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Study of CAR-T Cells Expressing CD30 and CCR4 for r/r CD30+ HL and CTCL

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03602157
Recruitment Status : Recruiting
First Posted : July 26, 2018
Last Update Posted : April 30, 2020
Sponsor:
Information provided by (Responsible Party):
UNC Lineberger Comprehensive Cancer Center

Brief Summary:

The body has different ways of fighting infection and disease. No single way is perfect for fighting cancer. This research study combines two different ways of fighting disease: antibodies and T cells. Antibodies are proteins that protect the body from disease caused by bacteria or toxic substances. Antibodies work by binding bacteria or substances, which stops them from growing and causing bad effects. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including tumor cells or cells that are infected with bacteria or viruses. Both antibodies and T cells have been used to treat patients with cancers. They both have shown promise, but neither alone has been sufficient to treat cancer. This study will combine both T cells and antibodies in order to create a more effective treatment called Autologous T Lymphocyte Chimeric Antigen Receptor cells targeted against the CD30 antigen (ATLCAR.CD30). Another treatment being tested includes the Autologous T Lymphocyte Chimeric Antigen Receptor cells targeted against the CD30 antigen with CCR4 (ATLCAR.CD30.CCR4) to help the cells move to regions in the patient's body where the cancer is present. Participants in this study will receive either ATLCAR.CD30.CCR4 cells alone or will receive ATLCAR.CD30.CCR4 cells combined with ATLCAR.CD30 cells.

Previous studies have shown that a new gene can be put into T cells that will increase their ability to recognize and kill cancer cells. The new gene that is put in the T cells in this study makes an antibody called anti-CD30. This antibody sticks to lymphoma cells because of a substance on the outside of the cells called CD30. Anti-CD30 antibodies have been used to treat people with lymphoma but have not been strong enough to cure most patients. For this study, the anti-CD30 antibody has been changed so instead of floating free in the blood it is now joined to the T cells. When an antibody is joined to a T cell in this way it is called a chimeric receptor. These CD30 chimeric (combination) receptor-activated T cells (ATLCAR.CD30) can kill some of the tumor, but they do not last very long in the body and so their chances of fighting the cancer are unknown.

Researchers are working to identify ways to improve the ability of ATLCAR.CD30 to destroy tumor cells. T cells naturally produce a protein called CCR4 which functions as a navigation system directing T cells toward tumor cells specifically. In this study, researchers will also genetically modify ATLCAR.CD30 cells to produce more CCR4 proteins and they will be called ATLCAR.CD30.CCR4. The study team believes that the ATLCAR.CD30.CCR4 cells will be guided directly toward the tumor cells based on their navigation system. In addition, the study team believes the majority of ATLCAR.CD30 cells will also be guided directly toward tumor cells when given together with ATLCAR.CD30.CCR4, increasing their anti-cancer fighting ability.

This is the first time ATLCAR>CD30.CCR4 cells or combination of ATLCAR.CD30.CCR4 and ATLCAR.CD30 cells are used to treat lymphoma. The purpose of this study to determine the following:

  • What is the safe dose of ATLCAR.CD30.CCR4 cells to give to patients
  • What is the safe dose of the combination of ATLCAR.CD30 and ATLCAR.CD30.CCR4 cells to give to patients

Condition or disease Intervention/treatment Phase
Lymphoma Immune System Diseases Immunoproliferative Disorders Lymphatic Diseases Lymphoproliferative Disorders Neoplasms Cutaneous Lymphoma Cutaneous Anaplastic Large Cell Lymphoma Mycosis Fungoides Sezary Syndrome Lymphomatoid Papulosis Cutaneous T Cell Lymphoma Gray Zone Lymphoma Biological: ATLCAR.CD30.CCR4 cells Biological: ALTCAR.CD30 cells Drug: Bendamustine Drug: Fludarabine Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 59 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Study of the Administration of T Lymphocytes Co-Expressing the CD30 Chimeric Antigen Receptor (CAR) and CCR4 for Relapsed/Refractory CD30+ Hodgkin Lymphoma and Cutaneous T-Cell Lymphoma
Actual Study Start Date : December 12, 2018
Estimated Primary Completion Date : September 30, 2026
Estimated Study Completion Date : September 30, 2041


