Melanoma
Conditions
Brief summary
This is a safety and efficacy study of different administration regimens of nivolumab plus Ipilimumab in subjects with previously untreated, unresectable or metastatic melanoma.
Interventions
BIOLOGICALNivolumab
-Specified dose on specified days
BIOLOGICALIpilimumab
-Specified dose on specified days
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 Bristol-Myers Squibb Clinical Trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria: * Males and Females, ages 15 years ≥ of age (Except where local regulations and/or institutional policies do not allow for subjects \< 18 years of age to participate) * Subjects must have been diagnosed with stage III or/and stage IV histologically confirmed melanoma that is unresectable or metastatic * Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 * Subjects have not been treated by systemic anticancer therapy for unresectable or metastatic melanoma
Exclusion criteria
* Subjects with active brain metastases or leptomeningeal metastases * Subjects with ocular melanoma * Subjects with active, known or suspected autoimmune disease Other protocol defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Affected by Adverse Events (AEs) in the Broad Scope MedDRA Anaphylactic Reaction Standardized MedDRA Queries (SMQ) | Within 2 days from administration of any of the 4 doses in part 1 period (approximately 12 weeks) | This outcome describes the percentage of participants experiencing at least 1 AE in the MedDRA Anaphylactic Reaction broad scope SMQ. Such AEs include any acute systemic reaction characterized by a large list of terms, including (but not limited to) pruritus, urticaria, flushing, hypotension, respiratory distress, and vascular insufficiency. It also includes other signs and symptoms such as asthma, choking sensation, coughing, sneezing, and difficulty breathing due to laryngeal spasm and/or bronchospasm. Less frequent clinical presentations are also captured and include hyperventilation, sensation of foreign body, and ocular edema. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Geometric Mean Trough Concentration of Ipilimumab | From Cycle 2, Day 1 to Cycle 4, Day 1 (approximately 6 weeks). Each cycle lasts 3 weeks. | — |
| Geometric Mean Trough Concentration of Nivolumab | From Cycle 2, Day 1 to Cycle 4, Day 1 (approximately 6 weeks). Each cycle lasts 3 weeks. | — |
| Percentage of Participants Affected by AEs in the Narrow Scope MedDRA Anaphylactic Reaction SMQ | Within 2 days from administration of any of the 4 doses in part 1 period (approximately 12 weeks) | This outcome describes the percentage of participants experiencing at least 1 AE in the MedDRA Anaphylactic Reaction narrow scope SMQ. The narrow scope SMQ is composed of a large list of terms, including (but not limited to) anaphylactic shock and reaction, shock and shock symptoms, and circulatory collapse, among the others. |
| Percentage of Participants Affected by Hypersensitivity/Infusion Reaction Select AEs | Within 2 days from administration of any of the 4 doses in part 1 period (approximately 12 weeks) | This outcome describes the percentage of participants experiencing at least 1 AE in the Hypersensitivity/Infusion select AEs category. The select AEs consist of a list of preferred terms defined by the Sponsor and represent AEs with a potential immune-mediated etiology. The following 5 MedDRA preferred terms are included in the hypersensitivity/infusion reaction select AE category: Anaphylactic Reaction, Anaphylactic Shock, Bronchospasm, Hypersensitivity, and Infusion Related Reaction |
| Geometric Mean Concentration of Nivolumab at End of Infusion (EOI) | From Cycle 1, Day 1 to Cycle 4, Day 1 (approximately 9 weeks). Each cycle lasts 3 weeks. Cycle 1 day 1, Cycle 2 day 1 and Cycle 4 day 1 values reported | — |
| Percentage of Participants Affected by Drug-related Grade 3 - 5 AEs | From initial dose of study treatment and within 30 days of the last dose of study treatment (approximately 25 months) | This outcome describes the percentage of participants who experienced at least 1 Drug-related AE of Grade 3 or higher defined using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 criteria |
| Geometric Mean Concentration of Ipilimumab at End of Infusion (EOI) | From Cycle 1, Day 1 to Cycle 4, Day 1 (approximately 9 weeks). Each cycle lasts 3 weeks. Cycle 1 day 1, Cycle 2 day 1 and Cycle 4 day 1 values reported. | — |
| Objective Response Rate (ORR) | Week 12 following randomization, every 8 weeks for the first 12 months and then every 12 weeks until disease progression (approximately 20 months) | The ORR is defined as the proportion of participants with a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR). The BOR is defined as the best response designation, as determined by the investigator, recorded between the date of randomization and the date of objectively documented progression per RECIST 1.1 or the date of subsequent anti-cancer therapy, whichever occurs first. |
| Progression Free Survival (PFS) | From the date of randomization to the first date of documented progression (approximately 26 months) | PFS is defined as the time between the date of randomization and the first date of documented progression, as determined by the investigator, or death due to any cause, whichever occurs first. |
| Percentage of Participants Affected by All Causality Grade 3 - 5 AEs | From initial dose of study treatment and within 30 days of the last dose of study treatment (approximately 25 months) | This outcome describes the percentage of participants who experienced at least 1 AE of Grade 3 or higher defined using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 criteria |
Countries
Australia, France, Italy, Spain
Participant flow
Pre-assignment details
106 participants were randomized and treated.
