A Phase I Trial Anti-CC Chemokine Receptor 4 Chimeric Antigen Receptor T Cells (CCR4 CAR T Cells) for CCR4 Expressing T-cell Malignancies Including Peripheral T-cell Non-Hodgkin Lymphoma (PTCL) and Cutaneous T-cell Non-Hodgkin Lymphoma (CTCL)

NCT07055477 | Recruiting Phase 1 FDA Drug

• 2 other identifiers: 10001774001774-C
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Chemokine receptor 4 (CCR4) is a protein that is found on the surface of certain T-cell lymphoma cells and is common in mature T-cell cancers. White blood cells can be changed with molecules called anti-CCR4 to express a chimeric antigen receptors (CAR), which is a molecule that directs a white blood cell to attack other cells. The CAR in this study attacks the CCR4 protein found on your T-cell lymphoma. This type if therapy is called gene therapy. Gene therapy involves a person s own white blood cells modified to target cancer cells. More research is needed to find out if gene therapy can treat T-cell cancers and do it safely. Objective: To test safety of giving people with certain mature T-cell lymphomas their own white blood cells modified with anti-CCR-4 CAR. Eligibility: People aged 18 and older with certain mature T-cell lymphomas that have not responded to or have come back after treatment. They must have a T-cell lymphoma that has CCR4 on the surface of the cancer cells. Design: Participants will be screened. They will have a medical history and physical exam. Tests of blood, urine, and heart and lung function will be done. Participants will have tests: Computed tomography (CT), positron emission tomography (PET), and magnetic resonance imaging scans: They will lie on a table that slides into a donut-shaped machine or a tube. Pictures of the inside of the body will be taken. Before the PET scan, they will get an injection of radioactive fluid in a vein in the arm. Before the MRI, they may get a contrast dye injected through a vein (IV) in the arm. A biopsy of the tumor may be taken. A bone marrow sample may be taken from the hip: The area will be numbed and a large needle inserted through the skin. Leukapheresis will be done to obtain T-cells that will be genetically modified to express anti-CCR4 CARs on T-cells: Blood is drawn through an IV in one arm, circulated through a machine, and then returned through an IV in the other arm. Chemotherapy drugs will be given in an IV to prepare the body to accept the modified CAR T cells. The modified cells will be given in an IV. Participants will be followed for 15 years: This will require blood tests over the first 1-2 years followed by yearly visits and possibly telehealth updates.

Conditions

Peripheral T-Cell Lymphoma; Relapsed and/or Refractory Mature T Cell Malignancy; Angioimmunoblastic T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Hepatosplenic T-cell Lymphoma; Monomorphic Epithelialtropic Intestinal Lymphoma; Enteropathy Associated T-cell Lymphoma; Cutaneous T-Cell Lymphoma; Mycosis Fungoides; Subacute Panniculitis-like T-cell Lymphoma

Keywords

CCR4; CAR T; Chemokine Receptor 4; Chimeric Antigen Receptor; Gene Therapy; Cell Therapy; Immunotherapy

Outcome Measures

Primary Outcomes (1)

• Determine safety profile of administering autologous CCR4 CAR T cells

  The number of participants who experience Adverse Events per CTCAE v5.0, by type, grade and frequency of toxicities from time of lymphodepleting regimen through 12 weeks after the last cell infusion.

  12 weeks

Secondary Outcomes (7)

• To determine the feasibility of manufacturing and delivering the targeted dose level of CCR4 CAR T cells to participants

  1 year

• Overall survival (OS)

  After confirmed disease progression or initiation of new anti-cancer therapy, survival assessed every 3-6 months (+/- 28 days) up to 15 years.

• Duration of response (DOR) and Progression-free survival (PFS)

  weeks 4, 12, then every 3 months until Month 12, then at Months 18 and 24 then every 6 months until Month 60 then yearly, after cell infusion, until progression or up to 15 years post cell infusion.

• Complete response rate (CR), Partial response rate (PR) and Overall response rate (ORR=CR+PR)

  Weeks 4, 12, then every 3 months until Month 12, then at Months 18 and 24 after cell infusion.

• Determine long-term safety profile of autologous CCR4 CAR T cells

  Day 0 (cell infusion) up to 15 year after cell infusion

Study Arms (2)

Arm 1

EXPERIMENTAL

Conditioning chemotherapy with cyclophosphamide and fludarabine followed by autologous CCR4 CAR T-cells (IV) at escalating doses

Drug: Cyclophosphamide; Drug: Fludarabine; Biological: Autologous CCR4 CAR T cells

Arm 2

EXPERIMENTAL

Conditioning chemotherapy with cyclophosphamide and fludarabine followed by autologous CCR4 CAR T-cells (IV) at the MTD

Drug: Cyclophosphamide; Drug: Fludarabine; Biological: Autologous CCR4 CAR T cells

