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

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ClinicalTrials.gov Identifier: NCT03602157
Recruitment Status : Recruiting
First Posted : July 26, 2018
Last Update Posted : January 4, 2019
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. Researchers believe that the ATLCAR.CD30.CCR4 cells will be guided directly toward the tumor cells based on their navigation system

The research team is conducting 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
  • To estimate the number of patients whose cancer does not get worse (progress) after receiving ATLCAR.CD30.CCR4 cells alone or combined with ATLCAR.CD30 cells.

Condition or disease Intervention/treatment Phase
Lymphoma Lymphoma, Non-Hodgkin Immune System Diseases Immunoproliferative Disorders Lymphatic Diseases Lymphoproliferative Disorders Neoplasms Biological: ATLCAR.CD30.CCR4 cells Biological: ALTCAR.CD30 cells Drug: Bendamustine Drug: Fludarabine Phase 1

Detailed Description:

This study is a single center, open-label Phase I clinical trial designed to determine the safety of escalating doses of autologous activated T lymphocytes (ATLs) expressing the chimeric antigen receptor specific for the CD30 antigen and the CCR4 chemokine receptor (ATLCAR.CD30.CCR4) in subjects with relapsed/refractory CD30+ Hodgkin (HL) and Non-Hodgkin lymphoma (NHL). Subjects will receive either ATLCAR.CD30.CCR4 or two ATL products simultaneously: one ATL product in which T cells co-express CAR.CD30 and CCR4 (ATLCAR.CD30.CCR4) and one ATL product encoding only the CAR.CD30 (ATLCAR.CD30). The dose for ATLCAR.CD30 will be fixed at the highest dose level as this product has been shown to be safe in phase I trials with and without lymphodepletion. Six dose levels of ATLCAR.CD30.CCR4 will be tested. Prior to receiving the infusions, subjects will undergo lymphodepletion with bendamustine and fludarabine, The 3+3 design will be used for estimating the maximum tolerated dose (MTD) of ATLCAR.CD30.CCR4 cell infusions. Secondary endpoints include evaluation of persistence of ATLCAR.CD30.CCR4 vs. ATLCAR.CD30 in the peripheral blood, accumulation of ATLCAR.CD30.CCR4 vs. ATLCAR.CD30 in tumor biopsies, and progression free survival (PFS). The study will enroll up to a maximum of 44 subjects.

OUTLINE

Cell Procurement

Up to 300 mL total of peripheral blood will be obtained (in up to 3 collections) from subjects for cell procurement. In subjects with a low absolute lymphocyte count (< 0.5 x 109/L) in the peripheral blood, a leukapheresis may be performed to isolate sufficient T cells. The parameters for pheresis will be up to 2 blood volumes.

Cell Administration

ATLCAR.CD30.CCR4 with or without ATLCAR.CD30 cells will be given to eligible subjects 2-14 days (preferably 2-4 days) after lymphodepletion with fludarabine and bendamustine. The dose of cells will vary, depending on the cohort enrolled. The cells will be administered by a licensed provider (oncology nurse or physician) via intravenous injection over 1-10 minutes through either a peripheral or a central line. The expected volume will be 1-50cc. Subjects in the dose expansion part of the study who received the highest safe dose level of ATLCAR.CD30 and ATLCAR.CD30.CCR4 may receive a second infusion of ATLCAR.CD30 and ATLCAR.CD30.CCR4 if cells are available equal to the dose administered for the first cell infusion (or a lower dose).

Duration of Therapy

Therapy in LCCC1606-ATL involves one to two infusion(s) of ATLCAR.CD30.CCR4 with or without ATLCAR.CD30 cells. Treatment with one infusion will be administered unless:

  • Subject decides to withdraw from study treatment, OR
  • General or specific changes in the subject's condition render the subject unacceptable for further treatment in the judgment of the investigator.

Duration of Follow-up

Subjects who receive a cell infusion will be followed for up to 15 years for replication competent retrovirus (RCR) evaluation or until death, whichever occurs first. Subjects who are removed from study and do not receive the cellular therapy product due to unacceptable adverse events will be followed until resolution or stabilization of the adverse event. Subjects who have progressive disease or initiate another cancer therapy after receiving a cell infusion(s) will still be required to complete abbreviated follow up procedures.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
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 CD30+ Non-Hodgkin Lymphoma
Actual Study Start Date : December 12, 2018
Estimated Primary Completion Date : May 30, 2021
Estimated Study Completion Date : May 30, 2036

Resource links provided by the National Library of Medicine


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). Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to adverse event.


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 NHL. [ 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 NHL 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 NHL 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 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.
  • Diagnosis of recurrent HL or NHL 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.
    • For CD30+ Non-Hodgkin Lymphoma, the subject must have failed an anthracycline containing regimen.
    • 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

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Responsible Party: UNC Lineberger Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT03602157     History of Changes
Other Study ID Numbers: LCCC 1606-ATL
First Posted: July 26, 2018    Key Record Dates
Last Update Posted: January 4, 2019
Last Verified: January 2019
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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Lymphoma
Disease
Lymphoproliferative Disorders
Lymphoma, Non-Hodgkin
Immune System Diseases
Lymphatic Diseases
Immunoproliferative Disorders
Neoplasms by Histologic Type
Neoplasms
Pathologic Processes
Fludarabine
Fludarabine phosphate
Bendamustine Hydrochloride
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Alkylating
Alkylating Agents