	7
Decreased platelet count †	2/13 (15.38%)	2	1/14 (7.14%)	1
Lipase increased †	2/13 (15.38%)	2	1/14 (7.14%)	1
Skin and subcutaneous tissue disorders
Pruritus †	2/13 (15.38%)	2	1/14 (7.14%)	1
Maculopapular rash †	4/13 (30.77%)	4	3/14 (21.43%)	3
† Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

Results Point of Contact

• Name/Title: Dr. Ahmed Kaseb
• Organization: MD Anderson Cancer Center
• Phone: (713) 792-2828
• EMail: akaseb@mdanderson.org

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Kaseb AO, Hasanov E, Cao HST, Xiao L, Vauthey JN, Lee SS, Yavuz BG, Mohamed YI, Qayyum A, Jindal S, Duan F, Basu S, Yadav SS, Nicholas C, Sun JJ, Singh Raghav KP, Rashid A, Carter K, Chun YS, Tzeng CD, Sakamuri D, Xu L, Sun R, Cristini V, Beretta L, Yao JC, Wolff RA, Allison JP, Sharma P. Perioperative nivolumab monotherapy versus nivolumab plus ipilimumab in resectable hepatocellular carcinoma: a randomised, open-label, phase 2 trial. Lancet Gastroenterol Hepatol. 2022 Mar;7(3):208-218. doi: 10.1016/S2468-1253(21)00427-1. Epub 2022 Jan 20.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT03222076
• Other Study ID Numbers: 2017-0097; NCI-2018-01106 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); 2017-0097 ( Other Identifier: M D Anderson Cancer Center )
• First Submitted: July 17, 2017
• First Posted: July 19, 2017
• Results First Submitted: April 27, 2023
• Results First Posted: July 10, 2023
• Last Update Posted: July 10, 2023