An Open-Label, Dose-Escalation Study of IMC-20D7S In Participants With Malignant Melanoma

Study Overview
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Brief Summary
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A dose-escalation study designed to determine the safety, maximum tolerated dose (MTD), anti-melanoma activity, antibody blood levels and progression-free survival (PFS) in participants with malignant melanoma receiving IMC-20D7S either every 2 weeks or every 3 weeks.

Official Title
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An Open-Label, Dose-Escalation Phase 1/1b Study of the Anti-gp75 Monoclonal Antibody IMC-20D7S In Patients With Malignant Melanoma Who Have Progressed After or During at Least One Treatment With Standard Cytotoxic Treatment or/and Immunotherapy Therapy or For Whom Standard Therapy is Not Indicated

Conditions
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Malignant Melanoma

Intervention / Treatment
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* Biological: IMC-20D7S (Cohort 1A)
* Biological: IMC-20D7S (Cohort 2A)
* Biological: IMC-20D7S (Cohort 3A)
* Biological: IMC-20D7S (Cohort 4A)
* Biological: IMC-20D7S (Cohort 1B)
* Biological: IMC-20D7S (Cohort 2B)
* Biological: IMC-20D7S (Cohort 3B)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant has histologically or cytologically confirmed cutaneous, mucosal, or uveal malignant melanoma which has progressed after or during at least 1 treatment with standard cytotoxic treatment or/and immunotherapy [for example (e.g.), treatment with cytokines, monoclonal antibodies, and vaccines] and is not regarded to be a candidate for a potentially curative, higher priority treatment for melanoma Participant is ≥18 years of age Participant has either measurable disease as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) or evaluable disease At least 21 days must have elapsed from major surgery, prior chemotherapy, prior treatment with an investigational agent or device, or prior radiation therapy. Relative to participant's treatment with non-approved biological products (eg, monoclonal antibodies), a minimum of 2 half-lives must have passed for eligibility to be considered Participant has resolution of all clinically significant toxic effects of prior cancer therapy to Grade ≤1 according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.02 (NCI-CTCAE v4.02) Participant has adequate hematological function, hepatic function, and renal function Exclusion Criteria: Participant has undergone major surgery [e.g., laparotomy, thoracotomy, removal of organ(s)] within 21 days prior to study entry Participant has elective or planned surgery to be conducted during the trial Participant has documented and/or symptomatic brain or leptomeningeal metastases Participant is receiving systemic steroids or other immunosuppressive medications. (Intermittent use of steroid-containing medications e.g., for asthma exacerbation or for skin lesions is permitted) Participant has an uncontrolled undercurrent illness Participant has a concurrent active malignancy other than adequately treated nonmelanomatous skin cancer or other noninvasive carcinoma or in situ neoplasm Participant has a known allergy to any of the treatment components (monoclonal antibodies or other therapeutic proteins such as fresh frozen plasma, human serum albumin, cytokines, or interleukins). In the event that there is suspicion the participant may have allergies, the participant should be excluded Participant is pregnant or lactating Participant has known human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS) infection

