A Study of the Intra-Patient Escalation Dosing Regimen With IMCgp100 in Patients With Advanced Uveal Melanoma

Study Overview
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Brief Summary
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IMCgp100-102 is a Phase I/II study of the weekly intra-patient escalation dose regimen with IMCgp100 as a single agent in participants with metastatic uveal melanoma (mUM). According to this regimen, all participants in the trial received 2 weekly doses of IMCgp100 at a dose level below the identified weekly recommended Phase II dose (RP2D-QW) and then a dose escalation commenced at the third weekly dose at C1D15. The Phase I testing of the intra-patient escalation dosing regimen is designed to achieve a higher exposure and maximal plasma concentration of IMCgp100 after doses at Cycle 1 Day 15 (C1D15) and thereafter.

Detailed Description
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This is a Phase I/II clinical study of IMCgp100 in participants with advanced uveal melanoma. This is a Phase I/II study of IMCgp100 administered on a weekly basis with an intra-patient escalation dosing regimen. The intra-patient escalation occurred at the third weekly dose on Cycle 1 Day 15 (C1D15). According to this regimen, all participants in the trial received 2 weekly doses of IMCgp100 at a dose level below the identified weekly recommended Phase II dose (RP2D-QW), and then a dose escalation commenced at the third weekly dose at C1D15 with the goal to achieve a long-term dosing regimen at a dose higher than that identified for the weekly dosing regimen (RP2D-QW). The dose escalation identified the intra-patient escalation regimen (RP2D-IE). The Phase I portion of the study was a standard 3+3 dose escalation design.The recommended Phase II dose of the intra-patient escalation dose regimen (RP2D-IE) was identified and expansion cohorts in metastatic uveal melanoma was accrued based on prior therapy.

Official Title
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A Phase I/II Open-label, Multi-center Study of the Safety and Efficacy of IMCgp100 Using the Intra-patient Escalation Dosing Regimen in Patients With Advanced Uveal Melanoma

Conditions
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Uveal Melanoma

Intervention / Treatment
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* Drug: IMCgp100


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female participants age ≥ 18 years of age at the time of informed consent. Ability to provide and understand written informed consent prior to any study procedures. Histologically or cytologically confirmed diagnosis of metastatic uveal melanoma (mUM). Surgically sterile participants or participants of child-bearing potential who agree to use highly effective methods of contraception during study dosing and for 6 months after last dose of study drug. Human leukocyte antigen (HLA)-A*0201 positive. ECOG Performance Status of 0 or 1 at Screening. Phase 2 will include participants with previously treated uveal melanoma in the metastatic setting. Exclusion Criteria: Presence of symptomatic or untreated central nervous system (CNS) metastases, or CNS metastases that require doses of corticosteroids. History of severe hypersensitivity reactions to other biologic drugs or monoclonal antibodies. Participants with any out-of-range laboratory values. Clinically significant cardiac disease or impaired cardiac function. Active infection requiring systemic antibiotic therapy. Known history of HIV infection. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection per institutional protocol. Participants receiving systemic treatment with systemic steroid therapy or any other immunosuppressive medication at any dose level that would interfere with the action of the study drugs in the opinion of the investigator. Malignant disease, other than that being treated in this study. Any medical condition that would, in the investigator's judgment, prevent participation in the clinical study due to safety concerns, compliance with clinical study procedures or interpretation of study results. Presence of NCI CTCAE ≥ grade 2 toxicity (except alopecia, peripheral neuropathy and ototoxicity, which are excluded if ≥ NCI CTCAE grade 3) due to prior cancer therapy. Pregnant, likely to become pregnant, or lactating women.

