Evaluate TCRT-ESO-A2 Autologous T Cells Expressing TCR Specific for NY-ESO-1 in Subjects With Advanced Solid Tumors

TCRT-ESO-A2 is an autologous cell therapy comprised of a subject's T cells stimulated ex vivo and transduced with a lentiviral vector encoding an affinity enhanced TCR targeting tumor-associated antigen NY-ESO-1.

This study will investigate the safety, tolerability, activity, and pharmacokinetics/ pharmacodynamics of TCRT-ESO-A2 infusion. A maximum tolerated dose study of TCRT-ESO-A2 in subjects with advanced malignancies expressing NY-ESO-1 is considered to be an acceptable risk. Once safety, tolerability, and pharmacokinetic/pharmacodynamic data are available, the activity of TCRT-ESO-A2 in NY-ESO-1-positive tumors may be explored further.

This is a Phase 1 open-label, multi-site, "3+3" dose escalation, study to evaluate the maximum tolerated dose, safety and tolerability, of TCRT-ESO-A2 suspension for IV infusion. Approximately 24 HLA-A\*0201-positive subjects with head and neck cancer, hepatocellular carcinoma, lung squamous cell carcinoma, synovial sarcoma, and triple-negative breast cancer expressing NY-ESO-1 who have received at least first-line therapy for their cancer, or which there is no accepted therapy will be enrolled. Tumor tissue samples will be evaluated and scored using the NY-ESO-1 IHC assay developed specifically to support this study.

Following screening and enrollment (approximately Days -63 to -36) subjects will undergo leukapheresis for T cell collection at approximately Day -35 (Figure 3). Harvested cells will be fractionated, genetically engineered, and expanded ex vivo to produce autologous TCRT-ESO-A2 TCR-T. Following TCRT-ESO-A2 product release, subjects will receive a 3-day, non-myeloablative lymphodepletion regimen of fludarabine/cyclophosphamide from approximately Days -5 to -3 (recommend Wednesday to Friday) to prime the subject for immune re-population. Subjects will receive their TCRT-ESO-A2 cell product on Day 1 (recommend Monday) as an IV infusion over approximately 30 minutes. Within 30 minutes after completion of TCRT-ESO-A2 infusion, low dose subcutaneous aldesleukin (rhIL-2) will be administered at 500,000 IU BID daily for 14 days.

Dose escalation will be divided into three dose groups of three subjects each, with doses calculated as the number of TCR Vβ8-positive cells (total TCRT-ESO-A2 dose), with an allowable variance in cell count of ±30%. Escalation to higher doses will be based on the safety and tolerability of the previous cohort evaluated. If dose-limiting toxicity is observed in one subject at a dose level, up to an additional three dose limiting toxicity-evaluable subjects will be enrolled at that dose level. Subjects will be evaluated for dose limiting toxicity up to 28 days post-TCRT-ESO-A2 infusion. Prior to increasing the dose, a cohort management meeting will be held after the final enrolled subject has been followed for up to 28 days. The decision to increase to the next dose level will be a joint decision of the clinical site Investigators and Sponsor. At each cohort, there will be at least 7 days between infusion of each subject in the cohort. Enrollment into a dose level will be suspended if two of no more than six subjects at a dose level experience dose-limiting toxicity.

Three dose groups of subjects will be enrolled:

Cohort 1: 0.3 × 1010 TCRT-ESO-A2 cells\* Cohort 2: 1.0 × 1010 TCRT-ESO-A2 cells\* Cohort 3: 3.0 × 1010 TCRT-ESO-A2 cells\*

\* ±30% Subjects will be monitored daily during in-patient hospitalization for 5 days post dose. Subjects will then visit an out-patient clinic weekly during the Dose Limiting Toxicity Evaluation Period of 4 weeks and followed at approximately Days 60, 90, and every 3 months until confirmation of disease progression. Disease monitoring will be conducted by Magnetic Resonance Imaging or Computed Tomography scan (as appropriate for disease), during screening (if recent scans are not available), during lead-in approximately 7 days prior to TCRT-ESO-A2 infusion, at approximately Days 28, 60, 90, and every 3 months until confirmation of disease progression. If subjects remain clinically stable, confirmation of progression may be assessed 4- to 8-weeks later. Positron emission tomography scanning may be used as appropriate as an adjunct. Tumor biopsies will be taken from non-target lesions, if accessible, at baseline, approximately Days 28, 90, 180, and upon progression. Ascites/pleural fluid may be collected in addition to biopsies for correlative research studies if the subject requires paracentesis or pleuracentesis. At progression, long term follow-up will commence. During long term follow-up, subjects will be followed twice yearly for up to 5 years post-infusion and then annually for up to 15 years.

Timing of tumor and liquid biopsies may be adjusted as may the timing of other procedures or safety studies. In addition, up to 150 additional mL of blood may be collected over a three-month period without amendment of the protocol. Additional safety measures may be included, and tests may be done at any time if clinically indicated. In addition, if objective responses are observed in tumors after the safety of each cohort has been evaluated, up to 12 additional subjects with that tumor type (up to 2 tumor types) may be enrolled to further explore the tumor response rate in that tumor type.