Participants by arm
| Arm | Count |
|---|---|
| Fixed Ratio Combination Concomitant administration of Nivolumab and Ipilimumab (1:3 protein-mass ratio) every 3 weeks for 4 doses followed by Nivolumab flat dose in the Maintenance Phase | 53 |
| Sequential Combination Sequential administration of Nivolumab and Ipilimumab every 3 weeks for 4 doses followed by Nivolumab flat dose in the Maintenance Phase | 53 |
| Total | 106 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Maintenance Phase Part 2 | Disease Progression | 9 | 2 |
| Maintenance Phase Part 2 | Maximum Clinical Benefit | 0 | 2 |
| Maintenance Phase Part 2 | Study Drug Toxicity | 3 | 4 |
| Transition From Part 1 to Part 2 | Adverse Event | 1 | 1 |
| Transition From Part 1 to Part 2 | Adverse event unrelated to study drug | 1 | 0 |
| Transition From Part 1 to Part 2 | Death | 0 | 1 |
| Transition From Part 1 to Part 2 | Disease progression | 2 | 1 |
| Transition From Part 1 to Part 2 | Participant withdrew consent | 0 | 1 |
| Transition From Part 1 to Part 2 | Study drug toxicity | 0 | 4 |
| Treatment Phase Part 1 | Disease Progression | 6 | 7 |
| Treatment Phase Part 1 | Participant Withdrew Consent | 1 | 0 |
| Treatment Phase Part 1 | Study Drug Toxicity | 22 | 16 |
Baseline characteristics
| Characteristic | Sequential Combination | Total | Fixed Ratio Combination |
|---|---|---|---|
| Age, Continuous | 56.3 years STANDARD_DEVIATION 14.6 | 57.2 years STANDARD_DEVIATION 14.5 | 58.1 years STANDARD_DEVIATION 14.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 28 Participants | 54 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 24 Participants | 50 Participants | 26 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 7 Participants | 4 Participants |
| Race (NIH/OMB) White | 50 Participants | 98 Participants | 48 Participants |
| Sex: Female, Male Female | 26 Participants | 44 Participants | 18 Participants |
| Sex: Female, Male Male | 27 Participants | 62 Participants | 35 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 14 / 53 | 14 / 53 |
| other Total, other adverse events | 51 / 53 | 51 / 53 |
| serious Total, serious adverse events | 35 / 53 | 35 / 53 |
Outcome results
Primary
Percentage of Participants Affected by Adverse Events (AEs) in the Broad Scope MedDRA Anaphylactic Reaction Standardized MedDRA Queries (SMQ)
This outcome describes the percentage of participants experiencing at least 1 AE in the MedDRA Anaphylactic Reaction broad scope SMQ. Such AEs include any acute systemic reaction characterized by a large list of terms, including (but not limited to) pruritus, urticaria, flushing, hypotension, respiratory distress, and vascular insufficiency. It also includes other signs and symptoms such as asthma, choking sensation, coughing, sneezing, and difficulty breathing due to laryngeal spasm and/or bronchospasm. Less frequent clinical presentations are also captured and include hyperventilation, sensation of foreign body, and ocular edema.
Time frame: Within 2 days from administration of any of the 4 doses in part 1 period (approximately 12 weeks)
Population: All treated participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fixed Ratio Combination | Percentage of Participants Affected by Adverse Events (AEs) in the Broad Scope MedDRA Anaphylactic Reaction Standardized MedDRA Queries (SMQ) | 15.1 Percent of Participants |
| Sequential Combination | Percentage of Participants Affected by Adverse Events (AEs) in the Broad Scope MedDRA Anaphylactic Reaction Standardized MedDRA Queries (SMQ) | 17.0 Percent of Participants |
95% CI: [0.3, 2.49]
95% CI: [-16, 12.2]
Secondary
Geometric Mean Concentration of Ipilimumab at End of Infusion (EOI)
Time frame: From Cycle 1, Day 1 to Cycle 4, Day 1 (approximately 9 weeks). Each cycle lasts 3 weeks. Cycle 1 day 1, Cycle 2 day 1 and Cycle 4 day 1 values reported.
