Neoplasms

Blood and Lymph Conditions

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All Conditions

Rare Diseases

Lymphoma

Leukemia

Lymphoma, T-Cell

Lymphoma, T-Cell, Peripheral

Leukemia, T-Cell

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphoma, Non-Hodgkin

Lymphosarcoma

Peripheral T-cell Lymphoma

Leukemia, T-cell, Chronic

Dose escalation phase: CD4 CAR T cells transduced with a lentiviral vector to express CD4 chimeric receptor domain on T cells with an escalation approach, 2e6 to 5e6 CAR-T cells/kg

CD4 CAR T cells administered to patients, will be either fresh or thawed CAR T cells by IV injection after receiving lymphodepleting chemotherapy.

CD4 CAR T cells

Kevin Pinz, MS

Yupo Ma, MD/PhD

Hongyu Zhang, MD/PhD

Fang Liu, MD/PhD

This is a phase I, interventional, single arm, open label, treatment study to evaluate the safety and tolerability of CD4 CAR T cells in patients with relapsed and/or refractory T cell lymphoma.

CD4-specific CAR is a chimeric antigen receptor immunotherapy treatment designed to treat lymphoma/leukemia expressing CD4 antigen. CD4+ T cell lymphomas are a subset of leukemias and lymphomas that are positive for the surface protein CD4. The purpose of this study is to evaluate the efficacy and safety of CD4 CAR T cells.

CD4-specific CAR T Cells (CD4 CAR T Cells) for Relapsed/Refractory T Cell Malignancies

Determine the toxicity profile of CD4 CAR T cell therapy

Incidence of treatment-emergent adverse events

Disease Free Survival (DFS) (IMWG criteria)

Progression-Free Survival (IMWG criteria)

iCAR Bio Therapeutics Ltd.

Peking University Shenzhen Hospital

iCell Gene Therapeutics

Infections

Symptoms and General Pathology

Communicable Diseases

Leukemia-Lymphoma, Adult T-Cell

HTLV-I Infections

Hematologic Diseases

Leukemia, Lymphoid

Retroviridae Infections

Virus Diseases

RNA Virus Infections

Syndrome

Immunologic Deficiency Syndromes

Adult T-cell Leukemia/lymphoma

Human T-cell Leukemia Virus Type 1

All Drugs and Chemicals

Anti-Inflammatory Agents

Antineoplastic Agents

Analgesics

Antibodies

Antibodies, Monoclonal

Triamcinolone

Triamcinolone Acetonide

Triamcinolone hexacetonide

Triamcinolone diacetate

Immunoglobulins

Interleukin-2

Daclizumab

Immunosuppressive Agents

Immunologic Factors

2 mg/kg daclizumab over 60 minutes intravenously on days 1 and 2

4 mg/kg daclizumab over 90 minutes intravenously on day 1, single dose

6 mg/kg daclizumab over 90 minutes intravenously on day 1, single dose

8 mg/kg daclizumab over 90 minutes intravenously on day 1, single dose

daclizumab

Thomas Waldmann, M.D.

