Study of CD4-Targeted Chimeric Antigen Receptor T-Cells (CD4- CAR-T) in Subjects With Relapsed or Refractory T-Cell Lymphoma

This is a Phase 1, first-in-human (FIH), open-label, multicenter, study of LB1901 administered to adult subjects with histologically confirmed CD4+ relapsed or refractory Peripheral T-cell lymphoma (PTCL) (PTCL not otherwise specified \[PTCL-NOS\] and angioimmunoblastic \[AITL\]), or relapsed or refractory cutaneous T-cell lymphoma (CTCL) (Sézary syndrome \[SS\] and mycosis fungoides \[MF\]).

Study Design: This is a Phase 1, first-in-human (FIH), open-label, multicenter, multicohort study of LB1901 administered to adult subjects with histologically confirmed CD4+ relapsed or refractory Peripheral T-cell lymphoma (PTCL) (PTCL not otherwise specified \[PTCL-NOS\] and angioimmunoblastic \[AITL\]), or relapsed or refractory cutaneous T-cell lymphoma (CTCL) (Sézary syndrome \[SS\] and mycosis fungoides \[MF\]).

Eligibility Criteria:
Inclusion Criteria:

1. Written informed consent.
2. Subjects ≥ 18 years of age.
3. Histologically confirmed diagnosis of CD4+ PTCL-NOS; OR CD4+ AITL; OR CD4+ CTCL(either MF or SS).
4. Relapsed or refractory disease with at least two prior lines of systemic antineoplastic therapy.

   * Subjects with confirmed CD30+ PTCL or MF must have previously received brentuximab vedotin.
   * Subjects should have received at least two prior lines of standard of care therapies.
5. For Subjects with PTCL-NOS or AITL, at least one measurable lesion according to the International Working Group (IWG) Response Criteria.
6. For subjects with CTCL, disease stage IIB or higher based on TNMB system.
7. Subjects must have an identified hematopoietic stem cell transplant (HSCT) donor available prior to enrollment. HLA typing may be performed for source identification.
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
9. Adequate organ function.
10. Women of childbearing potential must have a negative pregnancy test at screening.
11. All Subject must agree to practice a highly effective method of contraception.
12. Women and men must agree not to donate eggs (ova, oocytes) or sperm, respectively, until at least 1 year after receiving a LB1901.

Exclusion Criteria:

1. Histologically confirmed CD8+ TCL - CD8 positivity in tumor must be confirmed within 3 months prior to apheresis by IHC or flow cytometry.
2. Prior treatment with cellular immunotherapy (e.g., CAR-T) or gene therapy product directed at any target.
3. Prior treatment with CD4-targeted therapy.
4. History of allogeneic haematopoietic stem cells transplant.
5. Antitumor therapy prior to apheresis as follows:

   * Any systemic anticancer therapy (chemotherapy, targeted therapy including ADC, epigenetic therapy including HDAC inhibitor, retinoids, pralatrexate, proteasome inhibitor therapy, investigational drug) within 21 days or at least 5 half-lives, whichever is shorter.
   * Anti-CCR4 monoclonal antibody or any other monoclonal antibody within 4 weeks or at least 5 half-lives, whichever is shorter.
   * Cytotoxic therapy within 14 days.
   * Immunomodulatory agent therapy within 7 days.
   * Radiotherapy within 14 days.
6. Immunosuppressant (e.g., cyclosporine or systemic steroids) above physiologic dosing within 7 days of apheresis.
7. Therapeutic anticoagulants (such as warfarin, heparin, low molecular weight heparin) (at least 3 half-lives must have elapsed after the last dose at the time of apheresis).
8. CNS disease prophylaxis (e.g., intrathecal methotrexate) at least 7 days before apheresis.
9. History or active Hepatitis B or C infection (except hepatitis C cured with pharmacotherapy); or history of or current HIV infection.
10. History of autoimmune disease requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years.
11. Primary immunodeficiency.
12. Active CNS disease related to the underlying malignancy.
13. Stroke or seizure within 6 months of apheresis.
14. Impaired cardiac function or clinically significant cardiac disease.
15. Previous or concurrent malignancy with the following exceptions:

    * Adequately treated basal cell or squamous cell carcinoma.
    * In situ carcinoma of the cervix or breast, treated curatively and without evidence of recurrence for at least 3 years prior to screening.
    * A primary malignancy which has been completely resected, or treated, and is in complete remission for at least 3 years prior to screening.
16. Serious and/or uncontrolled medical condition that, in the Investigator's judgment, would cause unacceptable safety risk.
17. Ongoing toxicity from previous anticancer therapy that has not resolved to baseline levels or to Grade 1 or less, except for alopecia, fatigue, nausea, and constipation.
18. Major surgery within 4 weeks prior to apheresis, or planned within 4 weeks after LB1901 administration.
19. Contraindications or life-threatening allergies, hypersensitivity, or intolerance to LB1901 or its excipients, including dimethyl sulfoxide; or to fludarabine, cyclophosphamide, or tocilizumab.
20. Contraindication or life-threatening allergy to valacyclovir, unless another suitable option of antiviral prophylaxis is identified after consultation with an Infectious Disease specialist.
21. Pregnant or breast-feeding.
22. Plans to become pregnant or breastfeed, or father a child within 1 year after receiving a LB1901 infusion.