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
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|
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.
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.
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||36 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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|
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
70 mg/m^2/day Bendamustine for 3 days for lymphodepletion prior to cell infusion
30 mg/m^2/day Fludarabine for 3 days for lymphodepletion prior to cell infusion
- 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.
- 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
- 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
- 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
- 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
- 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
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
|Contact: Catherine Chengemail@example.com|
|Contact: Spencer Laingfirstname.lastname@example.org|
|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 email@example.com|
|Contact: Spencer Laing 919-962-8618 firstname.lastname@example.org|
|Principal Investigator:||Natalie Grover, MD||UNC Lineberger Comprehensive Cancer Center|