The purpose of the study was to determine: (1) the toxicity and maximum tolerated dose (MTD) of humanized anti-Tac (daclizumab), (Zenapax(Registered Trademark)) in patients with adult T-cell leukemia/lymphoma (ATL); (2) to define the dose of Zenapax(Registered Trademark) required to saturate interleukin 2 receptor alpha (IL-2R) alpha in patients with ATL; (3) determine the clinical response to humanized (Hu) anti-Tac (Zenapax(Registered Trademark) of patients with Tac-expressing adult T-cell leukemia; and (4) determine the serum dieaway curve (pharmacokinetics) of infused humanized (Hu)-anti-Tac in patients who have ATL. This study represented an extension of Metabolism Branch National Cancer Institute (NCI) protocols utilizing modifications of the original murine anti-Tac monoclonal antibody (mAb) developed by our group for the treatment of ATL. The scientific basis for these therapeutic studies is that the leukemic cells of patients with ATL express abnormally high levels of the Tac antigen (IL-2R alpha) on their surface whereas resting normal cells including normal T-cells of the patients do not. One presumed mode of action of Hu-anti-Tac in the treatment of ATL involves the interruption of the interaction of interleukin 2 (IL-2) with its growth factor receptor. To be effective in this goal we must maintain saturation of the IL-2 receptors (IL-2R) with humanized anti-Tac thereby preventing IL-2 mediated proliferation and yielding cytokine deprivation and apoptotic cell death of the leukemic cells. Eligible patients with ATL were treated with escalating doses of Zenapax(Registered Trademark) between groups in the Clinical Center of the National Institutes of Health (NIH). Groups of patients received sufficient Zenapax(Registered Trademark) to yield saturation of the IL-2 receptor for a period of 17 weeks. Clinical response was evaluated using routine immunological and clinical evaluation and by monitoring the saturation of the IL-2R and the absolute number of residual circulating malignant cells by fluorescence activated cell sorting (FACS) analysis using two fluorochrome-labeled non-crossreacting antibodies to the IL-2 receptor, anti-Tac and 7G7/B6, as well as antibodies to cluster of differentiation 3 (CD3), cluster of differentiation 4 (CD4), cluster of differentiation 7 (CD7), and cluster of differentiation 8 (CD8). Furthermore, responses were evaluated in patients with leukemia by Southern blot analysis of the arrangement of the T-cell receptor genes and human T-lymphotropic virus type 1 (HTLV-I) integration. Finally, in select patients, to define the pharmacokinetics of the therapeutic antibody, had planned to monitor the serum levels of the infused Hu-anti-Tac (Zenapax(Registered Trademark)) as a function of time. This study is an essential element of our program involving IL-2R-directed therapeutic studies. If as anticipated the therapy with humanized anti-Tac yields some partial and complete remissions in patients with ATL, we will propose that it be used as a single agent for patients with smoldering and chronic ATL and in association with chemotherapeutic agents to provide a novel approach for the treatment of acute and lymphoma forms of ATL. We also plan a future clinical trial where tentative plans also had been made to evaluate the efficacy and toxicity in ATL patients of saturating doses of Zenapax(Registered Trademark) as compared to identical doses of Zenapax(Registered Trademark) given in association with (90)Y-armed 7G7/B6, a non-competing antibody to IL-2R alpha or in combination with chemotherapy.

Background:

Human T-lymphotropic virus type 1 (HTLV-1)-associated adult T cell leukemia/lymphoma (ATL) is an aggressive lymphoproliferative disorder.

Chemotherapy has had limited impact on survival.

The interleukin 2 receptor alpha (IL-2R alpha) (CD25) is over expressed on ATL cells and the smoldering and chronic stages of ATL are often interleukin 2 (IL-2) dependent.

The monoclonal antibody daclizumab (Zenapax) inhibits interleukin 2 (IL-2) binding to its receptor.

It is hypothesized that daclizumab may inhibit ATL growth.

Objectives:

To determine the toxicity and maximum tolerated dose (MTD) of humanized anti-Tac (daclizumab, Zenapax) in patients with ATL.

To define the dose of Zenapax required to saturate IL-2R alpha in patients with ATL.

To determine the clinical response to humanized (Hu) anti-Tac (Zenapax) of patients with Tac-expressing smoldering and chronic stage adult T cell leukemia.

To determine the serum dieaway curve (pharmacokinetics) of infused humanized (Hu) - anti - Tac in patients who have ATL.

Eligibility:

Smoldering and chronic stage HTLV-1-associated adult T cell leukemia.

At least 5 percent of malignant cells in the peripheral blood or lymph nodes must react with the anti-Tac (CD25) antibody.

Age greater than or equal to 10-years-old.

Patients must have measurable disease.

Patients with and without prior treatment.

Patients must have a granulocyte count of greater than or equal to 500/micro L,

platelets greater than or equal to 25,000/micro L,

and creatinine less than 3.0 gm/dL.

