Efficacy Study of Ipilimumab Versus Placebo to Prevent Recurrence After Complete Resection of High Risk Stage III Melanoma

• ClinicalTrials.gov Identifier: NCT00636168
• Recruitment Status: Completed
• First Posted: March 14, 2008
• Results First Posted: August 19, 2014
• Last Update Posted: December 17, 2019
• Sponsor: Bristol-Myers Squibb
• Information provided by (Responsible Party): Bristol-Myers Squibb

Tracking Information

• First Submitted Date: March 7, 2008
• First Posted Date: March 14, 2008
• Results First Submitted Date: July 25, 2014
• Results First Posted Date: August 19, 2014
• Last Update Posted Date: December 17, 2019
• Actual Study Start Date: June 30, 2008
• Actual Primary Completion Date: July 26, 2013 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 4, 2019)

• Recurrence Free Survival (RFS) Per Independent Review Committee (IRC) in the Intent to Treat (ITT) Population [ Time Frame: Date of randomization to first date of recurrence or death or last available disease assessment with RFS data up to 5 years. Median follow-up was 2.7 years. ]
  Recurrence free survival (RFS) was programmatically determined based on the disease recurrence data provided by the IRC and was defined as the time between the date of randomization and the date of first recurrence or death (whatever the cause), whichever occurred first. A participant who died without reported recurrence was considered to have recurrence on the date of death. For those participants who remained alive and recurrence-free, RFS was censored on the date of last evaluable post-randomization tumor assessment. For those who remained alive and had no recorded post-randomization tumor assessment, RFS was censored on the day of randomization. Participants with disease at baseline were considered to have an event on the day of randomization. Computerized tomography (CT) and magnetic resonance imaging (MRI) were mandatory to establish recurrence. The primary analysis was event-driven and planned when at least 512 RFS events assessed per IRC were collected.
• Number of Participants With Recurrence or Death as Per Independent Review Committee (IRC) in the Intent to Treat (ITT) Population [ Time Frame: Date of randomization to first date of recurrence or death or last available disease assessment with RFS data upto 5 years. Median follow-up was 2.7 years. ]
  Recurrence was defined as appearance of one or more new melanoma lesions: local, regional or distant metastasis. Computerized tomography (CT) and magnetic resonance imaging (MRI) were mandatory to establish recurrence. A participant who died without reported recurrence was considered to have recurred on the date of death. Disease was assessed at randomization and every 12 weeks (±2 weeks) for 3 years, then every 24 weeks until documented distant progression.
• Recurrence-Free Survival (RFS) Rates Per IRC at 1 Year, 2 Years, and 3 Years in the ITT Population [ Time Frame: At years 1, 2, and 3 ]
  Yearly recurrence-free survival rates, eg. at 1 year, defined as the probability that a participant was recurrence-free at 1 year following randomization, were estimated for each treatment group using the Kaplan-Meier product-limit method, along with their corresponding log-log transformed 95% confidence intervals. RFS was defined as the time between the date of randomization and the date of first recurrence or death (whatever the cause), whichever occurred first. A participant who died without reported recurrence was considered to have recurrence on the date of death. For those who remained alive and recurrence-free, RFS was censored on the date of last evaluable post-randomization tumor assessment. For those who remained alive and had no recorded post-randomization tumor assessment, RFS was censored on the day of randomization. Participants with disease at baseline were considered to have an event on the day of randomization. CT and MRI were mandatory to establish recurrence.

• Original Primary Outcome Measures (submitted: March 7, 2008): To determine whether post-operative adjuvant therapy with ipilimumab improves recurrence-free survival (RFS) as compared to placebo

Current Secondary Outcome Measures (submitted: December 4, 2019)

