NY-ESO-1-redirected T Cells in Patients With Advanced Melanoma and Sarcoma
Trial statusRecruiting
Trial phasePhase 1
Trial typeInterventional
Biological sexAll
Age18+
SponsorCentre Hospitalier Universitaire Vaudois
About this trial
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 criteria
This trial does not accept healthy volunteersQualifiers
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.
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.
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.
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.
Disqualifiers
Patients with an active second malignancy
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.
History of idiopathic pulmonary fibrosis or evidence of active pneumonitis (any origin). History of radiation pneumonitis in the radiation field (fibrosis) is allowed.
History of recent myocardial infarction, or unstable angina, within six months prior to enrolment
Trial design
Design model
Single group
Treatments tested in this trial
NY-ESO-1 TCR redirected autologous T cell product
Biological/VaccineEx 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
Radiation1Gy will be administered using tomotherapy (Accuray) to all irradiable lesions, to all cohorts before the (first) LauT-1 infusion.
Non-myeloablative lymphodepleting chemotherapy
DrugCohort 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.
Treatment groups
9 Participants
are divided into 1 treatment groupGroup A: Single arm studyOther 3 interventions
Trial outcomes
Primary outcomes
1
Safety as measured by the incidence of treatment emergent adverse events
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.
Time frame
90 days following (first) LauT-1 infusion2
Feasibility as measured by the rates of production failure and drop-outs before infusion
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
Time frame
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)3
Maximum tolerated dose (MTD) for LauT-1 (applies to Cohorts 2 and 3)
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.
Time frame
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)Secondary outcomes
1
Long term safety as measured by the incidence of TEAE
Evaluated by documenting clinical and laboratory abnormalities, absence of replication-competent lentivirus, absence of abnormal clonal proliferation and organ toxicity using the MedDRA classification and the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE v5.0).
Time frame
24 months2
Objective response rate (ORR)
Evaluated according to Response Evaluation Criteria In Solid Tumors 1.1 (RECIST 1.1), overall and by cohort. ORR is defined as the rate of patients with best overall response objective response (Complete Response (CR) or Partial Response (PR)) within the first 90 days following LauT-1 infusion.
Time frame
90 days for each patient3
Disease control rate (DCR)
Evaluated according to RECIST 1.1, overall and by cohort. DCR is defined as the rate of patients with best overall response stable disease (for at least 3 months) or objective response (CR or PR) across all assessment time-points during the period from enrollment to termination of follow-up or progression (if it occurs before the end of follow-up).
Time frame
2 years4
Progression-free survival (PFS)
Is evaluated at 6, 12 and 24 months, where PFS is defined as the time from enrolment until objective tumor progression (using RECIST criteria) or death, if not documented progression.
Time frame
24 monthsSponsors and contacts
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Source ClinicalTrials.gov