Overview

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).

Eligibility

Inclusion Criteria:

1. Written informed consent;
2. Age ≥ 18 years;
3. 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;
4. Patients must be HLA-A2*0201 positive;
5. Primary tumor and/or metastasis (archival or fresh biopsy) is positive for MC2 (>5% of tumor cells) according to immunohistochemistry;
6. Measurable disease according to RECIST v1.1;
7. At least one lesion, suitable for sequential mandatory tumor biopsies;
8. ECOG performance status of 0 or 1. Life expectancy ≥ 12 weeks;
9. 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. antiPD -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;
10. 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;
11. 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;
12. 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:
          1. 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;
          2. 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;
          3. Presence of leptomeningeal metastasis;
          4. Presence of malignant pleural effusion or ascites;
          5. 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;
          6. 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;
          7. Any active systemic infections, coagulation disorders or other active major medical
             illnesses, such as active autoimmune diseases requiring anti-TNF treatment;
          8. History of myocardial infarction, cardial angioplasty or stenting, unstable angina, or
             other clinically significant cardiac disease within 6 months of enrollment;
          9. 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;
         10. Women who are pregnant or breastfeeding. A negative pregnancy test before inclusion in
             the trial is required for all women of child bearing age;
         11. Use of any live vaccines against infectious diseases within the last 3 months;
         12. Active infection requiring systemic antibiotic therapy at start of study treatment;
         13. Prior allogenic bone marrow or solid organ transplant;
         14. History of known hypersensitivity to any of the investigational drugs used in this
             study;
         15. 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.