Metastatic Malignant Melanoma
Conditions
Keywords
Phase II, Melanoma, IMC-1121B, ImClone
Brief summary
The primary objective of this study is to determine the progression-free survival (PFS) of participants with previously untreated metastatic malignant melanoma when treated with IMC-1121B (ramucirumab) alone or in combination with dacarbazine.
Detailed description
The purpose of this study is to determine the antitumor activity and safety profile of IMC-1121B (ramucirumab) when used alone or in combination with dacarbazine in participants with metastatic melanoma who have not received prior chemotherapy for this disease.
Interventions
BIOLOGICALIMC-1121B (ramucirumab)
10 milligrams/kilogram (mg/kg) intravenously every 3 weeks in the absence of disease progression, unacceptable toxicity, or other withdrawal criteria.
DRUGDacarbazine
1000 milligrams/square meter (mg/m2) intravenously every 3 weeks in the absence of disease progression, unacceptable toxicity, or other withdrawal criteria.
Sponsors
Eli Lilly and Company
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
* The participant has histologically or cytologically confirmed melanoma that is stage IV (metastatic) * The participant has an Eastern Cooperative Oncology Performance Status (ECOG PS) of 0-1 * The participant has completed any prior radiotherapy, biologic/immunotherapy or vaccine therapy (for adjuvant or advanced disease) at least six weeks prior to the first dose of study therapy * The participant has adequate hematological functions \[absolute neutrophil count (ANC) ≥ 1500 cells/microliter (μL), hemoglobin ≥ 9 grams/deciliter (g/dL) and platelets ≥ 100,000 cells/μL\]. * The participant has adequate hepatic function \[bilirubin within normal limits (WNL), aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤ 2.5 times the upper limit of normal (ULN), or ≤ 5.0 times the ULN if the transaminase elevation is due to liver metastases\] * The participant has serum creatinine ≤ 1.5 x ULN \[or a calculated creatinine clearance \> 60 milliliters/minute (mL/min)\] * The participant's urinary protein ≤ 1+ on dipstick or routine urinalysis \[(UA); if urine dipstick or routine analysis is ≥ 2+, a 24-hour urine for protein must demonstrate \< 1000 milligrams (mg) of protein in 24 hours to allow participation in the study\] * The participant must have adequate coagulation function as defined by International Normalized Ratio (INR) ≤ 1.5 and a partial thromboplastin time (PTT) ≤ 1.5 X ULN
Exclusion criteria
* The participant has mucosal or intra-ocular melanoma * The participant has known or suspected brain or leptomeningeal metastases * The participant has had prior cytotoxic chemotherapy for metastatic malignant melanoma * The participant has had more than one line of biologic, immunologic or vaccine-based therapy for metastatic malignant melanoma (including therapy for adjuvant or advanced disease) * The participant has a nonhealing wound or ulcer * The participant has a known alcohol or drug dependency * The participant is pregnant or breastfeeding * The participant has a coexisting medical or psychiatric problem of sufficient severity to limit compliance with the study and/or increase the risks associated with study participation or study drug administration or interfere with the interpretation of study results * The participant has an ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, symptomatic or poorly controlled cardiac arrhythmia, psychiatric illness/social situations, or any other serious uncontrolled medical disorders in the opinion of the investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | Baseline up to 36 months | PFS was defined as the time from the first day of therapy to the first evidence of disease progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST v1.0) or death from any cause. Progressive disease (PD) was defined as at least a 20% increase in the sum of the longest diameter (LD) of the target lesions, taking as reference the smallest sum LD recorded since the treatment started in comparison with the measurement of the nadir or the appearance of 1 or more new lesions. In addition, unequivocal progression of existing non-target lesions was considered PD. New or existing pleural effusion/ascites required cytological confirmation for PD according to the protocol. Participants who did not progress and who were alive or did not have documented progression or missed ≥2 visits, or had no post baseline assessment were censored at the day of their last tumor assessment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AE) | Baseline up to 40 months | The number of participants who experienced any IMC-1121B (ramucirumab \[RAM\]) treatment-related and treatment emergent AE (TEAE), treatment-related TEAE of Grade ≥3, treatment-related TE serious AEs (SAEs), treatment-related TEAE resulting in death (Grade 5 AE) and any TEAEs resulting in death. A summary of SAEs and all other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module. |