Interventions

Cyclophosphamide DRUG

Days -5 to -3: Cyclophosphamide 300 mg/m\^2 x 3 days

Arm 1; Arm 2

Fludarabine DRUG

Days -5 to -3: Fludarabine 30 mg/m\^2 IV daily over 30 minutes for 3 days

Arm 1; Arm 2

Autologous CCR4 CAR T cells BIOLOGICAL

Day 0: Cells will be infused intravenously (IV) over 10-30 minutes

Arm 1; Arm 2

Eligibility Criteria

• Age: 18 Years - 120 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Pathologically (biopsy) confirmed histologic diagnosis of a relapsed/refractory CCR4+ mature T-cell malignancy from one of the following subtypes: peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma (ALCL), hepatosplenic t-cell lymphoma (HSTCL), monomorphic epithelialtropic intestinal lymphoma (MEITL), enteropathy associated T-cell lymphoma (EATL) or cutaneous T-cell lymphoma (CTCL) including mycosis fungoides and subacute panniculitis-like T-cell Lymphoma, or lymphomatous subtypes of ATL without evidence of CNS involvement or substantial circulating disease confirmed by the Laboratory of Pathology, NCI.
• CCR4+ is defined as \>= 10% malignant cells positive for CCR4 by immunohistochemistry. It is preferred to have a fresh biopsy to confirm the CCR4 status. In the event a fresh biopsy cannot be safely performed in the opinion of the treating physician, an archival biopsy sample taken at the time of previous progression can be used.
• Adequate tissue \[a formalin fixed tissue block or 15 slides of tumor sample (archival or fresh)\] from diagnostic biopsy (archival or fresh) must be available.
• NOTE: Tissue will be used for assessment of CCR4 expression on malignant cells by immunohistochemistry with any leftover slides or samples to be used for correlative studies. Tumor tissue may be from any previously collected tissue and adequacy is at the discretion of the Principal Investigator. If prior tissue is not available, a screening biopsy will be necessary unless repeat biopsy is deemed unsafe by the treating physician in consultation with the Principal Investigator.
• Participants must have disease that is relapsed or refractory after prior therapy as follows:
• Participants with ALCL must have failed at least one prior line of Brentuximab-containing therapy.
• Due to the generally indolent nature of the disease, participants with Mycosis Fungoides must have exhausted all standard therapies as determined by the enrolling physician and principal investigator to be eligible for this study.
• All other participants must have failed at least two lines of prior therapy.
• Participants must have measurable or evaluable disease at the time of enrollment. For participants with systemic T-cell lymphoma, this is defined by any evidence from CT scan or PET-CT-avid disease based on the Lugano criteria. For participants with Cutaneous T-cell Lymphoma, positive scores based on Modified Severity-Weighted Assessment Tool (mSWAT) criteria are acceptable.
• Participants must be \>=18 years of age at the time of signing informed consent.
• Adequate performance status (PS) as follows: ECOG PS 0-1.
• Adequate organ function as evidenced by the following laboratory parameters:
• Absolute neutrophil count (ANC) \>= 1,000 /microL
• Platelets \>= 75,000 / microL
• Hemoglobin (Hgb) \>= 9 g/dL (transfusions permitted)

You may not qualify if:

• Participants with any current or prior CNS involvement by malignancy are excluded from this study. All potential participants will be screened with brain imaging prior to enrollment on study.
• Participants with \>1000 atypical cells/mm\^3 by peripheral blood flow cytometry at screening.
• Participants with a history of serologically or biopsy confirmed autoimmune disorders are excluded from this study. As an exception, participants with EATL whose celiac disease is well controlled and who will maintain a strict gluten-free diet are eligible.
• Participants with prior autoimmune thyroiditis who are now on stable thyroid replacement therapy are also eligible.
• HTLV I/II positive participants with a history of HTLV-associated myelopathy/tropical spastic paraparesis (TSP)
• Participants who have received prior CD25-directed therapy.
• Current or prior anti-cancer treatment prior to the first dose of study drug as defined below:
• Any cytotoxic therapy, immunotherapy, antitumor vaccines or monoclonal antibodies within 2 weeks before the start of lymphodepleting chemotherapy.
• High doses of systemic corticosteroids (\>20 mg prednisone or equivalent) 5 days before apheresis and/or 5 days before CAR T cell infusion.
• Participants who have not reached D+100 following auto-SCT or who have any unresolved Auto-SCT related complications (e.g. pneumonitis).
• Participants who have undergone prior allogeneic stem cell at any time.
• Participants taking any investigational agents for any disease/ condition.
• Seropositive for human immunodeficiency virus (HIV).
• Active bacterial infections or active viral infections (CMV, syphilis)
• Uncontrolled EBV infection Note: EBV positive test is allowed due to frequent association of active EBV with mature T-cell malignancies, which frequently resolve with improved control of the malignancy. EBV positive participants may be treated with rituximab or biosimilar prior to lymphodepleting chemotherapy at investigator s discretion.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

RECRUITING

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Lymphoma, T-Cell, Peripheral; Immunoblastic Lymphadenopathy; Lymphoma, Large-Cell, Anaplastic; Enteropathy-Associated T-Cell Lymphoma; Lymphoma, T-Cell, Cutaneous; Mycosis Fungoides

Interventions

Cyclophosphamide; fludarabine

Condition Hierarchy (Ancestors)

Lymphoma, T-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Lymphadenopathy

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Study Officials

• Samuel Y Ng, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

NCI Medical Oncology Referral Office

CONTACT

(240) 760-6050; ncimo_referrals@nih.gov

Samuel Y Ng, M.D.

CONTACT

(240) 858-7618; samuel.ng@nih.gov

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 8, 2025
• First Posted: July 9, 2025
• Study Start: September 29, 2025
• Primary Completion (Estimated): June 1, 2044
• Study Completion (Estimated): June 1, 2044
• Last Updated: February 20, 2026

Record last verified: 2026-02-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data will be made available as soon as possible or at the time of associated publication. Data not published in a manuscript will be shared via public source once the data set completes QC.
• Access Criteria: Clinical data will be made available upon request and with the permission of the study PI. Genomic data are made available via dbGAP through requests to the data custodians.

Locations

US (1)