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IMC-20D7S (1A-4A Cohorts)<br>Escalating doses up to 30 milligrams per kilogram (mg/kg) administered intravenously (i.v.) every 2 weeks; includes Cohorts 1A, 2A, 3A, and 4A. | Biological: IMC-20D7S (Cohort 1A)<br>* 5 mg/kg i.v. every 2 weeks. Administered every other week on Days 1 and 15 of each treatment cycle. If no dose-limiting toxicity (DLT) in first 3 participants or 1 DLT in 6 participants, then enrollment into Cohort 2A.<br>* Other names: LY3012215;Biological: IMC-20D7S (Cohort 2A)<br>* 10 mg/kg i.v. every 2 weeks. Administered every other week on Days 1 and 15 of each treatment cycle. If no DLT in first 3 participants or 1 DLT in 6 participants in Cohort 2A, then enrollment into Cohort 3A.<br>* Other names: LY3012215;Biological: IMC-20D7S (Cohort 3A)<br>* 20 mg/kg i.v. every 2 weeks. Administered every other week on Days 1 and 15 of each treatment cycle. If no DLT in first 3 participants or 1 DLT in 6 participants in Cohort 3A, then enrollment into Cohort 4A.<br>* Other names: LY3012215;Biological: IMC-20D7S (Cohort 4A)<br>* 30 mg/kg i.v. every 2 weeks. Administered every other week on Days 1 and 15 of each treatment cycle.<br>* Other names: LY3012215;|
| Experimental: IMC-20D7S (1B-3B Cohorts)<br>Escalating doses up to 30 mg/kg administered i.v. every 3 weeks; includes Cohorts 1B, 2B, and 3B. | Biological: IMC-20D7S (Cohort 1B)<br>* 10 mg/kg i.v. every 3 weeks. Administered every 3 weeks on Days 1 and 22 of each treatment cycle. If no dose-limiting toxicity (DLT) in first 3 participants or 1 DLT in 6 participants in Cohort 1B, then enrollment into Cohort 2B.<br>* Other names: LY3012215;Biological: IMC-20D7S (Cohort 2B)<br>* 20 mg/kg i.v. every 3 weeks. Administered every 3 weeks on Days 1 and 22 of each treatment cycle. If no DLT in first 3 participants or 1 DLT in 6 participants in Cohort 2B, then enrollment into Cohort 3B.<br>* Other names: LY3012215;Biological: IMC-20D7S (Cohort 3B)<br>* 30 mg/kg i.v. every 3 weeks. Administered every 3 weeks on Days 1 and 22 of each treatment cycle.<br>* Other names: LY3012215;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of IMC-20D7S | The MTD was defined as the dose preceding the dose level at which 2 participants experienced a dose-limiting toxicity (DLT) during treatment Cycle 1. A DLT was defined as any Grade 3 or above toxicity that emerged during study treatment and was clearly not attributable to malignant melanoma or co-medication and was possibly, probably, or definitely related to IMC-20D7S in the judgment of the investigator. No DLT was observed in the study; a provisional MTD was established. | Baseline to toxicity [up to end of Cycle 1 (4 or 6-week cycles)] | 
| Number of Participants With Serious Adverse Events (SAEs), Other Non-Serious Adverse Events (AEs), or Death | A summary of SAEs and other non-serious AEs, regardless of causality, is located in the Reported Adverse Event module. | Baseline through 30 days post last dose (up to 31 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| IMC-20D7S Pharmacokinetics (PK): Maximum Concentration (Cmax) | A non-validated assay was used to determine individual serum concentrations of IMC-20D7S. Thus, analyses of PK data were not conducted. | Cycles 1 and 3: Prior to, immediately after, and 0.5, 1, 2, 4, 8, 24, 48 (Cycle 3 only), 96, 168, 240, and 336 hours (h) post first infusion. Cycles 2 and 4: Prior to and 1 h post first infusion. | 
| IMC-20D7S PK: Minimal Concentration (Cmin) | A non-validated assay was used to determine individual serum concentrations of IMC-20D7S. Thus, analyses of PK data were not conducted. | Cycles 1 and 3: Prior to, immediately after, and 0.5, 1, 2, 4, 8, 24, 48 (Cycle 3 only), 96, 168, 240, and 336 h post first infusion. Cycles 2 and 4: Prior to and 1 h post first infusion. | 
| IMC-20D7S PK: Half-life (t½) | A non-validated assay was used to determine individual serum concentrations of IMC-20D7S. Thus, analyses of PK data were not conducted. | Cycles 1 and 3: Prior to, immediately after, and 0.5, 1, 2, 4, 8, 24, 48 (Cycle 3 only), 96, 168, 240, and 336 h post first infusion. Cycles 2 and 4: Prior to and 1 h post first infusion. | 
| IMC-20D7S PK: Clearance (Cl) | A non-validated assay was used to determine individual serum concentrations of IMC-20D7S. Thus, analyses of PK data were not conducted. | Cycles 1 and 3: Prior to, immediately after, and 0.5, 1, 2, 4, 8, 24, 48 (Cycle 3 only), 96, 168, 240, and 336 h post first infusion. Cycles 2 and 4: Prior to and 1 h post first infusion. | 
| IMC-20D7S PK: Area Under the Concentration Versus Time Curve (AUC) | A non-validated assay was used to determine individual serum concentrations of IMC-20D7S. Thus, analyses of PK data were not conducted. | Cycles 1 and 3: Prior to, immediately after, and 0.5, 1, 2, 4, 8, 24, 48 (Cycle 3 only), 96, 168, 240, and 336 h post first infusion. Cycles 2 and 4: Prior to and 1 h post first infusion. | 
| IMC-20D7S PK: Volume of Distribution (Vd) at Steady State | A non-validated assay was used to determine individual serum concentrations of IMC-20D7S. Thus, analyses of PK data were not conducted. | Cycles 1 and 3: Prior to, immediately after, and 0.5, 1, 2, 4, 8, 24, 48 (Cycle 3 only), 96, 168, 240, and 336 h post first infusion. Cycles 2 and 4: Prior to and 1 h post first infusion. | 
| Number of Participants Who Develop Antibodies Against IMC-20D7S (Immunogenicity) | Planned analyses for immunogenicity were not completed. A decision was made not to develop a validated immunogenicity assay because of the exploratory nature of the study and the analyses. | Prior to the first and second infusion in each cycle up to Cycle 7 (4- and 6-week cycles) | 
| Progression-Free Survival (PFS) | PFS was determined for participants who went beyond their first disease assessment and completed at least 1 treatment beyond Week 1 of treatment Cycle 3. | First dose to disease progression or death (up to 27 weeks) | 
| Recommend Doses for Phase 2/3 Studies Based on MTD | It was decided for administrative reasons to discontinue dosing at the provisional MTD rather than progress to Phase 1b. | Baseline to toxicity [up to end of Cycle 1 (4-or 6-week cycles)] | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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glycoprotein, Melanoma, Phase I, antibody, melanin, tyrosinase related protein 1, 20D7S