Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

Melanoma

Melanoma, Cutaneous Malignant

Nevus, Pigmented

Nevus

Nevus, Blue

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Acral Lentiginous Melanoma

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Pembrolizumab

Atezolizumab

Immunomodulating Agents

Muromonab-CD3

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Tebentafusp in combination with Pembrolizumab

Straight to on protocol survival follow up including investigators choice of therapy

soluble gp100-specific T cell receptor with anti-CD3 scFV

Tebentafusp

soluble gp100-specific T cell receptor with anti-CD3 scFV in combination with Pembrolizumab

Tebentafusp with Pembrolizumab

Investigators Choice

Immunocore Medical Information

Immunocore Medical Information EU

To evaluate the efficacy and safety of tebentafusp-based regimens tebentafusp monotherapy and in combination with anti-PD1 vs investigator choice (including clinical trials of investigational agents, salvage therapy per local standard of care (SoC), best supportive care (BSC)) on protocol survivor follow up) in patients with advanced non-ocular melanoma

This is a Phase 2/3, multicenter, open-label study to evaluate the efficacy and safety of tebentafusp as monotherapy (Arm A) and in combination with pembrolizumab (Arm B) compared with standard of care or best supportive care (Arm C) in participants with non-ocular advanced melanoma who have progressed on a prior anti-PD(L)1 regimen, received prior ipilimumab and, if the participant has a BRAF mutation, a prior BRAF tyrosine kinase inhibitor (TKI) regimen.

Tebentafusp Regimen Versus Investigator's Choice in Previously Treated Advanced Melanoma (TEBE-AM)

Phase 2/3 Randomized Study of Tebentafusp as Monotherapy and in Combination With Pembrolizumab Versus Investigator's Choice in HLA-A*02:01-positive Participants With Previously Treated Advanced Melanoma (TEBE-AM)

ctDNA reduction on treatment relative to baseline

Incidence and severity of AEs, SAEs and changes from baseline in laboratory parameters, vital signs, and ECGs

Dose Interruptions and discontinuations; Dose Reductions

Tebentafusp concentration. Tebentafusp PK parameters (eg, Cmax, Tmax, Cavg, t1/2)

Immunocore Ltd

Antibodies

Antibodies, Monoclonal

Durvalumab

Immunoglobulins

Tremelimumab

IV Tebentafusp (IMCgp100) with durvalumab (MEDI4736)

IV Tebentafusp (IMCgp100) with tremelimumab

IV Tebentafusp (IMCgp100) with durvalumab (MEDI4736) and tremelimumab

Tebentafusp (IMCgp100) (single agent) subcutaneous injection

Tebentafusp (IMCgp100)

durvalumab

tremelimumab

This study is a Phase Ib/II, multi-center, open-label study of tebentafusp (IMCgp100) as a single agent and in combination with durvalumab (MEDI4736) and/or tremelimumab in metastatic cutaneous melanoma. The purpose of this study is to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and to evaluate the anti-tumor activity of tebentafusp (IMCgp100) in combination with durvalumab (MEDI4736, programmed death-ligand 1 \[PD-L1\] inhibitor), tremelimumab (CLTA-4 inhibitor), and the combination of durvalumab with tremelimumab compared to single-agent tebentafusp (IMCgp100) alone administered as an intravenous or subcutaneous. The study will enroll patients who have metastatic melanoma that is refractory to treatment with an anti-PD-1 inhibitor in the metastatic setting. This study will also evaluate the safety, tolerability, and anti-tumor activity of tebentafusp (IMCgp100) monotherapy in patients with advanced non-uveal melanoma who progressed on prior PD-1 inhibitors approved for the treatment of advanced melanoma; patients with BRAF mutations must be refractory to approved BRAF-based therapy.

Recent biologic evidence indicates that optimal responses to programmed cell death-1 (PD-1) directed therapy require the presence of CD8+ T cells in the tumor microenvironment and thus therapies such as tebentafusp (IMCgp100) that recruit these effector cells to the tumor may overcome pre-existing resistance to checkpoint blockade. This emerging biology of checkpoint inhibitor resistance suggests the combination of tebentafusp (IMCgp100) with checkpoint inhibition may have enhanced activity in patients with pre-existing resistance.