Eligibility Criteria:
Inclusion Criteria:

1. Able to understand and voluntarily sign an informed consent form (ICF).
2. Age ≥18 years of age at the time of informed consent.
3. HLA-A\*0201 positive by high resolution testing.
4. Any of the following solid tumors with positive NY-ESO-1 expression characterized by IHC:

   1. Head and neck cancer with ≥85% of tumor cells scored ≥1+.
   2. Hepatocellular carcinoma with ≥20% of tumor cells scored ≥1+.
   3. Lung squamous cell carcinoma with ≥20% of tumor cells scored ≥1+.
   4. Synovial sarcoma with ≥65% of cells scored ≥1+.
   5. Triple-negative breast cancer with ≥20% of cells scored ≥1+.
5. Received standard curative or palliative therapy including any targeted therapy based on mutation status for their cancer, or advanced solid tumors for which there is no accepted therapy, standard therapies are no longer effective, or the subject refuses additional standard therapy.
6. Measurable disease as defined per RECIST 1.1 (Eisenhauer 2009).
7. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1.
8. Life expectancy of \>4 months.
9. Adequate hematologic status as demonstrated by not requiring transfusion support or granulocyte-colony stimulating factor (G-CSF) to maintain:

   1. White blood cell count ≥3,000/mcL.
   2. Absolute neutrophil count ≥1,000/mcL.
   3. Platelet count ≥100,000/mcL.
   4. Hemoglobin ≥9.0 g/dL.
10. Adequate liver function as demonstrated by:

    1. Serum alanine transaminase (ALT) and aspartate transaminase (AST) ≤3 × upper limit of normal, except in subjects with liver metastasis, who must have AST and ALT ≤5 × upper limit of normal.
    2. Total bilirubin ≤1.5 × upper limit of normal, except in subjects with Gilbert's Syndrome, who must have total bilirubin ≤3.0 × upper limit of normal.
11. Creatinine clearance ≥50 mL/min. Creatinine clearance of subjects \<65 years of age may be estimated by the Cockcroft-Gault formula. Subjects ≥65 years of age must have renal function measured either by 24-hour urine creatinine collection or by nuclear medicine glomerular filtration rate.
12. Prior therapies:

    1. Targeted or immunotherapy must be completed at least 4 weeks prior to leukapheresis.
    2. Chemotherapy must be completed at least 3 weeks prior to leukapheresis.
    3. Systemic corticosteroid or other immunosuppressive therapy must be completed at least 2 weeks prior to leukapheresis.
13. Recovered from previous surgery or treatment-related adverse reactions to \<grade 2 CTCAE (except for toxicities such as alopecia or vitiligo or toxicities that may be permanent such as neuropathy) prior to lymphodepletion chemotherapy.
14. Men who are sterile (including vasectomy confirmed by post vasectomy semen analysis) or agree to use a condom with spermicide and to not donate sperm during the study and until the persistence of TCRT-ESO-A2 is no longer detected by qPCR or up to 15 years.
15. Women of non-child bearing potential due to surgical sterilization (at least 6 weeks following surgical bilateral oophorectomy with or without hysterectomy or tubal ligation) confirmed by medical history or menopause (i.e., no menstrual bleeding for more than 12 months in a woman aged ≥45 years), OR women of childbearing potential who test negative for pregnancy at Screening based on serum pregnancy test must be using a highly effective method of contraception from the time of Screening until the persistence of TCRT-ESO-A2 is no longer detected by qPCR or up to 15 years. Note: Highly effective methods of contraception that result in a low failure rate (i.e., \<1% per year) when used consistently and correctly include combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or implantable), intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner, or sexual abstinence. True abstinence, when in line with the preferred and usual lifestyle of the subject, is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of study participation and until the persistence of TCRT-ESO-A2 is no longer detected by qPCR. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, and post-ovulation method) and withdrawal are not acceptable methods of contraception.

5.3 Exclusion Criteria

Eligible subjects must not have/be:

1. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease or AIDS).
2. Known allergic reactions to any component of the treatments in this study.
3. Echocardiography (ECHO) or multigated acquisition scan (MUGA) indicative of left ventricular ejection fraction (LVEF) ≤45%.

Exclusion Criteria:

* Eligible subjects must not have/be:

  1. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease or AIDS).
  2. Known allergic reactions to any component of the treatments in this study.
  3. Echocardiography (ECHO) or multigated acquisition scan (MUGA) indicative of left ventricular ejection fraction (LVEF) ≤45%.
  4. Pulmonary function test of forced expiratory volume in the first second (FEV1) ≤60% in subjects with a prolonged history of cigarette smoking (e.g. ≥20 pack-year smoking history).
  5. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, unstable cardiac arrhythmia, psychiatric illness, or social situations that would limit compliance with study requirements.
  6. Subjects with infection requiring treatment, including but not limited to active tuberculosis, COVID-19, known HIV positive subjects or subjects with clinically active hepatitis A, B and C.
  7. Planning to take the following medications within 4 weeks of TCRT-ESO-A2 infusion or during the study: long-term systemic use of steroid hormones, hydroxyurea, immunomodulatory drugs (such as interleukin 2, interferon α or γ, GM-CSF, mTOR inhibitor, cystatin, thymosin, etc.). Recent use of inhaled or topical steroids, topical 5-fluorouracil is not exclusionary, however, use of inhaled steroids before leukapheresis and blood draws should be discouraged.
  8. Untreated or symptomatic brain metastasis.
  9. History of organ transplantation or allogeneic stem cell transplantation.
  10. Known uncontrolled diabetes, pulmonary fibrosis, interstitial lung disease, acute lung disease or liver failure.
  11. Previous use of any gene therapy product.
  12. Not suitable for enrollment at the discretion of the Principal Investigator.