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose escalation<br>Dose escalation cohorts of the intra-patient escalation regimen. | Drug: IMCgp100<br>* Bispecific soluble HLA-A2 restricted gp100-specific T-cell receptor fused to anti-CD3<br>* Other names: Kimmtrak;|
| Experimental: Dose expansion<br>Dose expansion cohort with the recommended phase 2 dose of the intra-patient dose escalation regimen. | Drug: IMCgp100<br>* Bispecific soluble HLA-A2 restricted gp100-specific T-cell receptor fused to anti-CD3<br>* Other names: Kimmtrak;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a Dose Limiting Toxicity (DLT) in Phase 1 | Number of participants with a dose limiting toxicity, defined as an adverse event (AE) or abnormal laboratory value assessed as having a suspected relationship to study drug, and unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first cycle of treatment and meets any of the pre-specified criteria. | Up to 49 months | 
| Objective Response Rate in Phase 2 | Objective response rate (ORR) is defined as the percentage of participants with measurable disease with at least 1 visit response of complete response (CR) or partial response (PR) that is confirmed at least 4 weeks later, as defined in RECIST v.1.1 and assessed by an independent central review (ICR). The denominator in the calculation of the ORR is the number of participants in the full analysis set with measurable disease at baseline. | Up to 38 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate in Phase 1 | ORR is defined as the percentage of participants with measurable disease with at least 1 visit response of CR or PR that is confirmed at least 4 weeks later, as defined in RECIST v.1.1 and assessed by an investigator. The denominator in the calculation of the ORR is the number of participants in the full analysis set with measurable disease at baseline. | Up to 49 months | 
| Progression-free Survival | Progression-free survival is defined as the time in months from first dose of study drug until the date of disease progression or death (by any cause in the absence of disease progression) as assessed by RECIST v1.1 by the investigator for Phase 1 and ICR for Phase 2. | Up to 49 months | 
| Disease Control Rate | Disease control rate (DCR) is defined as the percentage of participants with a best overall response of CR or PR or stable disease (SD) recorded at least 24 weeks (± 1 week) after commencement of study drug and prior to any progressive disease (PD) event, as assessed by RECIST v1.1 by the investigator for Phase 1 and ICR for Phase 2. | 24 weeks | 
| Duration of Response | Duration of response (DOR) is defined as the time in months from the date of first documented objective response (CR or PR) until the date of documented disease progression or death by any cause in the absence of disease progression as assessed by RECIST v1.1 by the investigator for Phase 1 and ICR for Phase 2. | Up to 49 months | 
| Time to Response | Time to response (TTR) is defined as the time in months from the date of first dose of study drug until the date of first documented objective response as assessed by RECIST v1.1 by the investigator for Phase 1 and ICR for Phase 2. | Up to 49 months | 
| Overall Survival | Overall survival (OS) is defined as the time in months from the date of first dose of study drug until death due to any cause in general. | Up to 49 months | 
| Minor Response Rate | Rate of minor response (or better) is defined as the proportion of participants with a confirmed CR, PR, or minor response (MinR) as assessed by RECIST v1.1 by the investigator for Phase 1 or ICR for Phase 2, where MinR is a reduction from baseline in sum of diameters between 10%-29%. The sum of diameters is defined as per RECIST v1.1 as the sum of longest diameters or short axis of target lesions (mm). | Up to 49 months | 
| Number of Participants With Treatment Dose Interruptions or Reductions | Tolerability of study treatment was assessed by summarizing the number of participants with dose interruptions or reductions that occurred during the treatment period. | Up to 49 months | 
| Area Under the Plasma Concentration-Time Curve (AUC) of Tebentafusp | The AUC was determined in in dose escalation cohorts. | Cycle 1 Day 1 and Cycle 1 Day 15: predose, end of infusion, and 4 and 8 hours postdose | 
| Maximum Plasma Concentration (Cmax) of Tebentafusp | The Cmax is determined in dose escalation cohorts. | Cycle 1 Day 1 and Cycle 1 Day 15: predose, end of infusion, and 4 and 8 hours postdose | 
| Time to Maximum Plasma Concentration (Tmax) of Tebentafusp | The Tmax of tebentafusp is determined in dose escalation cohorts. | Cycle 1 Day 1 and Cycle 1 Day 15: predose, end of infusion, and 4 and 8 hours postdose | 
| Apparent Terminal Plasma Half-life (t½) of Tebentafusp | The t½ of tebentafusp is reported in dose escalation cohorts. | Cycle 1 Day 1 and Cycle 1 Day 15: predose, end of infusion, and 4 and 8 hours postdose | 
| Percentage of Participants With Anti-IMCgp100 Antibody Formation | Overall antidrug antibody (ADA) is presented as number of ADA-positive participants relative to total number of participants with evaluable ADA results in each cohort | Up to 49 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tebentafusp, IMCgp100, gp100, metastatic melanoma, ImmTAC, Immunotherapy, Bispecific T cell receptor fusion protein, Immune mobilizing monoclonal T cell receptor, against cancer, UM, mUM, Kimmtrak