Advanced or Metastatic Melanoma
Conditions
Brief summary
The purpose of this study is to evaluate the safety and efficacy of a sequential combination therapy of Nivolumab and Ipilimumab
Detailed description
In order to evaluate the potential synergistic activity of nivolumab and ipilimumab and also because there may be differences in biology between tumors which are stable or responding to therapy and those that are clinically progressing, this study, CA209064, looked at two sequential combination regimens in which the second agent is administered immediately after a pre-specified duration of therapy with the first agent and not delayed until the time of progression after the first agent. This sequential study design looked at pharmacodynamic changes during treatment with one agent which may predict clinical activity to subsequent treatment with the alternate agent. This was done because it has not been scientifically proven whether or not the order in which nivolumab and ipilimumab are given is clinically important.
Interventions
BIOLOGICALNivolumab
BIOLOGICALIpilimumab
Sponsors
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria: * Histologically confirmed unresectable Stage III or IV melanoma * Treatment-naive or experienced disease recurrence or progression during or after one prior systemic regimen for advanced disease * Measurable disease by Computed Tomography/Magnetic resonance imaging (CT/MRI) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria * Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 * Known BRAF V600 mutation status or consent to BRAF V600 mutation testing * Sufficient tumor tissue accessible for baseline and post-treatment biopsies.
Exclusion criteria
* Active central nervous system (CNS) metastases * Carcinomatous meningitis * Active, known or suspected autoimmune disease * Condition requiring systemic treatment with either corticosteroids (\>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of randomization * Prior therapy with anti-Programmed Death-1 (PD1), anti-Programmed Death-Ligand 1 (PD-L1), anti-PD-L2, anti-CD137, or anti-CTLA-4 (cytotoxic T lymphocyte antigen 4) antibody * Prior treatment with other immunotherapies * Prior therapy with BRAF inhibitor within 6 weeks of enrollment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Treatment-Related Grade 3-5 Adverse Events (AEs) During the Induction Period (Period 1 and 2) | From Day 1 to up to Week 25 | The percentage of participants with treatment-related grade 3-5 adverse events (AEs) is defined as the number of participants who experienced at least 1 treatment related grade 3 - 5 adverse event (AE) per national cancer institute common terminology criteria for adverse events (NCI CTCAE v4.0, any preferred term) with an onset date after or on first day of Induction Period #1 and not later than discontinuation date from Induction Period #2, divided by the total number of treated participants. Adverse Event (AE) = any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may or may not have a causal relationship with treatment. Treatment-related = having certain, probable, possible, or missing relationship to study drug. Grade (Gr) 3=Severe Gr 4=Potentially Life-threatening or disabling Gr 5=Death |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Investigator-Assessed Response Rate at Week 25 | Week 25 | Response rate is defined as the number of participants who have a complete response (CR) or partial response (PR) at Week 25 per modified RECIST 1.1 criteria, with confirmation on the scheduled scan at Week 33 (or any subsequent scan performed at least 4 weeks after the Week 25 scan), divided by the total number of treated participants. Results of the tumor assessment at Week 13 or any unscheduled tumor assessment obtained prior to Week 25, except for baseline/screening tumor assessment, were not considered in the assessment of response rate at Week 25. |
| Investigator-Assessed Duration of Response (DOR) | From week 25 to up to date of disease progression or death (Up to 6 years) | Duration of response (DOR) is defined as the time between the Week 25 date of response and the date of objectively documented disease progression as defined by modified RECIST 1.1 criteria or death, whichever occurs first. Median computed using Kaplan-Meier method. |
| Investigator-Assessed Rate of Progression | Week 13 and Week 25 | Progression rate at a specific timepoint is defined as the number of participants who have Progressive Disease (PD) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 at that specific timepoint divided by the total number of treated participants. As specified by modified RECIST 1.1, the evaluation of PD at Week 13 and Week 25 used the baseline tumor assessment as reference. A participant who died without a reported prior progression was considered to have progressed on the date of death. Deaths before or at Week 13 are counted as progression outcome. Confidence interval is based on the Clopper and Pearson method. |
Countries
United States
Participant flow
Pre-assignment details
Of the 140 randomized,138 treated because 1 experienced adverse event unrelated to study drug and 1 no longer met study criteria.