Arm Intervention/treatment
Experimental: ATLCAR.CD30.CCR4 & ATLCAR.CD30
A 3+3 design in adult subjects. Subjects in the first dose level will receive ATLCAR.CD30.CCR4 cells alone, once safety has been established, the initial dose of ATLCAR.CD30.CCR4 will be combined with a fixed dose of ATLCAR.CD30 cells in the next dose level. Every time the dose of ATLCAR.CD30.CCR4 is escalated, subjects in that dose level will receive ATLCAR.CD30.CCR4 alone prior to subsequent dose level enrolling subjects to receive a combination of fixed dose ATLCAR.CD30 and the selected dose level of ATLCAR.CD30.CCR4. The six dose levels will consist of: dose level 1 = 2 × 10^7 ATLCAR.CD30.CCR4 cells/m2; dose level 2 = 1 × 10^8 ATLCAR.CD30 cells/m2 and 2 × 10^7 ATLCAR.CD30.CCR4 cells/m2; dose level 3 = 5 × 10^7/m2 ATLCAR.CD30.CCR4 cells/m2; dose level 4 = 1 × 10^8 ATLCAR.CD30 cells/m2 and 5 × 10^7 ATLCAR.CD30.CCR4 cells/m2; dose level 5 = 1 × 10^8/m2 ATLCAR.CD30.CCR4 cells/m2; dose level 6 = 1 × 108 ATLCAR.CD30 cells/m2 and 1 × 108 ATLCAR.CD30.CCR4 cells/m2.
Biological: ATLCAR.CD30.CCR4 cells
Three dose levels are being evaluated: 2x10^7, 5x10^7, 1x10^8

Biological: ALTCAR.CD30 cells
Fixed dose level of 1x10^8

Drug: Bendamustine
70 mg/m^2/day Bendamustine for 3 days for lymphodepletion prior to cell infusion

Drug: Fludarabine
30 mg/m^2/day Fludarabine for 3 days for lymphodepletion prior to cell infusion




Primary Outcome Measures :
  1. Number of participants with adverse events (AE) as a measure of safety and tolerability ATLCAR.CD30.CCR4 and ATLCAR.CD30 cells [ Time Frame: 6 weeks ]
    Toxicity will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, version 5.0), CRS toxicity will be graded according to the toxicity scale outlined in CRS Grading Criteria/Link to CRS Management Guidelines and ICANS will be graded according to the toxicity scale outlined in Management of Neurotoxicity/Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) from CAR-T Therapy. The MTD will be based on the rate of dose-limiting toxicity.


Secondary Outcome Measures :
  1. Median progression free survival (PFS) after infusion of ATLCAR.CD30.CCR4 with and without ATLCAR.CD30 in subjects with CD30+ relapsed/refractory HL and CTCL. [ Time Frame: 15 years ]
    PFS is defined from day of ATLCAR.CD30.CCR4 with and without ATLCAR.CD30 infusion to relapse (in subjects in a documented complete response prior to conditioning chemotherapy) or progression (in subjects not in a complete response prior to conditioning chemotherapy), or death as a result of any cause

  2. Median overall survival (OS) in subjects with CD30+ relapsed/refractory HL and CTCL after administration of ATLCAR.CD30.CCR4 with and without ATLCAR.CD30 [ Time Frame: 15 years ]
    Overall survival will be measured from the date of administration of ATLCAR.CD30.CCR4 with and without ATLCAR.CD30 infusion to date of death

  3. Objective response rate by 7 weeks and best overall response rate in subjects with CD30+ relapsed/refractory HL and CTCL after infusion of ATLCAR.CD30.CCR4 with and without ATLCAR.CD30 [ Time Frame: 7 weeks ]
    The objective response rate will be defined as the rate of complete responses (CR) + partial responses (PR) by 7 weeks post ATLCAR.CD30.CCR4 with and without ATLCAR.CD30 infusion

  4. Differential infiltration of ATLCAR.CD30.CCR4 vs. ATLCAR.CD30 cells in tumor biopsies in subjects who received both ATLCAR.CD30.CCR4 and ATLCAR.CD30 cellular products [ Time Frame: 15 years ]
    Differential infiltration of ATLCAR.CD30.CCR4 vs. ATLCAR.CD30 cells in tumor biopsies in subjects receiving both ATLCAR.CD30.CCR4 and ATLCAR.CD30 cellular products will be determined by measuring the level of the transgene and by phenotypic analyses

  5. Persistence of ATLCAR.CD30.CCR4 vs. ATLCAR.CD30 in peripheral blood in subjects who received both ATLCAR.CD30.CCR4 and ATLCAR.CD30 cellular products [ Time Frame: 15 years ]
    Persistence of ATLCAR.CD30.CCR4 and ATLCAR.CD30 cells in peripheral blood will be determined by quantitative polymerase chain reaction (PCR) and flow cytometry in samples of peripheral blood in subjects who received infusion of both ATLCAR.CD30.CCR4 and ATLCAR.CD30 cellular products



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria - Unless otherwise noted, subjects must meet all of the following criteria to participate in this study:

  • Written informed consent and HIPAA authorization for release of personal health information. Subjects or their Legally Authorized Representative must sign a consent to undergo cell procurement. Written informed consent to enroll in the CAR T-cell therapy trial must be obtained prior to lymphodepletion.
  • Adults ≥18 years of age.
  • Subjects must have one of the following diagnoses by WHO criteria:
  • Classic Hodgkin Lymphoma
  • Mycosis fungoides
  • Sezary syndrome
  • Primary cutaneous CD30 positive T cell lymphoproliferative disorder including lymphomatoid papulosis or primary cutaneous anaplastic large cell lymphoma
  • B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classic Hodgkin Lymphoma (Grey Zone Lymphoma)
  • Diagnosis of recurrent lymphoma in subjects who have failed ≥2 prior treatment regimens.

