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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Malignant Melanoma

Intervention / Treatment
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* Drug: Tebentafusp (IMCgp100)
* Drug: durvalumab
* Drug: tremelimumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Written informed consent must be obtained from all patients prior to any study procedures Patients with advanced non-uveal melanoma defined as unresectable stage III or metastatic stage IV disease. Patients with acral or mucosal melanoma are acceptable. Patients with melanoma of unknown primary are acceptable for Phase 1b escalation cohorts (Arms 1 to 5) but are excluded in Phase 2. NOTE: Patients with the diagnosis of UM are excluded from all cohorts Phase 1b (Arm 4 and Arm 5) and Phase 2: Patients with disease progression following initiation of treatment with an approved PD-(L)1 inhibitor. Patients with BRAF mutations should be refractory to approved BRAF-inhibitor if clinically feasible. CTLA 4 inhibition therapy is acceptable as a prior line of therapy or in combination with anti-PD-(L)1 therapy. For Phase 2, no prior chemotherapy in the advanced setting is permitted Phase 1b Arms 1-3: no restriction on prior therapy HLA-A*02:01 positive by central assay or by an 510K approved assay run in CLIA-certified laboratory Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 Life expectancy of at least 3 months Phase 2 cohorts only: Patients must have measurable disease according to RECIST v1.1 criteria. Patients enrolled in Phase 1b cohorts may have either measurable or only non-measurable disease (ie, non-target lesion only) Phase 1b (Arm 4) and Phase 2 cohorts only: Patients must have a site of disease amenable to biopsy (ie, must not also be a target lesion OR if a target lesion must be > 2cm), and be a candidate for tumor biopsy according to the treating institution's guidelines. NOTE: Phase 1b Arms 1-3 and 5 patients are not required to have disease accessible to biopsy For Arms 1-3 only (ie, applies only to patients assigned to receive tebentafusp in combination with checkpoint inhibitor[s]): Those receiving prior immunotherapy must meet all the following conditions: Must not have experienced an immune-related adverse event (irAE) where the irAE was the reason for permanent discontinuation of prior immunotherapy in the most recent prior treatment regimen All irAEs while receiving prior immunotherapy must have resolved to ≤ Grade 1 or baseline prior to screening for this study. Must not have experienced a ≥ Grade 3 immune-related AE within the past 16 weeks or any Grade 4 life-threatening irAE (regardless of duration) or neurologic or ocular AE of any grade while receiving prior immunotherapy. (NOTE: Patients with endocrine AE of any grade are permitted to enroll if they are stably maintained on appropriate replacement therapy, but must have no history of adrenal crisis and be asymptomatic) Patients currently receiving chronic corticosteroid treatment (longer than 8 weeks duration) for management of pre-existing AEs, or patients with a history of chronic corticosteroid treatment longer than 8 weeks duration for AEs within 6 months of screening are excluded Exclusion Criteria: Presence of untreated or symptomatic central nervous system (CNS) metastases, leptomeningeal disease, or cord compression. History of severe hypersensitivity reactions to study medications History of treatment-related interstitial lung disease/pneumonitis Impaired baseline organ function as evaluated by out-of-range laboratory values. Clinically significant cardiac disease or impaired cardiac function Active autoimmune disease or a documented history of autoimmune disease Recent (< 12 months of planned first dose of study treatment) active diverticulitis (Phase 1b combination arms) Active infection requiring systemic antibiotic therapy. NOTE: Patients requiring systemic antibiotics for infection must have completed therapy before planned first dose of study treatment Known history of human immunodeficiency virus (HIV) infection. Testing for HIV status is not necessary unless clinically indicated or if required by local regulation Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, currently requiring medical intervention, per institutional protocol. Testing for HBV or HCV status is not necessary unless clinically indicated or the patient has a history of HBV or HCV infection requiring treatment with currently an unknown status. History of treated hepatitis is not exclusionary Malignant disease, other than that being treated in this study. Exceptions to this exclusion include the following: malignancies that were treated curatively and have not recurred within 2 years after completion of treatment; completely resected basal cell and squamous cell skin cancers; any malignancy considered to be indolent and that has never required therapy; and completely resected carcinoma in situ of any type Any medical condition that would, in the investigator's judgment, prevent the patient's participation in the clinical study due to safety concerns, compliance with clinical study procedures or interpretation of study results Systemic anti-cancer therapy within 2 weeks of the planned first dose of study treatment. For cytotoxic agents that have major delayed toxicity and any prior immunotherapy approach, 3 weeks is indicated as washout period 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 Systemic treatment with steroids or any other immunosuppressive drug use within 4 weeks of the planned first dose of study treatment, with the