Participants by arm
| Arm | Count |
|---|---|
| Nivolumab Followed by Ipilimumab Nivolumab 3 mg/kg Q2W IV over 60 min for up to 6 doses during Weeks 1 to 13 in Induction Period 1 followed by Ipilimumab 3 mg/kg Q3W IV over 90 min for up to 4 doses during Weeks 13 to 25 in Induction Period 2. | 68 |
| Ipilimumab Followed by Nivolumab Ipilimumab 3 mg/kg Q3W IV over 90 min for up to 4 doses during Weeks 1 to 13 in Induction Period 1 followed by Nivolumab 3 mg/kg Q2W IV over 60 min for up to 6 doses during Weeks 13 to 25 in Induction Period 2. | 70 |
| Total | 138 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event Unrelated to Study Drug | 4 | 2 |
| Overall Study | Disease Progression | 18 | 41 |
| Overall Study | Maximum Clinical Benefit | 1 | 0 |
| Overall Study | Other Reasons | 3 | 1 |
| Overall Study | Participant Request to Discontinue Study Treatment | 2 | 3 |
| Overall Study | Participant Withdrew Consent | 2 | 0 |
| Overall Study | Study Drug Toxicity | 27 | 14 |
Baseline characteristics
| Characteristic | Nivolumab Followed by Ipilimumab | Ipilimumab Followed by Nivolumab | Total |
|---|---|---|---|
| Age, Continuous | 59.1 years STANDARD_DEVIATION 14.08 | 60.6 years STANDARD_DEVIATION 15.17 | 59.8 years STANDARD_DEVIATION 14.61 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Asian | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Black or African American | 1 participants | 2 participants | 3 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Other | 2 participants | 2 participants | 4 participants |
| Race/Ethnicity, Customized White | 65 participants | 66 participants | 131 participants |
| Sex: Female, Male Female | 22 Participants | 24 Participants | 46 Participants |
| Sex: Female, Male Male | 46 Participants | 46 Participants | 92 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 35 / 68 | 48 / 70 |
| other Total, other adverse events | 68 / 68 | 68 / 70 |
| serious Total, serious adverse events | 59 / 68 | 57 / 70 |
Outcome results
Primary
Percentage of Participants With Treatment-Related Grade 3-5 Adverse Events (AEs) During the Induction Period (Period 1 and 2)
The percentage of participants with treatment-related grade 3-5 adverse events (AEs) is defined as the number of participants who experienced at least 1 treatment related grade 3 - 5 adverse event (AE) per national cancer institute common terminology criteria for adverse events (NCI CTCAE v4.0, any preferred term) with an onset date after or on first day of Induction Period #1 and not later than discontinuation date from Induction Period #2, divided by the total number of treated participants. Adverse Event (AE) = any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may or may not have a causal relationship with treatment. Treatment-related = having certain, probable, possible, or missing relationship to study drug. Grade (Gr) 3=Severe Gr 4=Potentially Life-threatening or disabling Gr 5=Death
Time frame: From Day 1 to up to Week 25
Population: All treated participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nivolumab Followed by Ipilimumab | Percentage of Participants With Treatment-Related Grade 3-5 Adverse Events (AEs) During the Induction Period (Period 1 and 2) | 64.7 Percentage of participants |
| Ipilimumab Followed by Nivolumab | Percentage of Participants With Treatment-Related Grade 3-5 Adverse Events (AEs) During the Induction Period (Period 1 and 2) | 51.4 Percentage of participants |
Secondary
Investigator-Assessed Duration of Response (DOR)
Duration of response (DOR) is defined as the time between the Week 25 date of response and the date of objectively documented disease progression as defined by modified RECIST 1.1 criteria or death, whichever occurs first. Median computed using Kaplan-Meier method.
Time frame: From week 25 to up to date of disease progression or death (Up to 6 years)
Population: All treated participants with confirmed response at week 25
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nivolumab Followed by Ipilimumab | Investigator-Assessed Duration of Response (DOR) | NA months |
| Ipilimumab Followed by Nivolumab | Investigator-Assessed Duration of Response (DOR) | 57.66 months |
Secondary
Investigator-Assessed Rate of Progression
Progression rate at a specific timepoint is defined as the number of participants who have Progressive Disease (PD) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 at that specific timepoint divided by the total number of treated participants. As specified by modified RECIST 1.1, the evaluation of PD at Week 13 and Week 25 used the baseline tumor assessment as reference. A participant who died without a reported prior progression was considered to have progressed on the date of death. Deaths before or at Week 13 are counted as progression outcome. Confidence interval is based on the Clopper and Pearson method.
Time frame: Week 13 and Week 25
Population: All treated participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Nivolumab Followed by Ipilimumab | Investigator-Assessed Rate of Progression | Week 13 | 36.8 Percentage of participants |
| Nivolumab Followed by Ipilimumab | Investigator-Assessed Rate of Progression | Week 25 | 36.8 Percentage of participants |
| Ipilimumab Followed by Nivolumab | Investigator-Assessed Rate of Progression | Week 13 | 62.9 Percentage of participants |
| Ipilimumab Followed by Nivolumab | Investigator-Assessed Rate of Progression | Week 25 | 60.0 Percentage of participants |
Secondary
Investigator-Assessed Response Rate at Week 25
Response rate is defined as the number of participants who have a complete response (CR) or partial response (PR) at Week 25 per modified RECIST 1.1 criteria, with confirmation on the scheduled scan at Week 33 (or any subsequent scan performed at least 4 weeks after the Week 25 scan), divided by the total number of treated participants. Results of the tumor assessment at Week 13 or any unscheduled tumor assessment obtained prior to Week 25, except for baseline/screening tumor assessment, were not considered in the assessment of response rate at Week 25.
Time frame: Week 25
Population: All treated participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nivolumab Followed by Ipilimumab | Investigator-Assessed Response Rate at Week 25 | 54.7 Percentage of participants |
| Ipilimumab Followed by Nivolumab | Investigator-Assessed Response Rate at Week 25 | 30.4 Percentage of participants |