Cutaneous T Cell Lymphoma (CTCL), Mycosis Fungoides, Sezary Syndrome
Conditions
Keywords
Cutaneous T Cell Lymphoma, Mycosis Fungoides, Sezary Syndrome
Brief summary
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.
Interventions
DRUGDT-7012
This study use the Bayesian one-stage time-to-event continual reassessment method (TITE-CRM) design for dose finding phase I clinical trials, using an empirical dose-toxicity model with linear weights. A maximum total of 30 patients with CTCL, given 4 candidate dose levels (0.3; 1.0; 3.0; 10.0 mg/kg) will be dose-assigned starting from 1mg/kg dose level, in cohorts of 1 patient and including safety rules notably to ensure staggered accrual.
Sponsors
Domain Therapeutics SA
Assistance Publique - Hôpitaux de Paris
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Single arm, open-label, multicenter prospective phase 1 dose-escalation study
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose limiting toxicity (DLT) defined by any treatment-emergent adverse event (TEAE) not attributable to the disease or disease-related processes | Up to 12 months | Any Grade ≥ 3 non-hematologic toxicity lasting at least 7 days is considered DLT, EXCEPT for: * Isolated laboratory findings with no clinical signs or symptoms, * Grade 3 fatigue, nausea, vomiting, diarrhea, or other manageable constitutional symptom that is responsive to supportive therapy and resolves to Grade ≤ 2 (or baseline if baseline is Grade ≥ 2) within 72 hours Any Grade ≥ 3 hematologic toxicity is considered DLT, EXCEPT for: * Grade 3 neutropenia (without fever and not requiring growth factor support) lasting for less than 7 days, * Grade 3 thrombocytopenia without clinically significant bleeding or requiring platelet transfusion, * Grade 3 leukopenia/lymphopenia, * Grade 3 anemia that does not require transfusion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area under the curve (AUC₀-₇) for the first administration | Up to 12 months | from time 0 to day 7 |
| Health Related Quality of Life | At 3 months | By a standardized skin-specific questionnaire (SkinDex29). Total score varies from 0 to 100. The higher the score the lower the quality of life |
| Time to next treatment (TTNT) | Up to 12 months | Time from initiation of DT-7012 until the time of initiation of any systemic treatment or total-skin treatment (phototherapy or TSEB). |
| Disease control rate | At 3 months | Defined as complete, partial response or stable disease |
| Duration of response (DoR) | Up to 12 months | Time from measurement of CR/PR (whichever is first recorded) until the date of documented recurrent or progressive disease, assessed in responder patients only |
| Progression-Free-Survival | Up to 12 months | Defined with the time from the first DT-7012 administration to progressive disease, relapse, death, or last follow-up. |
| Incidence of Adverse events | Up to 12 months | Adverse Events (AEs), Serious Adverse Events (SAEs), Drug related AEs, Drug related SAEs, Adverse Events of Special Interest (AESI) |
| Objective Response Rate | At 3 months | — |
| Complete Response (CR) | At 3 months | — |
| Partial Response (PR) | At 3 months | — |
| Maximum concentration (Cmax) of DT-7012 | Up to 12 months | At each administration |
| Trough concentration (Cmin) of DT-7012 | Up to 12 months | At each administration |
| Area under the curve (AUC₀-₇) for the fourth administration | Up to 12 months | from time 0 to day 7 |
| Accumulation index (AI) | Up to 12 months | Expressed as the ratio of concentrations between the fourth and first administration |
| Presence of anti-drug antibodies | Up to 12 months | — |
| Presence of pruritus | At 3 months | Assessed by a visual analogue scale (VAS) |
Other
| Measure | Time frame | Description |
|---|---|---|
| CCR8 mean fluorescence intensity by flow cytometry in peripheral blood | At baseline | — |
| Percentage of cells positive | At baseline | Exhaustion markers PD1, TIGIT, Tregs markers CD25 and FoxP3, activation markers CD69, CD25 and cell markers - CD68, CD163 macrophages, CD8 T cells) will be studied by flow cytometry in peripheral blood |
| Percentage of CCR8-positive tumor T cells and Tregs | At baseline | By multiplex Immunofluorescence in skin |
| Percentage of the blood tumor clone in skin and blood (in both cellular and cell-free DNA) | At baseline | — |
| Percentage of of positive cells within the infiltrate by immunohistochemistry | At baseline | Expression of CCR8, on tumor and reactive cells, in skin and blood |
Contacts
Primary ContactCaroline RAM WOLFF, MD
Backup ContactJérôme Lambert, MD PhD
Outcome results
None listed