    • These prior treatment regimens must include brentuximab vedotin.
    • If the subject has Hodgkin Lymphoma, the subject must have either failed autologous transplant or must not be eligible for autologous transplant.
    • If the subject has grey zone lymphoma, the subject must have failed an anthracycline containing regimen unless the subject was not previously a candidate for anthracycline
    • Subjects relapsed after autologous or allogeneic stem cell transplant are eligible for this study.
  • CD30+ disease (result can be pending at the time of cell procurement, but must be confirmed prior to treatment with ATLCAR.CD30.CCR4 and ATLCAR.CD30 cells); NOTE: CD30+ disease requires documented CD30 expression by immunohistochemistry based on the institutional hematopathology standard.
  • Karnofsky score of > 60%
  • Willing to undergo biopsy following the cell infusion. A biopsy may be required (i.e., considered mandatory) in subjects receiving both cellular products if the investigator determines the tumor site is easily accessible (e.g., palpable tumor). If the investigator feels that the biopsy would be difficult to obtain or poses a high degree of risk to the subject, it may be deferred.
  • Women of childbearing potential (WOCBP) must be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study, and for 6 months after the study is concluded. WOCBP are those who have not been surgically sterilized or have not been free from menses for > 1 year. The two birth control methods can be composed of: two barrier methods or a barrier method plus a hormonal method to prevent pregnancy. WOCBP subjects will also be instructed to tell their male partners to use a condom.

Exclusion Criteria - Subjects meeting any of the following exclusion criteria will not be able to participate in this study:

  • Pregnant or lactating.
  • Tumor in a location where enlargement could cause airway obstruction.
  • Current use of systemic corticosteroids at doses ≥10mg prednisone daily or its equivalent; those receiving <10mg daily may be enrolled at discretion of investigator.
  • Active infection with human immunodeficiency virus (HIV), human T-lymphotropic virus (HTLV), hepatitis B virus (HBV), hepatitis C virus (HCV) (can be pending at the time of cell procurement; only those samples confirming lack of active infection will be used to generate transduced cells) defined as not being well controlled on therapy. Subjects are required to have negative HIV antibody or negative HIV viral load, negative HTLV1 and 2 antibody, negative Hepatitis B surface antigen, and negative HCV antibody or viral load. In addition, subjects with positive Hepatitis B core antibody, will have Hepatitis B viral load tested and subjects with positive Hepatitis B viral load will also be excluded.
  • Subject must either have core antibody negative HBV (results can be pending at the time of cell procurement) OR if a subject is hepatitis B core antibody positive they must have their hepatitis B viral load checked. These subjects will be excluded if their viral load is positive at baseline. Subjects who are core antibody positive and viral load negative at baseline will be considered eligible.
  • Subject is not a good candidate for treatment with ATLCAR.CD30.CCR4 with and without ATLCAR.CD30 per investigator's discretion.

Eligibility Criteria to Be Met Prior to Procurement:

-Evidence of adequate organ function as defined by:

The following is required prior to procurement:

  • Hgb ≥ 8.0g/dL (transfusion independent for 2 weeks prior to enrollment)
  • Bilirubin ≤1.5 times the upper limit of normal (ULN). Subjects with Gilbert's syndrome may be enrolled despite a total bilirubin level >1.5 mg/dL if their conjugated bilirubin is <1.5× ULN)
  • Aspartate aminotransferase (AST) ≤ 3 times ULN
  • Serum creatinine ≤1.5 times ULN.
  • Creatinine Clearance (CrCl) >60mL/min per Cockcroft and Gault
  • Pulse oximetry of >90% on room air

    • Imaging results from within 120 days prior to procurement to assess presence of active disease (no tumor imaging is required prior to procurement for participants with cutaneous lymphoma).
    • Negative serum pregnancy test within 72 hours prior to procurement or documentation that the subject is post-menopausal. Post-menopausal status must be confirmed with documentation of absence of menses for > 1 year, or documentation of surgical menopause involving bilateral oophorectomy.
    • Subject has no clinical indication of rapidly progressing disease in opinion of treating physician.
    • Subject has adequate cardiac function, defined as:

      • No ECG evidence of acute ischemia
      • No ECG evidence of active, clinically significant conduction system abnormalities
      • Prior to study entry, any ECG abnormality at screening not felt to put the subject at risk has to be documented by the investigator as not medically significant
      • No uncontrolled angina or severe ventricular arrhythmias
      • No clinically significant pericardial disease
      • No history of myocardial infarction within the last 6 months prior to infusion
      • No Class 3 or higher New York Heart Association Congestive Heart Failure

Eligibility Criteria to Be Met Prior to Lymphodepletion:

  • Imaging results from within 7 days prior to lymphodepletion to assess presence of active disease. Patients who have received bridging chemotherapy must have imaging performed at least 3 weeks after most recent therapy (imaging does not need to be repeated if it is within 7 days prior to lymphodepletion).
  • Evidence of adequate organ function as defined by:

The following are required prior to lymphodepletion:

  • Adequate bone marrow function (ANC>1000 cells/mm3 and platelets >75,000/mm3). Subjects cannot have received platelet transfusion within 7 days of lymphodepletion.
  • Bilirubin ≤1.5 times the upper limit of normal (ULN). Subjects with Gilbert's syndrome may be enrolled despite a total bilirubin level >1.5 mg/dL if their conjugated bilirubin is <1.5× ULN)
  • AST ≤ 3 times ULN
  • Serum creatinine ≤1.5 times ULN.
  • Creatinine Clearance (CrCl) >60mL/min per Cockcroft and Gault
  • Pulse oximetry of > 90% on room air

    • Negative serum pregnancy test within 72 hours prior to procurement or documentation that the subject is post-menopausal. Post-menopausal status must be confirmed with documentation of absence of menses for > 1 year.
    • Subjects must have autologous transduced activated T-cells that meet the Certificate of Analysis (CofA) acceptance criteria.
    • Has not received any investigational agents or received any tumor vaccines within the previous six weeks prior to lymphodepletion.
    • Has not received anti-CD30 antibody-based therapy within the previous 4 weeks prior to lymphodepletion.
    • Has not received chemotherapy or radiation therapy within the previous 3 weeks prior to lymphodepletion.
    • Subjects cannot be on strong inhibitors of CYP1A2 (e.g., fluvoxamine, ciprofloxacin) as these may increase plasma concentrations of bendamustine, and decrease plasma concentrations of its metabolites. (This applies to subjects who receive bendamustine for lymphodepletion (required) up through 72 hours after the last dose of bendamustine).
    • Subjects who are HBV core antibody positive and HBV viral load negative prior to lymphodepletion must have initiated anti-HBV prophylaxis prior to lymphodepletion.

Eligibility Criteria to Be Met Prior to Cell Infusion after Lymphodepletion:

  • No evidence of uncontrolled infection or sepsis.
  • Evidence of adequate organ function as defined by:

    1. Bilirubin ≤2 times the upper limit of normal (ULN)
    2. AST ≤3 times ULN
    3. Alanine aminotransferase (ALT) ≤3 times ULN
    4. Creatinine Clearance (CrCl) >60mL/min per Cockcroft and Gault (see Section 11.13)
    5. Pulse oximetry of >90% on room air

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03602157


Contacts
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Contact: Catherine Cheng 919-445-4208 catherine_cheng@med.unc.edu
Contact: Spencer Laing 919-962-8618 ssblaing@email.unc.edu

Locations
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United States, North Carolina
Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Catherine Cheng    919-445-4208    catherine_cheng@med.unc.edu   
Contact: Spencer Laing    919-962-8618    spencer.laing@med.unc.edu   
Sponsors and Collaborators
UNC Lineberger Comprehensive Cancer Center
Investigators
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Principal Investigator: Natalie Grover, MD UNC Lineberger Comprehensive Cancer Center
Additional Information:
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Responsible Party: UNC Lineberger Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT03602157    
Other Study ID Numbers: LCCC 1606-ATL
First Posted: July 26, 2018    Key Record Dates
Last Update Posted: April 30, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by UNC Lineberger Comprehensive Cancer Center:
CAR T cells
CD30
CCR4
Lymphoma
T lymphocytes
Additional relevant MeSH terms:
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Mycoses
Lymphoma
Lymphoma, T-Cell
Mycosis Fungoides
Sezary Syndrome
Lymphoma, Large-Cell, Anaplastic
Lymphoma, T-Cell, Cutaneous
Lymphomatoid Papulosis
Lymphoproliferative Disorders
Lymphatic Diseases
Immune System Diseases
Immunoproliferative Disorders
Disease
Neoplasms by Histologic Type
Neoplasms
Pathologic Processes
Lymphoma, Non-Hodgkin
Fludarabine
Bendamustine Hydrochloride
Antineoplastic Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Alkylating
Alkylating Agents