| Percentage of Participants With Complete Response (CR) or Partial Response (PR) [Overall Response Rate (ORR)] | Cycle 1 Day 1 (of 21-day cycle) up to 17.1 months | The ORR was defined as the percentage of all randomized participants with the best overall response of PR or CR using Response Evaluation Criteria in Solid Tumors (RECIST v1.0). CR was defined as the disappearance of all target and non-target lesions. PR was defined as at least a 30% decrease in sum of longest diameter of target lesions. CR and PR had to be confirmed by repeat assessments and performed no fewer than 4 weeks after the criteria for response were first met. |
| Duration of Response | Cycle 1 Day 1 (of 21-day cycle) up to 17.1 months | The duration of overall response was defined as the time from first assessment of complete response (CR) or partial response (PR) to the first date of progressive disease (PD) using Response Evaluation Criteria in Solid Tumors (RECIST v1.0), initiation of other or additional antitumor therapy, or death from any cause. CR was defined as the disappearance of all target lesions. PR was defined as having at least a 30% decrease in sum of longest diameter of target lesions. CR and PR had to be confirmed by repeat assessments and performed no fewer than 4 weeks after the criteria for response were first met. PD was defined as at least 20% increase in sum of longest diameter of target lesions. Participants who did not relapse were censored at the day of their last objective tumor assessment. |
| Percentage of Participants With Stable Disease (SD) or Better (Disease Control Rate) at 6 Weeks | 6 weeks (2 cycles of treatment) | Disease Control Rate (DCR) was defined as complete response (CR) plus partial response (PR) plus SD using Response Evaluation Criteria in Solid Tumors (RECIST v1.0). CR was defined as the disappearance of all target and non-target lesions and the normalization of non-target lesion tumor marker levels. PR was defined as at least a 30% decrease from baseline in sum of longest diameter of target lesions. CR and PR had to be confirmed by repeat assessments and performed no fewer than 4 weeks after the criteria for response were first met. SD was defined as: neither sufficient increase to qualify for progressive disease (PD) nor sufficient shrinkage to qualify for PR, taking as reference the smallest sum of the longest diameters recorded since treatment began. PD was defined as at least 20% increase in sum of longest diameter of target lesions. |
| Maximum Concentration (Cmax) for Cycle 1 Day 14 | Cycle 1 Day 14 (21-day cycle) | Cmax was not calculated due to sparse sampling. |
| Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Response Rate) at 12 Weeks | 12 weeks (4 cycles of treatment) | Response rate was defined as a CR or a PR using Response Evaluation Criteria in Solid Tumors (RECIST v1.0). CR was defined as the disappearance of all target and non-target lesions and the normalization of non-target lesion tumor marker levels. PR was defined as at least a 30% decrease from baseline in sum of longest diameter of target lesions. CR and PR had to be confirmed by repeat assessments and performed no fewer than 4 weeks after the criteria for response were first met. |
| Maximum Concentration (Cmax) for Cycle 1 Day 1 | Cycle 1 Day 1 (21-day cycle) 1-hour post infusion | Cmax was not calculated due to sparse sampling. |
| Maximum Concentration (Cmax) for Cycle 1 Day 7 | Cycle 1 Day 7 (21-day cycle) | Cmax was not calculated due to sparse sampling. |
| Percentage of Participants With Stable Disease (SD) or Better (Disease Control Rate) at 12 Weeks | 12 weeks (4 cycles of treatment) | Disease Control Rate (DCR) was defined as complete response (CR) plus partial response (PR) plus SD using Response Evaluation Criteria in Solid Tumors (RECIST v1.0). CR was defined as the disappearance of all target and non-target lesions and the normalization of non-target lesion tumor marker levels. PR was defined as at least a 30% decrease from baseline in sum of longest diameter of target lesions. CR and PR had to be confirmed by repeat assessments and performed no fewer than 4 weeks after the criteria for response were first met. Stable Disease (SD) was defined as: neither sufficient increase to qualify for progressive disease (PD) nor sufficient shrinkage to qualify for PR, taking as reference the smallest sum of the longest diameters recorded since treatment began. PD was defined as at least 20% increase in sum of longest diameter of target lesions. |
Countries
United States
Participant flow
Pre-assignment details
Participants who completed the study were those who died or were alive but off treatment at the end of the study.