• Distant Metastasis-Free Survival (DMFS) Per Independent Review Committee (IRC) in the Intent to Treat (ITT) Population [ Time Frame: From June 2008 to January 2016 (approximately 90 months) ]
  Distant Metastasis-Free Survival (DMFS) was programmatically determined based on the first date of distant metastasis provided by the IRC and was defined as the time between the date of randomization and the date of first distant metastasis or death (whatever the cause), whichever occurred first. A participant who died without reported disease distant metastasis was considered to have distant metastasis on the date of death. For those who remained alive and metastasis-free, DMFS was censored on the date of last evaluable post-randomization tumor assessment. For those who remained alive and had no recorded post-randomization tumor assessment, DMFS was censored on the day of randomization. Participants with disease at baseline were considered to have an event on the day of randomization. Disease was assessed at baseline (randomization) and every 12 weeks (±2 weeks) for 3 years, then every 24 weeks until documented distant progression.
• Number of Participants With Distant Metastasis-Free Survival (DMFS) Per Independent Review Committee (IRC) in the Intent to Treat (ITT) Population [ Time Frame: From June 2008 to January 2016 (approximately 90 months) ]
  DMFS was programmatically determined based on the first date of distant metastasis provided by the IRC and was defined as the time between the date of randomization and the date of first distant metastasis or death (whatever the cause), whichever occurred first. A participant who died without reported disease distant metastasis was considered to have distant metastasis on the date of death. For those who remained alive and metastasis-free, DMFS was censored on the date of last evaluable post-randomization tumor assessment. For those who remained alive and had no recorded post-randomization tumor assessment, DMFS was censored on the day of randomization. Participants with disease at baseline were considered to have an event on the day of randomization. Disease was assessed at baseline (randomization) and every 12 weeks (2 weeks) for 3 years, then every 24 weeks until documented distant progression.
• Distant Metastasis-Free Survival (DMFS) Rates Per IRC at 1 Year, 2 Years, 3 Years, 4 Years and 5 Years in the ITT Population [ Time Frame: At years 1, 2, 3, 4 and 5 ]
  Yearly distant metastasis-free survival rates, e.g. at 1 year, defined as the probability that a participant was alive at 1 year following randomization, were estimated via the Kaplan-Meier method. Distant Metastasis-Free Survival (DMFS) was programmatically determined based on the first date of distant metastasis provided by the IRC and was defined as the time between the date of randomization and the date of first distant metastasis or death (whatever the cause), whichever occurred first. A participant who died without reported disease distant metastasis was considered to have distant metastasis on the date of death. For those who remained alive and metastasis-free, DMFS was censored on the date of last evaluable post-randomization tumor assessment. For those who remained alive and had no recorded post-randomization tumor assessment. Participants with disease at baseline were considered to have an event on the day of randomization.
• Overall Survival in the Intent to Treat (ITT) Population [ Time Frame: From June 2008 to January 2016 (approximately 90 months) ]
  OS was defined as the time from the date of randomization to the date of death. For those participants who had not died, OS was censored at the recorded last non-missing date of contact for which the participant was known to be alive.
• Rate of Overall Survival (OS) [ Time Frame: From date of randomization to date of death, assessed up to 9 years ]
  OS was defined as the time from the date of randomization to the date of death. For those participants who had not died, OS was censored at the recorded last non-missing date of contact for which the participant was known to be alive.Yearly survival rates, e.g. at 3 years, defined as the probability that a participant was alive at 3 years following randomization, were estimated via the Kaplan-Meier method
• Number of Participants With On-Study Adverse Events (AEs) Leading to Discontinuation of Treatment, Serious AEs (SAEs), Drug-Related SAEs, Immune-related AEs (irAEs), Immune-mediated Adverse Reactions (imARs), Deaths in Treated Population [ Time Frame: Day 1 up to 70 days after last dose; up to 5 years ]
  AEs: Medical Dictionary for Regulatory Activities (MedDRA) version 16.1. irAEs=unknown etiology consistent with an immune phenomenon, considered as causally related to drug. imARs=based on investigator's assessment of immune-mediated etiology [excluding novel maintenance events (ie, patients with imARs occurring for the first time during maintenance)]. AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Drug-related (D-R)=having certain, probable, possible, or missing relationship to study drug. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4= Potentially Life-threatening or disabling, Gr 5=Death.
• Number of Participants With Serious Adverse Events (SAEs), Non-serious AEs (NSAEs) and Number of Deaths: Overall Study [ Time Frame: SAEs and NSAEs: Day 1 up to 70 days after last dose(safety window). Deaths: All deaths regardless of 70 day safety window.Up to 10 years ]
  AEs: Medical Dictionary for Regulatory Activities (MedDRA) version 16.1. AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization.
• Exposure Adjusted Incidence Rate of Adverse Events Including Multiple Occurrences of Unique Events [ Time Frame: Day 1 up to 70 days after last dose; up to 5 years ]
  P-Y = person-years of exposure. Incidence rate per 100 person-years of exposure (IR/100 P-Y) was calculated as event count * 100 /person-years of exposure. MedDRA Version: 19. Duplicate AEs have been eliminated and overlapping and contiguous occurrences of the same event have been collapsed.
• Mean Change From Baseline in Global Health Status Scores at Each Assessment Timepoint [ Time Frame: Baseline up to 2 years from randomization ]
  Global health status was measured using European Organization for Research and Treatment of Cancer (EORTC) Quality Life Questionnaire (QLQ) C-30. This health related quality of life (HRQoL) questionnaire was comprised of 15 questions on functional scales, 13 questions on symptom scales and 2 on global health status scale. Global Health Status used a 7 point Likert-type scale of 1 (Very poor) to 7 (Excellent). All scales linearly transformed to 0-100 scales. Higher scores for Global Health Status indicate better HRQoL. An increase from baseline indicates improvement in HRQoL compared to baseline. HRQoL was administered within 1 week prior to first dose (baseline) and on Days 22, 43, 64 (+/- 3 days), Week 24 and every 12 weeks up to 2 years, independent of disease progression.

