NY-ESO-1-redirected T Cells in Patients With Advanced Melanoma and Sarcoma

Official title

A Phase I Study Evaluating Safety and Feasibility of Redirected Autologous T Cells Expressing a High Affinity TCR Specific for NY-ESO-1 (LauT-1) in Patients With Advanced Melanoma and Sarcoma

Overview

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.

Detailed description

In this study, the investigators target the cancer testis antigen NY-ESO-1, which is highly expressed in a subset of sarcoma and melanoma but is largely absent in normal tissues. The affinity enhanced, Human Leukocyte Antigen - A2 (HLA-A2) restricted I53F T-cell receptor (TCR) used in this study is derived from a TCR originally isolated from a melanoma patient and recognizes the 157-165 epitope of the NY-ESO-1 protein with high affinity. The patients' own T-cells will be isolated, then genetically modified to express the I53F NY-ESO-1 TCR and expanded to generate the product "LauT-1", which is reinfused into the patients following lymphodepleting chemotherapy (LDCT) and low dose tumor irradiation (LDTI). LDCT allows maximal expansion of the infused T cells, and LDTI has been shown to inflame the tumor microenvironment in preliminary clinical data from recent studies, which may be useful to enhance T-cell infiltration and provide co-stimulatory signals within the tumor microenvironment, thereby maximising the chance to detect and potentially eliminate NY-ESO-1 expressing tumor cells.

In the current phase I study, the investigators assess the safety, maximum tolerated dose (MTD) and feasibility of adoptive transfer of LauT-1 after LDCT and LDTI in HLA-A\*0201 and/or HLA-A\*0205 positive patients with advanced melanoma or sarcoma expressing NY-ESO-1. The experimental products are given initially to a group of 3 patients (safety cohort; cohort 1). If safe, the next 6 patients will be enrolled using a rule-based 3-patient cohort dose-escalation design using split-dosing to determine the MTD of LauT-1 (cohorts 2 and 3).

Procedures:

After confirming the expression of the NY-ESO-1 protein in at least 50% of the tumor cells and the presence of a permissive HLA allele during the pre-screeening procedure, patients eligible for the study will be undergo medical screening and registration to the study, followed by leukapheresis for the collection of autologous white blood cells (T lymphocytes) for the production of the gene-modified LauT-1 product. After successful leukapheresis, patients are allowed to receive a bridging therapy at the discretion of the PI/treating physician.

If all conditions are met and LauT-1 production is completed, the patient will start intravenous (IV) non-myeloablative lymphodepleting chemotherapy (LDCT) composed of fludarabine and cyclophosphamide. Both treatments will be started on the same day. Fludarabine will be given for four days, and cyclophosphamide for 2 days. LDTI will be administered as a single dose on Day 0 to all irradiable lesions using tomotherapy.

On D0, patients will receive NY-ESO-1 TCR T cell infusion, intravenously. Supportive care will be given as needed during the whole treatment period, and patients will be discharged according to institutional practice standards once they have achieved hematologic recovery, in the absence of other reasons for hospitalization. Patients will then be followed weekly in the outpatient clinic until the end of the Treatment-Limiting Toxicity (TLT) period. For cohort 1, the TLT period which extends from the first day of lymphodepleting chemotherapy to D30 after LauT-1 infusion. For cohorts 2 and 3, the TLT period 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). After the end of treatment visit, patients will be followed at the outpatient clinic by clinical \& laboratory examination, as well as tumor assessment according to study schedule.

Interventions

• Biological 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 transduce
• Radiation Low-dose irradiation
  1Gy will be administered using tomotherapy (Accuray) to all irradiable lesions, to all cohorts before the (first) LauT-1 infusion.
• Drug 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.

Primary outcome measures

• Safety as measured by the incidence of treatment emergent adverse events [Time frame: 90 days following (first) LauT-1 infusion]
• Feasibility as measured by the rates of production failure and drop-outs before infusion [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)]
• Maximum tolerated dose (MTD) for LauT-1 (applies to Cohorts 2 and 3) [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 outcome measures (5)

• Long term safety as measured by the incidence of TEAE [Time frame: 24 months]
• Objective response rate (ORR) [Time frame: 90 days for each patient]
• Disease control rate (DCR) [Time frame: 2 years]
• Progression-free survival (PFS) [Time frame: 24 months]
• Overall survival (OS) [Time frame: 24 months]

Eligibility criteria

Inclusion criteria at pre-screening

1\) Patients with histologically confirmed advanced or metastatic cutaneous melanoma or any type of sarcoma.

Inclusion criteria at screening

• 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.
• Patients with metastatic melanoma:

• 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.
• Age ≥ 18 years
• Able to undergo apheresis
• At least one lesion accessible to biopsy for translational research (TR) at D30, without putting the patient at unusual risk.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
• Life expectancy of greater than 12 weeks.
• Radiologically measurable disease (as per RECIST v1.1).
• Adequate organ function

Exclusion criteria

• 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
• Patients with prior allogeneic stem cell transplantation or organ transplantation
• Active severe systemic infections within 2 weeks prior to apheresis
• 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 .
• History of severe immediate hypersensitivity reaction to any of the agents/ excipients of the study products.
• Women who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant.
• Subjects, for whom there are concerns that they will not reliably comply with the requirements for contraception, should not be enrolled into the study.
• Any serious underlying medical condition that could interfere with study medication and potential adverse events.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Switzerland · 2 centers

• Centre Hospitalier Universitaire Vaudois (CHUV) — Lausanne
• Centre Hospitalier Universitaire Vaudois — Lausanne

Identifiers

NCT: NCT06889766 · CHUV-DO-0026-NYESO1-2023

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