Population: All treated participants
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Fixed Ratio Combination | Geometric Mean Concentration of Ipilimumab at End of Infusion (EOI) | Cycle 1 Day 1 | 60.4 micrograms per milliliter (ug/mL) | Geometric Coefficient of Variation 93 |
| Fixed Ratio Combination | Geometric Mean Concentration of Ipilimumab at End of Infusion (EOI) | Cycle 2 Day 1 | 66.8 micrograms per milliliter (ug/mL) | Geometric Coefficient of Variation 134 |
| Fixed Ratio Combination | Geometric Mean Concentration of Ipilimumab at End of Infusion (EOI) | Cycle 4 Day 1 | 77.9 micrograms per milliliter (ug/mL) | Geometric Coefficient of Variation 94.2 |
| Sequential Combination | Geometric Mean Concentration of Ipilimumab at End of Infusion (EOI) | Cycle 1 Day 1 | 61.5 micrograms per milliliter (ug/mL) | Geometric Coefficient of Variation 72.3 |
| Sequential Combination | Geometric Mean Concentration of Ipilimumab at End of Infusion (EOI) | Cycle 2 Day 1 | 72.1 micrograms per milliliter (ug/mL) | Geometric Coefficient of Variation 71.8 |
| Sequential Combination | Geometric Mean Concentration of Ipilimumab at End of Infusion (EOI) | Cycle 4 Day 1 | 84.6 micrograms per milliliter (ug/mL) | Geometric Coefficient of Variation 104 |
Secondary
Geometric Mean Concentration of Nivolumab at End of Infusion (EOI)
Time frame: From Cycle 1, Day 1 to Cycle 4, Day 1 (approximately 9 weeks). Each cycle lasts 3 weeks. Cycle 1 day 1, Cycle 2 day 1 and Cycle 4 day 1 values reported
Population: All treated participants
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Fixed Ratio Combination | Geometric Mean Concentration of Nivolumab at End of Infusion (EOI) | Cycle 1 Day 1 | 20.9 micrograms per milliliter (ug/mL) | Geometric Coefficient of Variation 77.3 |
| Fixed Ratio Combination | Geometric Mean Concentration of Nivolumab at End of Infusion (EOI) | Cycle 2 Day 1 | 24.2 micrograms per milliliter (ug/mL) | Geometric Coefficient of Variation 122 |
| Fixed Ratio Combination | Geometric Mean Concentration of Nivolumab at End of Infusion (EOI) | Cycle 4 Day 1 | 27.9 micrograms per milliliter (ug/mL) | Geometric Coefficient of Variation 79.8 |
| Sequential Combination | Geometric Mean Concentration of Nivolumab at End of Infusion (EOI) | Cycle 1 Day 1 | 21.8 micrograms per milliliter (ug/mL) | Geometric Coefficient of Variation 117 |
| Sequential Combination | Geometric Mean Concentration of Nivolumab at End of Infusion (EOI) | Cycle 2 Day 1 | 22.4 micrograms per milliliter (ug/mL) | Geometric Coefficient of Variation 101 |
| Sequential Combination | Geometric Mean Concentration of Nivolumab at End of Infusion (EOI) | Cycle 4 Day 1 | 27.4 micrograms per milliliter (ug/mL) | Geometric Coefficient of Variation 79.9 |
Secondary
Geometric Mean Trough Concentration of Ipilimumab
Time frame: From Cycle 2, Day 1 to Cycle 4, Day 1 (approximately 6 weeks). Each cycle lasts 3 weeks.
Population: All treated participants
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Fixed Ratio Combination | Geometric Mean Trough Concentration of Ipilimumab | Cycle 2 Day 1 | 10.8 micrograms per milliliter (ug/mL) | Geometric Coefficient of Variation 30.2 |
| Fixed Ratio Combination | Geometric Mean Trough Concentration of Ipilimumab | Cycle 4 Day 1 | 16.5 micrograms per milliliter (ug/mL) | Geometric Coefficient of Variation 36.9 |
| Sequential Combination | Geometric Mean Trough Concentration of Ipilimumab | Cycle 2 Day 1 | 9.94 micrograms per milliliter (ug/mL) | Geometric Coefficient of Variation 38.9 |
| Sequential Combination | Geometric Mean Trough Concentration of Ipilimumab | Cycle 4 Day 1 | 13.7 micrograms per milliliter (ug/mL) | Geometric Coefficient of Variation 46 |
Secondary
Geometric Mean Trough Concentration of Nivolumab
Time frame: From Cycle 2, Day 1 to Cycle 4, Day 1 (approximately 6 weeks). Each cycle lasts 3 weeks.
