MC2TCR: MAGE-C2 TCR T Cell Trial to Treat Melanoma and Head and Neck Cancer
Study Details
Study Description
Brief Summary
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).
Condition or Disease | Intervention/Treatment | Phase |
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Phase 1/Phase 2 |
Detailed Description
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:
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CGA not targeted before by T cell therapy
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New T cell processing method to generate young T cells
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Pretreatment of patients with epigenetic drugs
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No chemotherapy prior to T cell infusion
Leads:
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Clinical PI: Astrid van der Veldt, MD, PhD
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Clinical logistics: Karlijn de Joode, MD
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T cell production: Monique de Beijer, PhD; and Cor Lamers, PhD
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Coordinator/Preclinical PI: prof. Reno Debets, PhD
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Experimental: Adoptive therapy with autologous MC2 TCR T cells 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
Adoptive therapy with autologous MC2 TCR T cells combined with AZA/VP
Other Names:
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Outcome Measures
Primary Outcome Measures
- Maximum Tolerated Dose (MTD) of MC2 TCR T cells [1 year]
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
- Objective anti-tumor responses of MC2 TCR T cells [2 years]
Anti-tumor responses are recorded according to RECIST v1.1 using the MTD from outcome 1
Eligibility Criteria
Criteria
Inclusion Criteria:
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Written informed consent;
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Age ≥ 18 years;
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One of the following three malignancies:
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Previously treated for unresectable or metastatic cutaneous or mucosal melanoma for whom no standard treatment is available (anymore);
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Metastatic uveal melanoma, progressing after standard of care therapy, if available;
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R/M HSNCC for whom no standard treatment is available anymore;
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Patients must be HLA-A2*0201 positive;
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Primary tumor and/or metastasis (archival or fresh biopsy) is positive for MC2 (>5% of tumor cells) according to immunohistochemistry;
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Measurable disease according to RECIST v1.1;
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At least one lesion, suitable for sequential mandatory tumor biopsies;
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ECOG performance status of 0 or 1. Life expectancy ≥ 12 weeks;
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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;
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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;
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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;
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Patients must meet the following laboratory values at the screening visit in the absence of growth factors and/or transfusion support:
Hematology:
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absolute neutrophil count greater than 1.5x10^9/L;
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platelet count greater than 75x10^9/L;
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hemoglobin greater than 5 mmol/L or 8.0 in g/dl;
Chemistry:
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serum ALAT/ASAT less than 3 times the upper limit of normal (ULN), unless patients have liver metastasis (<5 times ULN);
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serum creatinine < 1.5 ULN;
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total bilirubin ≤ 20 micromol/L, except in patients with Gilbert's Syndrome who must have a total bilirubin ≤ 50 micromol/L;
Serology:
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seronegative for HIV antibody;
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seronegative for hepatitis B antigen, and hepatitis C antibody;
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seronegative for lues.
Exclusion Criteria:
Subjects who meet any of the following criteria will be excluded from participation of this study:
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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;
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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;
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Presence of leptomeningeal metastasis;
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Presence of malignant pleural effusion or ascites;
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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;
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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;
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Any active systemic infections, coagulation disorders or other active major medical illnesses, such as active autoimmune diseases requiring anti-TNF treatment;
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History of myocardial infarction, cardial angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 6 months of enrollment;
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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;
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Women who are pregnant or breastfeeding. A negative pregnancy test before inclusion in the trial is required for all women of child bearing age;
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Use of any live vaccines against infectious diseases within the last 3 months;
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Active infection requiring systemic antibiotic therapy at start of study treatment;
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Prior allogenic bone marrow or solid organ transplant;
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History of known hypersensitivity to any of the investigational drugs used in this study;
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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.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | Erasmus Medical Center | Rotterdam | Netherlands | 3015GD |
Sponsors and Collaborators
- Erasmus Medical Center
- Ludwig Institute for Cancer Research
- Dutch Cancer Society
- Stichting Coolsingel Rotterdam grant
- Jan Ivo Stichting grant
Investigators
None specified.Study Documents (Full-Text)
More Information
Publications
None provided.- NL69011.000.19