following exceptions: Treatment for well-controlled and asymptomatic adrenal insufficiency is permitted, but replacement dosing is limited to prednisone ≤ 12 mg daily or the equivalent. Local steroid therapies (eg, optic, ophthalmic, intra-articular, or inhaled medications) are acceptable Premedication for allergy to contrast reagent or premedication regimen instituted per protocol Steroids for management of CNS metastases > 2 weeks prior to the planned first dose of study treatment Use of any live vaccines against infectious diseases within 4 weeks of initiation of study treatment Major surgery as defined by the investigator within 2 weeks of the first dose of study treatment. Radiotherapy within 2 weeks of the first dose of study treatment, with the exception of palliative radiotherapy to a limited field, such as for the treatment of bone pain or a focally painful tumor mass Use of hematopoietic colony-stimulating growth factors (eg, G-CSF, GMCSF, MCSF) ≤ 2 weeks prior start or study treatment. NOTE: Patients must have completed therapy with hematopoietic colony-stimulating factors at least 2 weeks before the first dose of study treatment is given. An erythroid stimulating agent is allowed as long as it was initiated at least 2 weeks prior to the first dose of study treatment and the patient is not red blood cell transfusion dependent Pregnant or breast-feeding women Women of child-bearing potential who are sexually active with a non-sterilized male partner, unless they are using highly effective contraception during study treatment, and must agree to continue using such precautions for 1 week after the final dose of investigational product; cessation of birth control after this point should be discussed with a responsible physician. Male patients must be surgically sterile or use double barrier contraception method and are not allowed to donate sperm from enrollment through treatment and for 3 months following administration of the last dose of study drug Patients who are relatives or dependents of the investigator

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: Arm 1<br>IV Tebentafusp (IMCgp100) with durvalumab (MEDI4736) | Drug: Tebentafusp (IMCgp100)<br>* soluble gp100-specific T cell receptor with anti-CD3 scFV<br>Drug: durvalumab<br>* anti-PD-L1 monoclonal antibody<br>* Other names: MEDI4736;|
| Experimental: Arm 2<br>IV Tebentafusp (IMCgp100) with tremelimumab | Drug: Tebentafusp (IMCgp100)<br>* soluble gp100-specific T cell receptor with anti-CD3 scFV<br>Drug: tremelimumab<br>* anti-CTLA-4 monoclonal antibody<br>|
| Experimental: Arm 3<br>IV Tebentafusp (IMCgp100) with durvalumab (MEDI4736) and tremelimumab | Drug: Tebentafusp (IMCgp100)<br>* soluble gp100-specific T cell receptor with anti-CD3 scFV<br>Drug: durvalumab<br>* anti-PD-L1 monoclonal antibody<br>* Other names: MEDI4736;Drug: tremelimumab<br>* anti-CTLA-4 monoclonal antibody<br>|
| Experimental: Arm 4<br>Tebentafusp (IMCgp100) (single agent) | Drug: Tebentafusp (IMCgp100)<br>* soluble gp100-specific T cell receptor with anti-CD3 scFV<br>|
| Experimental: Arm 5<br>Tebentafusp (IMCgp100) (single agent) subcutaneous injection | Drug: Tebentafusp (IMCgp100)<br>* soluble gp100-specific T cell receptor with anti-CD3 scFV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b Number of dose-limiting toxicities | 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. | 12 months | 
| Phase 2b Objective Response Rate | 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. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Time from the date of first dose until death due to any cause. | 2 years | 
| Safety: AEs and SAEs | Safety incidence and severity of AEs and SAEs including changes in laboratory. parameters, vital signs, and electrocardiograms (ECG). | 2 years | 
| Safety: Tolerability | Dose interruptions | 2 years | 
| Safety: Tolerability | Dose Reductions | 2 years | 
| Safety: Tolerability | Dose Intensity | 2 years | 
| Serum Pharmacokinetics | AUClast : Area under the curve (AUC) from time zero to the last measurable concentration sampling time (tlast) (mass x time x volume-1) | 2 years | 
| Serum Pharmacokinetics | AUCinf : The AUC from time zero to infinity (mass x time x volume-1) | 2 years | 
| Serum Pharmacokinetics | Cmax : Maximum Plasma Concentration | 2 years | 
| Serum Pharmacokinetics | Tmax: The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after single dose administration (time) | 2 years | 
| Serum Pharmacokinetics | t1/2 : Elimination half-life associated with the terminal slope (λz) of a semi logarithmic concentration-time curve (time) | 2 years | 
| Correlation of PD-L1 and gp100 |  | 2 years | 
| Progression Free Survival | Correlation of gp100 and PD-L1 expression by immunohistochemistry evaluated in pre-treatment biopsies with anti-tumor activity. | 2 years | 
| Duration of Response | 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. | 2 years | 
| Time to Response | Time from initiation of therapy to the time that an OR per RECISTv1.1 is achieved. | 2 years | 
| Disease Control Rate | 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. | 2 years | 
| Formation of Anti-drug Antibodies | 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. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IMCgp100, gp100, metastatic cutaneous melanoma, checkpoint inhibitor, PD-1, PD-L1, CTLA-4, durvalumab, tremelimumab, Tebentafusp, Bispecific T cell receptor fusion protein, ImmTAC, Immune mobilizing monoclonal T cell receptor against cancer, Immunotherapy, mucosal melanoma, acral melanoma, tebentafusp (IMCgp100), Kimmtrak