Design:

Phase I patients on cohorts 1-4 received the following: cohort 1: 2 mg/kg over 60 minutes intravenously on days 1 and 2; cohort 2: 4 mg/kg over 90 minutes intravenously on day 1, single dose; cohort 3: 6 mg/kg over 90 minutes intravenously on day 1, single dose; and cohort 4: 8 mg/kg over 90 minutes intravenously on day 1, single dose.

Patients with smoldering or chronic stage ATL will be treated with intravenous daclizumab 8 mg/kg on day 0 and weeks 2, 5, 8, 11 and 14.

Patients achieving a response will continue on treatment with daclizumab 8 mg/kg every 3 weeks for up to 24 months.

Patients achieving a complete response (CR) will continue on treatment with daclizumab 8mg/kg every 3 weeks for up to 24 months.

Patients achieving a partial response (PR) will be maintained on daclizumab 8 mg/kg administered every 3 weeks provided the PR is maintained and no serious adverse event or toxicity related to daclizumab therapy is observed.

Anti-Tac for Treatment of Leukemia

A Phase I/II Study of the Efficacy and Toxicity of Humanized Anti-Tac (Zenapax(Trademark)) in the Therapy of Tac-Expressing Adult T-Cell Leukemia

Duration of response was defined as the interval from the time response is first achieved to the time progression from the best response is detected. Responses are assessed by a modified World Health Organization (WHO) criteria. Partial response is a reduction of \>=50% saturation in the circulating leukemic cell count; complete response is disappearance of all measurable and non-measurable disease lasting more than 1 month; stable disease is patients who did not meet the criteria; and progressive disease is a \>=25% increase in leukemic cell count.

Measured from the time the patient is consented until death.

Participants overall response rate was defined as complete response (CR) + partial response (PR) from study consent until progression was measured. Responses was assessed by a modified World Health Organization (WHO) criteria. Partial response is a reduction of \>=50% saturation in the circulating leukemic cell count; complete response is disappearance of all measurable and non-measurable disease lasting more than 1 month; and progressive disease is a \>=25% increase in leukemic cell count

Here is the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.

National Cancer Institute (NCI)

Thomas A. Waldmann, M.D./National Cancer Institute

Phase II- 8 mg/kg Cohort

Phase I - 2 mg/kg cohort 2 mg/kg daclizumab over 60 minutes intravenously on days 1 and 2 Phase I - 4 mg/kg cohort 4 mg/kg daclizumab over 90 minutes intravenously on day 1, single dose Phase I - 6 mg/kg cohort 6 mg/kg daclizumab over 90 minutes intravenously on day 1, single dose Phase I - 8 mg/kg cohort 8 mg/kg daclizumab over 90 minutes intravenously on day 1, single dose Phase II- 8 mg/kg cohort 8 mg/kg daclizumab over 90 minutes intravenously on day 1, single dose

Phase I & II Cohorts (2-8 mg/kg)

Age, Categorical

Age Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Black

Hispanic

White

Asian

Race/Ethnicity, Customized

United States

Region of Enrollment

Study was closed to accrual since the cessation of the production of daclizumab.

Phase I is not reported because phase I studies only determine maximum tolerated dose.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
CD4-specific CAR T Cells (CD4 CAR T Cells) for Relapsed/Refractory T Cell Malignancies	NCT04162340	T Cell Lymphoma... Refractory T-Ce...	CD4 CAR T cells	18 Years -	iCell Gene Therapeutics
CD4-specific CAR T Cells (CD4 CAR T Cells) for Relapsed/Refractory T Cell Malignancies	NCT04162340	T Cell Lymphoma... Refractory T-Ce...	CD4 CAR T cells	18 Years -	iCell Gene Therapeutics
Anti-Tac for Treatment of Leukemia	NCT00001941	HTLV-I Infectio... T Cell Leukemia	daclizumab	10 Years -	National Institutes of Health Clinical Center (CC)

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