A Study of IMC-1121B (Ramucirumab) With or Without Dacarbazine in Metastatic Malignant Melanoma

Study Overview
=================
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.

Official Title
-----------------
Phase II Randomized, Open-Label Study of IMC-1121B With or Without Dacarbazine in Patients With Metastatic Malignant Melanoma

Conditions
-----------------
Metastatic Malignant Melanoma

Intervention / Treatment
-----------------
* Biological: IMC-1121B (ramucirumab)
* Drug: Dacarbazine


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IMC-1121B (ramucirumab)<br>IMC-1121B (ramucirumab) | Biological: IMC-1121B (ramucirumab)<br>* 10 milligrams/kilogram (mg/kg) intravenously every 3 weeks in the absence of disease progression, unacceptable toxicity, or other withdrawal criteria.<br>* Other names: LY3009806;|
| Active Comparator: IMC-1121B (ramucirumab) + dacarbazine<br>IMC-1121B (ramucirumab) + dacarbazine | Biological: IMC-1121B (ramucirumab)<br>* 10 milligrams/kilogram (mg/kg) intravenously every 3 weeks in the absence of disease progression, unacceptable toxicity, or other withdrawal criteria.<br>* Other names: LY3009806;Drug: Dacarbazine<br>* 1000 milligrams/square meter (mg/m2) intravenously every 3 weeks in the absence of disease progression, unacceptable toxicity, or other withdrawal criteria.<br>* Other names: Carboxamide;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline up to 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline up to 40 months | 
| 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. | Cycle 1 Day 1 (of 21-day cycle) up to 17.1 months | 
| 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. | Cycle 1 Day 1 (of 21-day cycle) up to 17.1 months | 
| 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. | 6 weeks (2 cycles of treatment) | 
| 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. | 12 weeks (4 cycles of treatment) | 
| 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. | 12 weeks (4 cycles of treatment) | 
| Maximum Concentration (Cmax) for Cycle 1 Day 1 | Cmax was not calculated due to sparse sampling. | Cycle 1 Day 1 (21-day cycle) 1-hour post infusion | 
| Maximum Concentration (Cmax) for Cycle 1 Day 7 | Cmax was not calculated due to sparse sampling. | Cycle 1 Day 7 (21-day cycle) | 
| Maximum Concentration (Cmax) for Cycle 1 Day 14 | Cmax was not calculated due to sparse sampling. | Cycle 1 Day 14 (21-day cycle) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Phase II, Melanoma, IMC-1121B, ImClone