Phase 1b/2 Study of the Combination of IMCgp100 With Durvalumab and/or Tremelimumab in Advanced Cutaneous Melanoma

A Phase Ib/II Open-label, Multi-center Study of the Safety and Efficacy of IMCgp100 in Combination With Durvalumab (MEDI4736) or Tremelimumab or the Combination of Durvalumab and Tremelimumab Compared to IMCgp100 Alone in Patients With Advanced Melanoma

The number of dose-limiting toxicities (DLT) observed during the DLT observation period. DLT observation period for the Arms 1 to 3 Phase Ib cohorts will be the first 2 cycles of treatment (C1D1 until C2D28). The DLT observation period for Arm 4 Phase Ib will be from C1D22 to C2D14. A DLT is defined as an adverse event or abnormal laboratory value that occurs during the relevant DLT period which is assessed as having a suspected relationship to study drug, and unrelated to disease, disease progression, inter-current illness, or concomitant medications, occurs during the DLT Observation Period or is Grade 3 or higher per NCI CTCAE version 4.03, or as specified in the protocol.

Objective Response Rate (RECIST v1.1) Objective response rate, defined as the proportion of patients with a best response of CR or PR based on investigator assessment, as defined in RECIST v1.1.

Time from the date of first dose until death due to any cause.

Safety incidence and severity of AEs and SAEs including changes in laboratory. parameters, vital signs, and electrocardiograms (ECG).

AUClast : Area under the curve (AUC) from time zero to the last measurable concentration sampling time (tlast) (mass x time x volume-1)

AUCinf : The AUC from time zero to infinity (mass x time x volume-1)

Tmax: The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after single dose administration (time)

t1/2 : Elimination half-life associated with the terminal slope (λz) of a semi logarithmic concentration-time curve (time)

Correlation of gp100 and PD-L1 expression by immunohistochemistry evaluated in pre-treatment biopsies with anti-tumor activity.

Time from the date of first documented response until date of documented progression or death in the absence of disease progression. The median duration of response and corresponding 90% confidence interval will be presented.

Time from initiation of therapy to the time that an OR per RECISTv1.1 is achieved.

Proportion of patients with either a best response of PR or CR or with SD over 24 weeks after first dose in the study. The DCR and associated 90% confidence interval will be presented by treatment arm.

Incidence of anti-IMCgp100, anti-durvalumab, and anti-tremelimumab antibody formation following multiple infusions of IMCgp100 alone and in combination with durvalumab and/or tremelimumab.

AstraZeneca

Eye Diseases

Uveal Neoplasms

Eye Neoplasms

Uveal Diseases

Ocular Melanoma

Intraocular Melanoma

Ipilimumab

Dacarbazine

Imidazole

Antineoplastic Agents, Alkylating

Alkylating Agents

Enzyme Inhibitors

Biologic:IMCgp100 (Soluble gp 100-specific T cell receptor with anti - CD3 scFV: IMCgp100)

1 of 3 Investigator's Choice options: Systemic Dacarbazine

1 of 3 Investigator's Choice options: Systemic Ipilimumab

1 of 3 Investigator's Choice options: Systemic Pembrolizumab

IMCgp100 is to be administered at 20 mcg cycle 1 day1, then 30 mcg cycle 1 day 8, then 68 mcg cycle 1 day 15 and weekly thereafter by IV infusion over 15 minutes until confirmed disease progression or unacceptable toxicity

IMCgp100

Dacarbazine is to be administered at 1,000 mg/m2 of body surface area IV infusion every 3 weeks until disease progression or unacceptable toxicity

Ipilimumab is to be administered at 3 mg/kg IV infusion over 90 minutes every 3 weeks for a total of 4 treatments

Pembrolizumab is to be administered at 2 mg/kg IV infusion up to a maximum of 200 mg administered Intravenously over 30 minutes every 3 weeks or 200 mg fixed dose administered intravenously every 3 weeks where approved locally until confirmed disease progression or unacceptable toxicity

To evaluate the overall survival of HLA-A\*0201 positive adult patients with previously untreated advanced UM receiving IMCgp100 compared to Investigator's Choice of dacarbazine, ipilimumab, or pembrolizumab.

This Phase II study is designed to evaluate the safety and efficacy of IMCgp100 compared with Investigator's Choice (dacarbazine, ipilimumab or pembrolizumab) in HLA-A\*0201 positive adult patients with advanced UM treated in the first line setting with no prior systemic or liver-directed chemo-, radio- or immune-therapy administered in the advanced setting (prior surgical resection of liver metastases and adjuvant systemic therapy are acceptable). Comparison of the IMCgp100 efficacy results in this Phase II study will be made with the concurrently randomized arm (Investigator's Choice) with a primary endpoint of overall survival (OS) and secondary efficacy endpoints of progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), and disease control rate (DCR).