Population: All treated participants
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Fixed Ratio Combination | Geometric Mean Trough Concentration of Nivolumab | Cycle 2 Day 1 | 3.94 micrograms per milliliter (ug/mL) | Geometric Coefficient of Variation 56.6 |
| Fixed Ratio Combination | Geometric Mean Trough Concentration of Nivolumab | Cycle 4 Day 1 | 6.50 micrograms per milliliter (ug/mL) | Geometric Coefficient of Variation 44.6 |
| Sequential Combination | Geometric Mean Trough Concentration of Nivolumab | Cycle 2 Day 1 | 2.75 micrograms per milliliter (ug/mL) | Geometric Coefficient of Variation 65.9 |
| Sequential Combination | Geometric Mean Trough Concentration of Nivolumab | Cycle 4 Day 1 | 4.05 micrograms per milliliter (ug/mL) | Geometric Coefficient of Variation 75.3 |
Secondary
Objective Response Rate (ORR)
The ORR is defined as the proportion of participants with a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR). The BOR is defined as the best response designation, as determined by the investigator, recorded between the date of randomization and the date of objectively documented progression per RECIST 1.1 or the date of subsequent anti-cancer therapy, whichever occurs first.
Time frame: Week 12 following randomization, every 8 weeks for the first 12 months and then every 12 weeks until disease progression (approximately 20 months)
Population: All treated participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fixed Ratio Combination | Objective Response Rate (ORR) | 52.8 Percentage of Participants |
| Sequential Combination | Objective Response Rate (ORR) | 60.4 Percentage of Participants |
95% CI: [-26.1, 11]
95% CI: [0.35, 1.58]
Secondary
Percentage of Participants Affected by AEs in the Narrow Scope MedDRA Anaphylactic Reaction SMQ
This outcome describes the percentage of participants experiencing at least 1 AE in the MedDRA Anaphylactic Reaction narrow scope SMQ. The narrow scope SMQ is composed of a large list of terms, including (but not limited to) anaphylactic shock and reaction, shock and shock symptoms, and circulatory collapse, among the others.
Time frame: Within 2 days from administration of any of the 4 doses in part 1 period (approximately 12 weeks)
Population: All treated participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fixed Ratio Combination | Percentage of Participants Affected by AEs in the Narrow Scope MedDRA Anaphylactic Reaction SMQ | 0.0 Percent of Participants |
| Sequential Combination | Percentage of Participants Affected by AEs in the Narrow Scope MedDRA Anaphylactic Reaction SMQ | 0.0 Percent of Participants |
95% CI: [0, 0]
Secondary
Percentage of Participants Affected by All Causality Grade 3 - 5 AEs
This outcome describes the percentage of participants who experienced at least 1 AE of Grade 3 or higher defined using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 criteria
Time frame: From initial dose of study treatment and within 30 days of the last dose of study treatment (approximately 25 months)
Population: All treated participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fixed Ratio Combination | Percentage of Participants Affected by All Causality Grade 3 - 5 AEs | 69.8 Percent of participants |
| Sequential Combination | Percentage of Participants Affected by All Causality Grade 3 - 5 AEs | 56.6 Percent of participants |
Secondary
Percentage of Participants Affected by Drug-related Grade 3 - 5 AEs
This outcome describes the percentage of participants who experienced at least 1 Drug-related AE of Grade 3 or higher defined using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 criteria
Time frame: From initial dose of study treatment and within 30 days of the last dose of study treatment (approximately 25 months)
Population: All treated participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fixed Ratio Combination | Percentage of Participants Affected by Drug-related Grade 3 - 5 AEs | 58.5 Percent of participants |
| Sequential Combination | Percentage of Participants Affected by Drug-related Grade 3 - 5 AEs | 47.2 Percent of participants |
Secondary
Percentage of Participants Affected by Hypersensitivity/Infusion Reaction Select AEs
This outcome describes the percentage of participants experiencing at least 1 AE in the Hypersensitivity/Infusion select AEs category. The select AEs consist of a list of preferred terms defined by the Sponsor and represent AEs with a potential immune-mediated etiology. The following 5 MedDRA preferred terms are included in the hypersensitivity/infusion reaction select AE category: Anaphylactic Reaction, Anaphylactic Shock, Bronchospasm, Hypersensitivity, and Infusion Related Reaction
Time frame: Within 2 days from administration of any of the 4 doses in part 1 period (approximately 12 weeks)
Population: All treated participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fixed Ratio Combination | Percentage of Participants Affected by Hypersensitivity/Infusion Reaction Select AEs | 7.5 Percent of Participants |
| Sequential Combination | Percentage of Participants Affected by Hypersensitivity/Infusion Reaction Select AEs | 9.4 Percent of Participants |
Secondary
Progression Free Survival (PFS)
PFS is defined as the time between the date of randomization and the first date of documented progression, as determined by the investigator, or death due to any cause, whichever occurs first.
Time frame: From the date of randomization to the first date of documented progression (approximately 26 months)
Population: All treated participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fixed Ratio Combination | Progression Free Survival (PFS) | 10.25 Months |
| Sequential Combination | Progression Free Survival (PFS) | NA Months |
95% CI: [0.78, 2.37]