Participants by arm
| Arm | Count |
|---|---|
| IMC-1121B (Ramucirumab) + Dacarbazine IMC-1121B (ramucirumab): 10 milligrams/kilogram (mg/kg) administered intravenously on Day 1 of 21-day cycle in the absence of disease progression, unacceptable toxicity, or other withdrawal criteria.
Dacarbazine: 1000 milligrams/square meter (mg/m2) administered intravenously on Day 1 of 21-day cycle in the absence of disease progression, unacceptable toxicity, or other withdrawal criteria. | 52 |
| IMC-1121B (Ramucirumab) IMC-1121B (ramucirumab): 10 mg/kg administered intravenously on Day 1 of 21-day cycle in the absence of disease progression, unacceptable toxicity, or other withdrawal criteria. | 50 |
| Total | 102 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Found ineligible after randomization | 2 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 1 |
Baseline characteristics
| Characteristic | IMC-1121B (Ramucirumab) + Dacarbazine | IMC-1121B (Ramucirumab) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 23 Participants | 22 Participants | 45 Participants |
| Age, Categorical Between 18 and 65 years | 29 Participants | 28 Participants | 57 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 1 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 47 Participants | 49 Participants | 96 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race Asian | 1 participants | 0 participants | 1 participants |
| Race Other | 1 participants | 0 participants | 1 participants |
| Race White | 50 participants | 50 participants | 100 participants |
| Region of Enrollment United States | 52 participants | 50 participants | 102 participants |
| Sex: Female, Male Female | 15 Participants | 12 Participants | 27 Participants |
| Sex: Female, Male Male | 37 Participants | 38 Participants | 75 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 52 / 52 | 48 / 50 |
| serious Total, serious adverse events | 14 / 52 | 15 / 50 |
Outcome results
Primary
Progression Free Survival (PFS)
PFS was defined as the time from the first day of therapy to the first evidence of disease progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST v1.0) or death from any cause. Progressive disease (PD) was defined as at least a 20% increase in the sum of the longest diameter (LD) of the target lesions, taking as reference the smallest sum LD recorded since the treatment started in comparison with the measurement of the nadir or the appearance of 1 or more new lesions. In addition, unequivocal progression of existing non-target lesions was considered PD. New or existing pleural effusion/ascites required cytological confirmation for PD according to the protocol. Participants who did not progress and who were alive or did not have documented progression or missed ≥2 visits, or had no post baseline assessment were censored at the day of their last tumor assessment.
Time frame: Baseline up to 36 months
Population: Intent-to-Treat Population: All enrolled participants who were treated with any quantity of study drug. Censored participants: IMC-1121B (ramucirumab) + dacarbazine=9; IMC-1121B (ramucirumab)=4.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| IMC-1121B (Ramucirumab) + Dacarbazine | Progression Free Survival (PFS) | 2.6 months |
| IMC-1121B (Ramucirumab) | Progression Free Survival (PFS) | 1.7 months |
Secondary
Duration of Response
The duration of overall response was defined as the time from first assessment of complete response (CR) or partial response (PR) to the first date of progressive disease (PD) using Response Evaluation Criteria in Solid Tumors (RECIST v1.0), initiation of other or additional antitumor therapy, or death from any cause. CR was defined as the disappearance of all target lesions. PR was defined as having at least a 30% decrease in sum of longest diameter of target lesions. CR and PR had to be confirmed by repeat assessments and performed no fewer than 4 weeks after the criteria for response were first met. PD was defined as at least 20% increase in sum of longest diameter of target lesions. Participants who did not relapse were censored at the day of their last objective tumor assessment.
