MAGE-C2 TCR T Cell Trial to Treat Melanoma and Head and Neck Cancer

Study Overview
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Brief Summary
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Single-centre, first-in-man phase I/II trial to demonstrate safety and efficacy of MAGE-C2/HLA-A2 TCR T cells (MC2 TCR T cells) in advanced melanoma (MEL) and head-and-neck carcinoma (HNSCC).

Detailed Description
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In this patient study, the investigators target the Cancer Germline Antigen (CGA) MAGE-C2 (MC2), and use T cells with a young phenotype. MC2 is highly expressed in melanoma (MEL) and head-and-neck squamous cell carcinoma (HNSSC), but not in healthy adult tissues. The investigators isolated MC2-specific TCRs from MEL patients who showed clinical responses following vaccination that were accompanied by significant frequencies of anti-MC2 CD8 T cells in blood and tumor without apparent side effects. Following extensive evaluation of in vitro anti-tumor and self-reactivities, the investigators have selected a TCR that recognizes the ALK epitope in the context of HLA-A2 for clinical development. Furthermore, preclinical studies showed that epigenetic pretreatment of tumor cells, but not normal cells, up-regulated MC2 gene expression and resulted in enhanced recognition of MC2 by the selected TCR. In parallel to the above studies, the investigators renewed their GMP protocol to process T cells, using stimulating antibodies and cytokines, to generate T cells with a young phenotype. In the current phase I/II study, the investigators explore the safety and anti-tumor efficacy of T cells engineered with the selected TCR in patients with MC2-positive MEL and HNSSC. The study contains the following unique elements: CGA not targeted before by T cell therapy New T cell processing method to generate young T cells Pretreatment of patients with epigenetic drugs No chemotherapy prior to T cell infusion Leads: Clinical PI: Astrid van der Veldt, MD, PhD Clinical logistics: Karlijn de Joode, MD T cell production: Monique de Beijer, PhD; and Cor Lamers, PhD Coordinator/Preclinical PI: prof. Reno Debets, PhD

Official Title
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Adoptive Therapy With TCR Gene-engineered T Cells to Treat Patients With MAGE-C2-positive Melanoma and Head and Neck Cancer

Conditions
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Melanoma, Melanoma, Uveal, Head and Neck Cancer

