Head and Neck Cancer, Melanoma, Melanoma, Uveal
Conditions
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).
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: * 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
Interventions
BIOLOGICALAdoptive therapy with autologous MC2 TCR T cells
Adoptive therapy with autologous MC2 TCR T cells combined with AZA/VP
Sponsors
Ludwig Institute for Cancer Research
Dutch Cancer Society
Stichting Coolsingel Rotterdam grant
Jan Ivo Stichting grant
Erasmus Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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. 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; 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
Netherlands
Contacts
Primary ContactA.A.M. van der Veldt, MD, PhD
Backup ContactR. Debets, PhD, Prof
Outcome results
None listed