Time frame: Cycle 1 Day 1 (of 21-day cycle) up to 17.1 months
Population: Intent-to-Treat Population: All enrolled participants who were treated with any quantity of study drug and who had CR or PR. Censored participants: IMC-1121B (ramucirumab) + dacarbazine=2; IMC-1121B (ramucirumab)=0.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| IMC-1121B (Ramucirumab) + Dacarbazine | Duration of Response | 11.0 months |
| IMC-1121B (Ramucirumab) | Duration of Response | NA months |
Secondary
Maximum Concentration (Cmax) for Cycle 1 Day 1
Cmax was not calculated due to sparse sampling.
Time frame: Cycle 1 Day 1 (21-day cycle) 1-hour post infusion
Population: Zero participants were analyzed.
Secondary
Maximum Concentration (Cmax) for Cycle 1 Day 14
Cmax was not calculated due to sparse sampling.
Time frame: Cycle 1 Day 14 (21-day cycle)
Population: Zero participants were analyzed.
Secondary
Maximum Concentration (Cmax) for Cycle 1 Day 7
Cmax was not calculated due to sparse sampling.
Time frame: Cycle 1 Day 7 (21-day cycle)
Population: Zero participants were analyzed.
Secondary
Number of Participants With Adverse Events (AE)
The number of participants who experienced any IMC-1121B (ramucirumab \[RAM\]) treatment-related and treatment emergent AE (TEAE), treatment-related TEAE of Grade ≥3, treatment-related TE serious AEs (SAEs), treatment-related TEAE resulting in death (Grade 5 AE) and any TEAEs resulting in death. A summary of SAEs and all other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module.
Time frame: Baseline up to 40 months
Population: Safety Population: All enrolled participants who were treated with any quantity of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IMC-1121B (Ramucirumab) + Dacarbazine | Number of Participants With Adverse Events (AE) | Any RAM related TEAE | 43 participants |
| IMC-1121B (Ramucirumab) + Dacarbazine | Number of Participants With Adverse Events (AE) | RAM related SAE | 9 participants |
| IMC-1121B (Ramucirumab) + Dacarbazine | Number of Participants With Adverse Events (AE) | RAM related ≥ Grade 3 AE | 20 participants |
| IMC-1121B (Ramucirumab) + Dacarbazine | Number of Participants With Adverse Events (AE) | RAM related death | 1 participants |
| IMC-1121B (Ramucirumab) + Dacarbazine | Number of Participants With Adverse Events (AE) | RAM related TEAE leading to discontinuation of RAM | 3 participants |
| IMC-1121B (Ramucirumab) + Dacarbazine | Number of Participants With Adverse Events (AE) | Any AE with outcome of death | 2 participants |
| IMC-1121B (Ramucirumab) | Number of Participants With Adverse Events (AE) | RAM related TEAE leading to discontinuation of RAM | 4 participants |
| IMC-1121B (Ramucirumab) | Number of Participants With Adverse Events (AE) | Any RAM related TEAE | 40 participants |
| IMC-1121B (Ramucirumab) | Number of Participants With Adverse Events (AE) | RAM related death | 1 participants |
| IMC-1121B (Ramucirumab) | Number of Participants With Adverse Events (AE) | RAM related SAE | 5 participants |
| IMC-1121B (Ramucirumab) | Number of Participants With Adverse Events (AE) | Any AE with outcome of death | 2 participants |
| IMC-1121B (Ramucirumab) | Number of Participants With Adverse Events (AE) | RAM related ≥ Grade 3 AE | 13 participants |
Secondary
Percentage of Participants With Complete Response (CR) or Partial Response (PR) [Overall Response Rate (ORR)]
The ORR was defined as the percentage of all randomized participants with the best overall response of PR or CR using Response Evaluation Criteria in Solid Tumors (RECIST v1.0). CR was defined as the disappearance of all target and non-target lesions. PR was defined as at least a 30% decrease in sum of longest diameter of target lesions. CR and PR had to be confirmed by repeat assessments and performed no fewer than 4 weeks after the criteria for response were first met.
