A Phase 1, Multicenter, Open-label, Prospective, First-in-human Dose-escalation Clinical Trial of Domain Therapeutics' Anti-CCR8 Monoclonal Antibody (DT-7012) in Patients With Relapsed or Refractory Cutaneous T-cell Lymphomas (CTCL)

A Phase 1, Multicenter, Open-label, Prospective, First-in-human Dose-escalation Clinical Trial of Domain Therapeutics' Anti-CCR8 Monoclonal Antibody (DT-7012) in Patients With Relapsed or Refractory Cutaneous T-cell Lymphomas (CTCL)

Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of lymphomas characterized by a primary involvement of the skin. Among them, mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes. SS is defined as erythroderma (erythema of the entire skin surface), and circulating tumor blood cells. The circulating tumor T cells express CD4 and may lose expression of CD7 and CD26, while exhibiting in most cases aberrant expression of CD158k (KIR3DL2), which is a surface marker of Sézary cells. CCR8 is a surface marker of tumor-infiltrating regulatory T cells. It has recently be observed that CCR8 was expressed by tumor cells in CTCL and other peripheral T-cell lymphomas. CCR8 is expressed by skin resident-memory T cells which are believed to be the tumor cell-of-origin in mycosis fungoides. Domain Therapeutics (DT) showed the in vitro efficacy of their proprietary anti-CCR8 mAb DT7012 in the depletion of CTCL cells. Therapeutic depletion of CCR8-expressing cells by DT-7012 could eliminate tumor cells and activate the anti-tumor immunity in CTCL. We hypothesize that treatment with DT-7012 is effective in the treatment of relapsed or refractory (R/R) CTCL as advanced MF and SS.

Inclusion Criteria:

1. Adult Patients (≥18 years) with no upper age limit

2. Confirmed diagnosis of mycosis fungoides or Sezary syndrome

3. Stage IB to IVB in the ISCL / EORTC classification

4. Relapsed or refractory (no response) after at least two systemic treatments

5. ECOG performance status 0-1

6. Adequate liver function:

   • Total bilirubin ≤ 1.5 xULN, or Direct bilirubin ≤ 1.5xULN if total bilirubin is >1.5xULN, or total bilirubin >1.5 xULN if elevated total bilirubin is attributed to Gilbert's syndrome or to histologically-proven liver involvement by CTCL
   • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2,5 x ULN, unless elevated to up to 5 x ULN due to CTCL

7. Adequate hematological function:

   • Absolute neutrophil count of ≥ 1.5 G/L without G-CSF support for at least 7 days
   • Platelet count of ≥ 75 G/L without platelet transfusion within 7 days
   • Hemoglobin ≥ 9 g/dL without RBC transfusion within 7 days

8. Adequate renal function: creatinine clearance calculated by Cockcroft & Gault formula of ≥ 50 mL/min

9. HBV: negative blood HBs Ag or blood HBV DNA. Vaccinated patients may be included. Patients with HBc antibody may be included if HBV DNA is negative

10. HCV: negative HCV serology, or negative HCV RNA if HCV serology is positive

11. HIV: negative HIV serology

12. Negative serum or urinary pregnancy test within 7 days or at baseline prior to study treatment in women of childbearing potential

13. Patients must agree to use a highly effective contraceptive method from inclusion until:

    • If the patient is a male: at least 6 months after the last dose of DT-7012. Men must refrain from donating sperm during this same period
    • If patient is a female of childbearing potential: at least 6 months after the last dose of DT-7012

14. Patients must have the following minimum wash-out from previous treatments:

    • 12 weeks for total skin electron beam irradiation,
    • 4 weeks for monoclonal antibodies
    • 3 weeks for local radiation therapy, systemic cytotoxic anticancer therapy, treatment with other anti-neoplastic investigational agents
    • 3 weeks for systemic retinoids, interferons, vorinostat, romidepsin, fusion proteins
    • 3 weeks for phototherapy
    • 2 weeks for topical therapy (including steroids, retinoids, nitrogen mustard or imiquimod). Topical steroids and oral steroids (10 mg prednisone equivalent/day maximum) are allowed, if the patient has been on a stable dose with stable symptoms for at least 4 weeks prior to study entry.

15. Patient covered by any social security system (registered or being a beneficiary of such a scheme) for French participants only

16. Signed informed consent

Exclusion Criteria:

1. Known central nervous system involvement by CTCL
2. Participation in any study of a health product within 30 days prior to study entry
3. Patients with a history of other malignancies during the past three years (except for: non-melanoma skin cancer, lymphomatoid papulosis, curatively treated localized prostate cancer, curatively treated localized breast cancer, resected thyroid cancer, biopsy proven cervical intraepithelial neoplasia or cervical carcinoma in situ, which are not considered exclusion criteria).
4. Uncontrolled congestive heart failure (New York Heart Association Classification 3 or 4), or angina, myocardial infarction, cerebrovascular accident, transient ischemic attack within 6 months prior to study entry
5. Any severe acute or chronic medical or psychiatric condition
6. Patients with immunodeficiency
7. Any active systemic viral, bacterial, or fungal infection requiring systemic antibiotics within 1 week prior to first study drug dose
8. Chronic use of systemic corticosteroids of prednisone or equivalent >10 mg prednisone equivalent/day for a chronic condition (washout of 8 days from start of treatment is accepted)
9. Other immunosuppressive therapies are also excluded, (washout of 7 days from start of treatment is accepted)
10. Autologous Hematopoietic Stem Cell Transplantation (HSCT) within 100 days prior to DT-7012 infusion
11. Prior allogeneic HSCT
12. Prior solid organ transplantation
13. Patient with history of confirmed progressive multifocal leukoencephalopathy
14. Known or suspected allergies, hypersensitivity, or intolerance to DT-7012 or its excipients
15. Pregnant or breast-feeding woman, or desire (for both man and woman participant) to conceive a child within 6 months after end of treatment
16. Patient under guardianship or curatorship and protected adults or unable to consent
17. Coagulation disorder contra indicating intravenous infusion
18. History of anaphylactic reaction following vaccination or immunotherapy
19. History or current immune pneumonitis or interstitial lung disease