Intervention / Treatment
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* Biological: Adoptive therapy with autologous MC2 TCR T cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent; Age ≥ 18 years; One of the following three malignancies: Previously treated for unresectable or metastatic cutaneous or mucosal melanoma for whom no standard treatment is available (anymore); Metastatic uveal melanoma, progressing after standard of care therapy, if available; R/M HSNCC for whom no standard treatment is available anymore; Patients must be HLA-A2*0201 positive; Primary tumor and/or metastasis (archival or fresh biopsy) is positive for MC2 (>5% of tumor cells) according to immunohistochemistry; Measurable disease according to RECIST v1.1; At least one lesion, suitable for sequential mandatory tumor biopsies; ECOG performance status of 0 or 1. Life expectancy ≥ 12 weeks; Patients with melanoma must have had objective evidence of disease progression while on or after standard systemic therapy. The last dose of prior therapy (e.g. anti- PD-1, chemotherapy) must have been received more than 4 weeks prior to the start of study treatment. For melanoma patients who are treated with BRAF- and MEK inhibitors, an interval of 2 weeks between discontinuation of BRAF- and MEK inhibition and start of study treatment is sufficient; Patients with R/M HNSCC must have had objective evidence of disease progression and are ineligible for or unwilling to get platinum-based chemotherapy or for whom no standard treatment is available; Patients of both genders must be willing to practice a highly effective method of birth control during treatment and for four months after receiving the preparative regimen; Patients must meet the following laboratory values at the screening visit in the absence of growth factors and/or transfusion support: Hematology: absolute neutrophil count greater than 1.5x10^9/L; platelet count greater than 75x10^9/L; hemoglobin greater than 5 mmol/L or 8.0 in g/dl; Chemistry: serum ALAT/ASAT less than 3 times the upper limit of normal (ULN), unless patients have liver metastasis (<5 times ULN); serum creatinine < 1.5 ULN; total bilirubin ≤ 20 micromol/L, except in patients with Gilbert's Syndrome who must have a total bilirubin ≤ 50 micromol/L; Serology: seronegative for HIV antibody; seronegative for hepatitis B antigen, and hepatitis C antibody; seronegative for lues. Exclusion Criteria: Subjects who meet any of the following criteria will be excluded from participation of this study: presence of symptomatic brain metastasis. Note: subjects with symptomatic brain lesions who have been definitively treated with stereotactic radiation therapy, surgery, or gamma knife therapy are eligible; Presence of active brain metastasis defined as new or progressive brain metastasis at the time of study entry. Note: subjects with treated or stable brain metastasis are eligible; Presence of leptomeningeal metastasis; Presence of malignant pleural effusion or ascites; Systemic chronic steroid therapy (>10 mg/day prednisone or equivalent) or any other immunosuppressive therapy within 7 days prior to leukapheresis or 72 hours prior to infusion of the MC2 TCR T cells. Note: local steroids such as topical, inhaled, nasal and ophthalmic steroids are allowed; Active, known or suspected autoimmune disease or a documented history of autoimmune disease. Note: subjects with vitiligo, controlled type 1 diabetes mellitus on stable insulin dose, residual autoimmune-related hypothyroidism only requiring hormone replacement or psoriasis not requiring systemic treatment are permitted; Any active systemic infections, coagulation disorders or other active major medical illnesses, such as active autoimmune diseases requiring anti-TNF treatment; History of myocardial infarction, cardial angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 6 months of enrollment; AEs of previous treatment. Toxicities associated with prior systemic and non- systemic treatment must have recovered to a grade 1 or less. Patients may have undergone minor surgical procedures or palliative radiotherapy (for non-target lesions) within the past 4 weeks, as long as all toxicities have recovered to grade 1 or less; Women who are pregnant or breastfeeding. A negative pregnancy test before inclusion in the trial is required for all women of child bearing age; Use of any live vaccines against infectious diseases within the last 3 months; Active infection requiring systemic antibiotic therapy at start of study treatment; Prior allogenic bone marrow or solid organ transplant; History of known hypersensitivity to any of the investigational drugs used in this study; Malignant disease, other than being treated in this study. Exceptions to this exclusion include the following: malignancies that were treated curatively and have not recurred within 2 years prior to start of study treatment, completely resected basal cell and squamous cell skin cancers and any completely resected carcinoma in situ.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Adoptive therapy with autologous MC2 TCR T cells<br>Accelerated titration phase I design and a subsequent single arm phase II study Prior to T cell transfer (day 0), patients will be treated with valproic acid (dose 50 mg/kg/d, 7d; days -9 to day -3) and 5' azacytidine (dose 75mg/m2/d, 7d; days -9 to day -3) Phase I: patients will be treated with one single intravenous administration of MC2 TCR T cells at 5 different escalated doses of 5x10E7, 5x10E8, 5x10E9,1.0x10E10, and the total number of cultured TCR T cells (i.e., usually 1.0-5.0 x10E10 TCR T cells). MC2 TCR T cell infusions will be supported by low dose of IL-2 administrations (s.c. 5x10E5 IU/m2 2qd for 5 days) T cells will be processed using IL-15 and IL-21 to generate young T cells | Biological: Adoptive therapy with autologous MC2 TCR T cells<br>* Adoptive therapy with autologous MC2 TCR T cells combined with AZA/VP<br>* Other names: Interleukin 2 (IL2);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of MC2 TCR T cells | MTD is determined using an accelerated titration phase with T cell doses as described in treatment arm; AEs are recorded according to CTCAE 5.0 | 1 year | 
| Objective anti-tumor responses of MC2 TCR T cells | Anti-tumor responses are recorded according to RECIST v1.1 using the MTD from outcome 1 | 2 years |