Time frame: Cycle 1 Day 1 (of 21-day cycle) up to 17.1 months
Population: Intent-to-Treat Population: All enrolled participants who were treated with any quantity of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMC-1121B (Ramucirumab) + Dacarbazine | Percentage of Participants With Complete Response (CR) or Partial Response (PR) [Overall Response Rate (ORR)] | 17.3 percentage of participants |
| IMC-1121B (Ramucirumab) | Percentage of Participants With Complete Response (CR) or Partial Response (PR) [Overall Response Rate (ORR)] | 4.0 percentage of participants |
Secondary
Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Response Rate) at 12 Weeks
Response rate was defined as a CR or a PR using Response Evaluation Criteria in Solid Tumors (RECIST v1.0). CR was defined as the disappearance of all target and non-target lesions and the normalization of non-target lesion tumor marker levels. PR was defined as at least a 30% decrease from baseline in sum of longest diameter of target lesions. CR and PR had to be confirmed by repeat assessments and performed no fewer than 4 weeks after the criteria for response were first met.
Time frame: 12 weeks (4 cycles of treatment)
Population: Intent-to-Treat Population: All enrolled participants who were treated with any quantity of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMC-1121B (Ramucirumab) + Dacarbazine | Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Response Rate) at 12 Weeks | 13.5 percentage of participants |
| IMC-1121B (Ramucirumab) | Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Response Rate) at 12 Weeks | 4.0 percentage of participants |
Secondary
Percentage of Participants With Stable Disease (SD) or Better (Disease Control Rate) at 12 Weeks
Disease Control Rate (DCR) was defined as complete response (CR) plus partial response (PR) plus SD using Response Evaluation Criteria in Solid Tumors (RECIST v1.0). CR was defined as the disappearance of all target and non-target lesions and the normalization of non-target lesion tumor marker levels. PR was defined as at least a 30% decrease from baseline in sum of longest diameter of target lesions. CR and PR had to be confirmed by repeat assessments and performed no fewer than 4 weeks after the criteria for response were first met. Stable Disease (SD) was defined as: neither sufficient increase to qualify for progressive disease (PD) nor sufficient shrinkage to qualify for PR, taking as reference the smallest sum of the longest diameters recorded since treatment began. PD was defined as at least 20% increase in sum of longest diameter of target lesions.
Time frame: 12 weeks (4 cycles of treatment)
Population: Intent-to-Treat Population: All enrolled participants who were treated with any quantity of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMC-1121B (Ramucirumab) + Dacarbazine | Percentage of Participants With Stable Disease (SD) or Better (Disease Control Rate) at 12 Weeks | 40 percentage of participants |
| IMC-1121B (Ramucirumab) | Percentage of Participants With Stable Disease (SD) or Better (Disease Control Rate) at 12 Weeks | 24 percentage of participants |
Secondary
Percentage of Participants With Stable Disease (SD) or Better (Disease Control Rate) at 6 Weeks
Disease Control Rate (DCR) was defined as complete response (CR) plus partial response (PR) plus SD using Response Evaluation Criteria in Solid Tumors (RECIST v1.0). CR was defined as the disappearance of all target and non-target lesions and the normalization of non-target lesion tumor marker levels. PR was defined as at least a 30% decrease from baseline in sum of longest diameter of target lesions. CR and PR had to be confirmed by repeat assessments and performed no fewer than 4 weeks after the criteria for response were first met. SD was defined as: neither sufficient increase to qualify for progressive disease (PD) nor sufficient shrinkage to qualify for PR, taking as reference the smallest sum of the longest diameters recorded since treatment began. PD was defined as at least 20% increase in sum of longest diameter of target lesions.
Time frame: 6 weeks (2 cycles of treatment)
Population: Intent-to-Treat Population: All enrolled participants who were treated with any quantity of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMC-1121B (Ramucirumab) + Dacarbazine | Percentage of Participants With Stable Disease (SD) or Better (Disease Control Rate) at 6 Weeks | 54 percentage of participants |
| IMC-1121B (Ramucirumab) | Percentage of Participants With Stable Disease (SD) or Better (Disease Control Rate) at 6 Weeks | 44 percentage of participants |