Safety and Efficacy of IMCgp100 Versus Investigator Choice in Advanced Uveal Melanoma

A Phase II Randomized, Open-label, Multi-center Study of the Safety and Efficacy of IMCgp100 Compared With Investigator Choice in HLA-A*0201 Positive Patients With Previously Untreated Advanced Uveal Melanoma

Overall survival is defined as the time from randomization to date of death due to any cause.

Safety was defined as the number of participants with treatment emergent adverse events, including laboratory abnormalities, ECG changes, and/or physical examination findings.

Progression free survival (PFS) is defined as the time from randomization to the date of progression (RECIST v1.1) or death due to any cause.

General health status was assessed using the EQ-5D,5L questionnaire, which includes five dimensions (5D): mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 3 scoring levels, where 1 indicates a better health state (no problems) and 3 indicates a worse health state. A positive change indicates improvement.

The EQ-5D VAS score records the participant's self-rated health on a vertical visual analogue scale, with 0 being the worst imaginable health state and 100 being the best imaginable health state. A positive change indicates improvement.

Global health status and quality of life was assessed using the EORTC QLQ-C30 questionnaire. The score range for the EORTC QLQ-C30 is from 0 to 100, with higher scores indicating better functioning and better global health status and health-related quality of life. A positive change indicates improvement.

Serum PK concentrations of tebentafusp were collected over time.

Objective response rate (ORR) is defined as the proportion of patients achieving an objective response (RECIST v1.1).

Duration of response (DOR) is defined as the time from first documented objective response (RECIST v1.1) until the date of documented disease progression.

Disease control rate (DCR) is defined as the proportion of patients with either an objective response or stable disease (RECIST v1.1)

The Safety Analysis Set included all randomized participants who received at least 1 full or partial dose of tebentafusp or investigator's choice. Combining participants into a single group (Investigator's Choice) was pre-specified as part of the study design and data for each treatment in that arm were not analyzed separately. Adverse events were defined as events that were new or worsened during the on-treatment period.

Tebentafusp administered at 20 mcg at Cycle 1 Day 1, 30 mcg at Cycle 1 Day 8, and 68 mcg at Cycle 1 Day 15 by IV infusion and weekly thereafter.

1 of 3 Investigator's Choice options: Systemic Dacarbazine, Ipilimumab or Pembrolizumab. Dacarbazine: administered at 1,000 mg/m2 of body surface area IV infusion every 3 weeks until disease progression or unacceptable toxicity; Ipilimumab: administered at 3 mg/kg IV infusion over 90 minutes every 3 weeks for a total of 4 treatments; Pembrolizumab: administered at 2 mg/kg IV infusion up to a maximum of 200 mg administered Intravenously over 30 minutes every 3 weeks or 200 mg fixed dose administered intravenously every 3 weeks where approved locally until confirmed disease progression or unacceptable toxicity.

Investigator's Choice

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

The Intent-to-treat (ITT) Analysis Set comprises all participants assigned to treatment analyzed by the treatment assignment whether or not the participant received the assigned treatment. Combining participants into a single group as part of the Investigator's Choice arm was pre-specified as part of the study design.

Study Director

The Intent-to-treat (ITT) Analysis Set comprises all participants assigned to treatment analyzed by the treatment assignment whether or not the participant received the assigned treatment. Combining participants into a single group as part of the Investigator's Choice arm was pre-specified as part of the study design; therefore, data per different treatments were not analyzed.

Efficacy: Overall Survival

The Safety Analysis Set includes all randomized participants who received at least 1 full or partial dose of tebentafusp or investigator's choice. Combining participants into a single group as part of the Investigator's Choice arm was pre-specified as part of the study design; therefore, data per different treatments were not analyzed.