Original Secondary Outcome Measures (submitted: March 7, 2008)

• To determine whether post-operative adjuvant therapy with ipilimumab improves overall survival (OS) as compared to placebo
• To determine whether post-operative adjuvant therapy with ipilimumab improves distant metastases-free survival (DMFS) as compared to placebo
• To compare adverse event profiles between patients receiving ipilimumab versus patients receiving placebo
• To compare quality of life and quality-of-life-adjusted survival between the two treatment groups (ipilimumab versus placebo)

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Efficacy Study of Ipilimumab Versus Placebo to Prevent Recurrence After Complete Resection of High Risk Stage III Melanoma
• Official Title: Adjuvant Immunotherapy With Anti-CTLA-4 Monoclonal Antibody (Ipilimumab) Versus Placebo After Complete Resection of High Risk Stage III Melanoma: A Randomized, Double-blind Phase 3 Trial of the EORTC Melanoma Group
• Brief Summary: The purpose of the study is to determine if ipilimumab is effective in preventing or delaying recurrence and prolongs survival after complete resection of high risk stage III melanoma
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: High Risk Stage III Melanoma

Intervention

• Drug: ipilimumab
  IV solution, IV, 10 mg/kg, 4x every 21 days, then starting from Week 24 every 12 weeks until Week 156 (3 years), disease recurrence, unacceptable toxicity or patient withdrawal
  Other Names:

  • BMS-734016
  • MDX-010
• Drug: Placebo
  IV solution, IV, 10 mg/kg, 4x every 21 days then starting from Week 24 every 12 weeks until Week 156 (3 years), disease recurrence, unacceptable toxicity or patient withdrawal

Study Arms

• Active Comparator: A
  Intervention: Drug: ipilimumab
• Placebo Comparator: B
  Intervention: Drug: Placebo

Publications *

• Weber JS, Ascierto PA, Middleton MR, Hennicken D, Zoffoli R, Pieters A, Amadi A, Kupas K, Kotapati S, Moshyk A, Schadendorf D. Indirect treatment comparison of nivolumab versus placebo as adjuvant treatment for resected melanoma. Eur J Cancer. 2021 Nov;158:225-233. doi: 10.1016/j.ejca.2021.08.028. Epub 2021 Oct 15.
• Coens C, Suciu S, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbe C, Ferraresi V, Smylie M, Weber JS, Maio M, Bottomley A, Kotapati S, de Pril V, Testori A, Eggermont AMM. Health-related quality of life with adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): secondary outcomes of a multinational, randomised, double-blind, phase 3 trial. Lancet Oncol. 2017 Mar;18(3):393-403. doi: 10.1016/S1470-2045(17)30015-3. Epub 2017 Feb 3.
• Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbe C, Ferraresi V, Smylie M, Weber JS, Maio M, Bastholt L, Mortier L, Thomas L, Tahir S, Hauschild A, Hassel JC, Hodi FS, Taitt C, de Pril V, de Schaetzen G, Suciu S, Testori A. Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy. N Engl J Med. 2016 Nov 10;375(19):1845-1855. doi: 10.1056/NEJMoa1611299. Epub 2016 Oct 7. Erratum In: N Engl J Med. 2018 Nov 29;379(22):2185.
• Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbe C, Ferraresi V, Smylie M, Weber JS, Maio M, Konto C, Hoos A, de Pril V, Gurunath RK, de Schaetzen G, Suciu S, Testori A. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015 May;16(5):522-30. doi: 10.1016/S1470-2045(15)70122-1. Epub 2015 Mar 31. Erratum In: Lancet Oncol. 2015 Jun;16(6):e262. Lancet Oncol. 2016 Jun;17 (6):e223.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 4, 2019): 1211
• Original Estimated Enrollment (submitted: March 7, 2008): 950
• Actual Study Completion Date: November 26, 2018
• Actual Primary Completion Date: July 26, 2013 (Final data collection date for primary outcome measure)

Eligibility Criteria

For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com.

Inclusion Criteria:

• Age ≥ 18 years
• Complete and adequate resection of Stage III melanoma with histologically confirmed melanoma metastatic to lymph node
• Disease-free
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1
• Randomization within 12 weeks of surgery

Exclusion Criteria:

• Prior therapy for melanoma except surgery
• Auto-immune disease

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Austria, Belgium, Canada, Czechia, Denmark, Finland, France, Germany, Italy, Netherlands, Norway, Poland, Russian Federation, Spain, Sweden, Switzerland, United Kingdom, United States
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT00636168
• Other Study ID Numbers: CA184-029; EORTC 18071
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Bristol-Myers Squibb
• Original Responsible Party: Study Director, Bristol-Myers Squibb
• Current Study Sponsor: Bristol-Myers Squibb
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Bristol-Myers Squibb; Bristol-Myers Squibb

• PRS Account: Bristol-Myers Squibb
• Verification Date: December 2019