NY-ESO-1 TCR redirected autologous T cell productLow-dose irradiationNon-myeloablative lymphodepleting chemotherapy
NY-ESO-1 TCR redirected autologous T cell product: Ex vivo expanded autologous CD4+/CD8+ cells expressing the transgenic TCR I53F recognizing NY-ESO-1 peptides presented on tumor cells in the context of HLA-A\*02.
Cohort 1: The LauT-1-ACT infusion contains a minimum of 3x10\^8 transduced cells (i.e. CD3+vβ13.1+) and a maximum of 1x10\^10 total cells.
Cohort 2 : Patients will receive a fixed dose of 3x10\^8 transduced LauT-1 cells (i.e. CD3+vβ13.1+) split over 2 administrations.
Cohort 3: Patients will receive a fixed dose of 6x10\^8 transduced LauT-1 cells (i.e. CD3+vβ13.1+) split over 2 administrations.
Low-dose irradiation: 1Gy will be administered using tomotherapy (Accuray) to all irradiable lesions, to all cohorts before the (first) LauT-1 infusion.
Non-myeloablative lymphodepleting chemotherapy: Cohort 1: Fludarabine (30 mg/m2 per day, from D-6 to D-3) and cyclophosphamide (2400 mg/ m2 x 2 days, on days -6 and -5) are administered as an IV infusion. The cyclophosphamide dose may be reduced to 1800mg/m2 on days -6 and -5, if the patient has previously been exposed to significant cumulative doses of chemotherapy).
Cohorts 2 and 3: Fludarabine (30 mg/m2 per day, from D-6 to D-3) and cyclophosphamide (900 mg/ m2 x 2 days, on days -6 and -5) are administered as an IV infusion.
Study summary
A single center, dose escalaion, Phase I clinical trial to demonstrate safety and efficacy of LauT-1, autologous "New York Esophageal Squamous Cell Carcinoma-1 T-Cell Receptor (NY-ESO-1 TCR)-directed T cells in combination with non-myeloablative (NMA) lymphodepleting chemotherapy and low dose irradiation (LDI) in patients with NY-ESO-1 positive sarcoma and melanoma.
Eligibility
Sex
ALL
Min age
18 Years
Max age
—
Healthy volunteers
No
Inclusion criteria at pre-screening
1\) Patients with histologically confirmed advanced or metastatic cutaneous melanoma or any type of sarcoma.
Inclusion criteria at screening
1. Patients with sarcoma, who have received at least one line of standard therapy (if available) and failed to respond, progressed or were intolerant to that therapy, will be eligible. If the participant refuses or is, in the opinion of the investigator, ineligible for these treatments, the reason must be documented in the medical record.
2. Patients with metastatic melanoma:
1. Without proto-oncogene B-Raf (BRAF) mutation who have received at least one line of standard therapy and failed to respond, progressed or were intolerant to that therapy, will be eligible. If the participant refuses or is, in the opinion of the investigator, ineligible for these treatments, the reason must be documented in the medical record.
2. With BRAF mutation who have received at least two lines of standard therapy and failed to respond, progressed or were intolerant to that therapy, will be eligible. If the participant refuses or is, in the opinion of the investigator, ineligible for these treatments, the reason must be documented in the medical record.
3. Patient must have immunohistochemically documented NY-ESO-1 expression, defined as ≥ 1+ expression on either archival or fresh tumor tissue by immunohistochemistry, in ≥50% of the sampled tumor tissue AND HLA-A\*0201 and/or HLA-A\*0205 positive, as identified by high-resolution genomic deoxyribonucleic acid (DNA) typing of the HLA-A locus.
4. Age ≥ 18 years
5. Able to undergo apheresis
6. At least one lesion accessible to biopsy for translational research (TR) at D30, without putting the patient at unusual risk.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
8. Life expectancy of greater than 12 weeks.
9. Radiologically measurable disease (as per RECIST v1.1).
10. Adequate organ function
Exclusion Criteria:
1. Patients with an active second malignancy
2. Patients with symptomatic and/or untreated brain metastases, as well as leptomeningeal carcinomatosis. Patients with definitively treated brain metastases will be considered for enrolment after agreement with the Principal Investigator, as long as lesions are stable, there are no new brain lesions, and the patient does not require chronic corticosteroid treatment.
3. History of idiopathic pulmonary fibrosis or evidence of active pneumonitis (any origin). History of radiation pneumonitis in the radiation field (fibrosis) is allowed.
4. History of recent myocardial infarction, or unstable angina, within six months prior to enrolment
5. Patients with prior allogeneic stem cell transplantation or organ transplantation
6. Active severe systemic infections within 2 weeks prior to apheresis
7. Patient requiring regular systemic immunosuppressive therapy. All immunosuppressive medications including but not limited to steroids, mycophenolate mofetil, azathioprine, methotrexate, thalidomide, and anti-Tumor Necrosis Factor-alpha (TNF-alpha) agents must have been discontinued at least 2 weeks before apheresis .
8. History of severe immediate hypersensitivity reaction to any of the agents/ excipients of the study products.
9. Women who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant.
10. Subjects, for whom there are concerns that they will not reliably comply with the requirements for contraception, should not be enrolled into the study.
11. Any serious underlying medical condition that could interfere with study medication and potential adverse events.
Primary outcome measure(s)
Safety as measured by the incidence of treatment emergent adverse events — 90 days following (first) LauT-1 infusion Safety of LauT-1 plus LDI after lymphodepleting chemotherapy will be established by classifying the observed toxicities by the MedDRA system and grading them using the National Cancer Institute (NCI) Common Toxicity Criteria (CTCAE Version 5.0), American Society for Transplantation and Cellular Therapy (ASTCT) Cytokine Release Syndrom (CRS) or European Hematology Association (EHA) / European Society for Blood and Marrow Transplantation (EBMT) consensus grading for immune effector cell-associated hematotoxicity (ICAHT) , as applicable.
Feasibility as measured by the rates of production failure and drop-outs before infusion — From start of LauT-1 production to administration of intended dose (Cohort 1: 3 weeks after start of LauT-1 production; Cohorts 2-3: second administration of LauT-1 - up to 9 weeks of start of LauT-1 production) Feasibility of LauT-1 production and administration will be evaluated as the number of patients who receive LauT-1 at the intended dose according to the assigned dose-level, among all registered patients
Maximum tolerated dose (MTD) for LauT-1 (applies to Cohorts 2 and 3) — End of TLT period (which extends from the first day of lymphodepleting chemotherapy to D45 after the first LauT-1 infusion, but no less than 30 days after the second LauT-1 infusion (which may extend the 45-day period by 6 days) Defined as the highest LauT-1 dose where no TLTs are observed in at least 3 treated patients, or a maximum of 1 non-lethal TLT is observed in a minimum of 5 treated patients.
Trial sites (2)
Facility
City
Region
Status
Centre Hospitalier Universitaire Vaudois (CHUV)
Lausanne
Canton of Vaud
Not Yet Recruiting
Centre Hospitalier Universitaire Vaudois
Lausanne
Canton of Vaud
Recruiting
More Centre Hospitalier Universitaire Vaudois trials in Switzerland
This page summarises publicly available registry data for informational purposes — not medical advice. Eligibility is determined by each study team; patients should discuss participation with their clinician.
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