Safety: Number of Participants With Treatment Emergent Adverse Events

Efficacy: Progression Free Survival (PFS)

Mobility - Baseline Cycle 1

Mobility - Change at Cycle 3

Mobility - Change at Cycle 5

Mobility - Change at Cycle 9

Mobility - Change at Cycle 13

Mobility - Change at Cycle 17

Mobility - Change at Cycle 21

Mobility - Change at Cycle 25

Mobility - Change at Cycle 29

Mobility - Change at EOT

Self-care - Baseline Cycle 1

Self-care - Change at Cycle 3

Self-care - Change at Cycle 5

Self-care - Change at Cycle 9

Self-care - Change at Cycle 13

Self-care - Change at Cycle 17

Self-care - Change at Cycle 21

Self-care - Change at Cycle 25

Self-care - Change at Cycle 29

Self-care - Change at EOT

Usual activities - Baseline Cycle 1

Usual activities - Change at Cycle 3

Usual activities - Change at Cycle 5

Usual activities - Change at Cycle 9

Usual activities - Change at Cycle 13

Usual activities - Change at Cycle 17

Usual activities - Change at Cycle 21

Usual activities - Change at Cycle 25

Usual activities - Change at Cycle 29

Usual activities - Change at EOT

Pain/Discomfort - Baseline Cycle 1

Pain/Discomfort - Change at Cycle 3

Pain/Discomfort - Change at Cycle 5

Pain/Discomfort - Change at Cycle 9

Pain/Discomfort - Change at Cycle 13

Pain/Discomfort - Change at Cycle 17

Pain/Discomfort - Change at Cycle 21

Pain/Discomfort - Change at Cycle 25

Pain/Discomfort - Change at Cycle 29

Pain/Discomfort - Change at EOT

Anxiety/Depression - Baseline Cycle 1

Anxiety/Depression - Change at Cycle 3

Anxiety/Depression - Change at Cycle 5

Anxiety/Depression - Change at Cycle 9

Anxiety/Depression - Change at Cycle 13

Anxiety/Depression - Change at Cycle 17

Anxiety/Depression - Change at Cycle 21

Anxiety/Depression - Change at Cycle 25

Anxiety/Depression - Change at Cycle 29

Anxiety/Depression - Change at EOT

Quality-of-Life: Change From Baseline in EQ-5D,5L Domain Scores

Baseline Cycle 1

Change at Cycle 3

Change at Cycle 5

Change at Cycle 9

Change at Cycle 13

Change at Cycle 17

Change at Cycle 21

Change at Cycle 25

Change at Cycle 29

Change at EOT

Quality-of-life: Change From Baseline in EQ-5D Visual Analogue Score (VAS)

Quality-of-Life: Change From Baseline in EORTC QLQ-C30 Global Health Status

Cycle 1 Day 1 - End of Infusion

Cycle 1 Day 1 - 12 to 24 hours post-infusion

Cycle 1 Day 8 - End of Infusion

Cycle 1 Day 8 - 12 to 24 hours post-infusion

Cycle 1 Day 15 - End of Infusion

Cycle 1 Day 15 - 12 to 24 hours post-infusion

The PK Analysis Set included participants in the Safety Analysis Set who had at least 1 measurable PK concentration and who had relevant date, time, and dosing data for the sample.

Pharmacokinetics (PK): Tebentafusp Concentration

Efficacy: Objective Response Rate (ORR)

Efficacy: Duration of Response (DOR)

Efficacy: Disease Control Rate (DCR)

Pharmacokinetics: Frequency of Anti-IMCgp100 Antibody Formation

Dacarbazine administered at 1,000 mg/m\^2 of body surface area IV infusion every 3 weeks until confirmed disease progression or unacceptable toxicity.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Tebentafusp Regimen Versus Investigator's Choice in Previously Treated Advanced Melanoma (TEBE-AM)	NCT05549297	Advanced Melano...	Tebentafusp Tebentafusp wit... Investigators C...	18 Years -	Immunocore Ltd
Phase 1b/2 Study of the Combination of IMCgp100 With Durvalumab and/or Tremelimumab in Advanced Cutaneous Melanoma	NCT02535078	Malignant Melan...	Tebentafusp (IM... durvalumab tremelimumab	18 Years -	Immunocore Ltd
Safety and Efficacy of IMCgp100 Versus Investigator Choice in Advanced Uveal Melanoma	NCT03070392	Uveal Melanoma	IMCgp100 Dacarbazine Ipilimumab Pembrolizumab	18 Years - 99 Years	Immunocore Ltd
Safety and Efficacy of IMCgp100 Versus Investigator Choice in Advanced Uveal Melanoma	NCT03070392	Uveal Melanoma	IMCgp100 Dacarbazine Ipilimumab Pembrolizumab	18 Years - 99 Years	Immunocore Ltd
A Cohort IND Expanded Access Program for Supporting Patient Access to Tebentafusp	NCT04960891	Uveal Melanoma	Tebentafusp	18 Years -	Immunocore Ltd

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