Symptoms and General Pathology

All Conditions

Neoplasms

Blood and Lymph Conditions

Immune System Diseases

Infections

Rare Diseases

Syndrome

Lymphoma

Lymphoma, T-Cell

Lymphoma, T-Cell, Peripheral

Mycoses

Lymphoproliferative Disorders

Hodgkin Disease

Mycosis Fungoides

Lymphoma, T-Cell, Cutaneous

Sezary Syndrome

Immunoproliferative Disorders

Lymphatic Diseases

Lymphoma, Large-Cell, Anaplastic

Lymphomatoid Papulosis

Neoplasms by Histologic Type

Lymphoma, Non-Hodgkin

Communicable Diseases

Bacterial Infections

Bacterial Infections and Mycoses

Lymphosarcoma

Peripheral T-cell Lymphoma

Hodgkin Lymphoma

Cutaneous T-cell Lymphoma

Gray Zone Lymphoma

Anaplastic Large Cell Lymphoma

Antineoplastic Agents

All Drugs and Chemicals

Fludarabine

Fludarabine phosphate

Bendamustine Hydrochloride

Antineoplastic Agents, Alkylating

Alkylating Agents

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.

Three dose levels are being evaluated: 2x10\^7, 5x10\^7, 1x10\^8

ATLCAR.CD30.CCR4 cells

ALTCAR.CD30 cells

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

Bendamustine

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

Catherine Cheng

Caroline Babinec

Natalie Grover, MD

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

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) co-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 cutaneous T Cell Lymphoma (CTCL). Subjects with grey zone lymphoma will also be eligible to enroll on this protocol; the characteristics of grey zone lymphoma are very similar to HL and therefore will be referred to collectively throughout the protocol under the general term of HL. Subjects will receive either ATLCAR.CD30.CCR4 or the ATLCAR.CD30.CCR4 product in combination with an 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 total dose levels of ATLCAR.CD30.CCR4 with or without ATLCAR.CD30 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 in combination with ATLCAR.CD30. Any dose level may be expanded to 4-9 subjects to explore adverse events (AEs) of special interest prior to moving to the next dose level. If due to the expansion ≥1/3 of the total number of subject on that dose level experiences a DLT, the study would not escalate to the next highest dose level and the maximum tolerated dose would be exceeded. The final MTD will be the highest dose of ATLCAR.CD30.CCR4 and ATLCAR.CD30 with observed DLT rate of less than 1/3. An expansion cohort will enroll up to 8 subjects at the MTD of ATLCAR.CD30.CCR4 and ATLCAR.CD30 to further assess safety and efficacy of these cellular products. 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).

LCCC1606-ATL builds on LCCC1532-ATL, a phase Ib/II trial investigating the safety and efficacy of ATLCAR.CD30 in subjects with CD30+ lymphoma.

OUTLINE

Cell Procurement

Up to 300 mL total of peripheral blood will be obtained (in up to 3 collections) from subjects for cell procurement. Up to 300 mL total of peripheral blood will be obtained (in up to 3 collections) from subjects for cell procurement. Additionally, leukapheresis may be performed to isolate sufficient cells in subjects with a low absolute lymphocyte count or who had inadequate peripheral blood collection. The parameters for apheresis will be up to 2 blood volumes. Collected peripheral blood may be used for generation of CAR-T cells if the cells were collected on another CAR-T cell trial for which Lineberger Comprehensive Cancer Center is the sponsor and if the subject is eligible for procurement/screening on the LCCC 1606-ATL protocol. ATLCAR.CD30 cells manufactured for a different protocol may be used for LCCC 1606-ATL, if they fit specifications for the protocol and the patient qualifies for the protocol.

Lymphodepletion Regimen

In order to receive lymphodepletion and CAR-T cells, subjects must still have evidence of active disease.

All subjects will receive lymphodepletion with bendamustine 70 mg/m2 and fludarabine 30 mg/m2 for 3 days to reduce possible toxicity associated with the agent prior to administration of CAR-T cells.

NOTE: Any subject who tests positive for Hepatitis B core antibody and negative for Hepatitis B viral load during screening must initiate an anti-Hepatitis B prophylaxis regimen prior to lymphodepletion.

Bendamustine and fludarabine will be administered concomitantly for lymphodepletion (i.e., intravenous (IV) administration of bendamustine 70 mg/m2/day over 3 consecutive days and IV fludarabine 30 mg/m2/day over 3 consecutive days) prior to the first CAR-T cell infusion. Bendamustine should be administered first followed by IV administration of fludarabine.

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.

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

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

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.

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

Overall survival will be measured from the date of administration of ATLCAR.CD30.CCR4 with and without ATLCAR.CD30 infusion to date of death

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 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 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

University Cancer Research Fund at Lineberger Comprehensive Cancer Center

Stand Up To Cancer

UNC Lineberger Comprehensive Cancer Center

Recurrence

Leukemia

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Hematologic Neoplasms

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Lymphoma, Large B-Cell, Diffuse

Burkitt Lymphoma

Hematologic Diseases

Lymphoma, B-Cell

Epstein-Barr Virus Infections

Virus Diseases

Herpesviridae Infections

DNA Virus Infections

Tumor Virus Infections

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Acute Non Lymphoblastic Leukemia

Diffuse Large B-Cell Lymphoma

Acute Graft Versus Host Disease

B-cell Lymphoma

Anti-Infective Agents

Cytarabine

Daunorubicin

CPX-351 is made up of two chemotherapy drugs that patients may have already received called cytarabine and daunorubicin that are now packaged together. Subjects will receive a single course of CPX-351 administered on Days 1, 3, and 5.

CPX-351

John Perentesis, MD

The purpose of this study is to test the safety of a study drug called CPX-351. This drug has been tested in adults but not yet in children and adolescents. This study tests different doses of the drug to see which dose is safer in children and adolescents.

Patients who have blood cancer are being asked to take part in this study . Blood cancers may include leukemia and lymphoma. Patients able to be in this study have already been treated with standard chemotherapy for their disease and the disease is still growing or has come back.

CPX-351 is a drug that is not yet approved by the United States Food and Drug Administration (FDA) and is only used in research studies like this one. CPX-351 is made up of two chemotherapy drugs that patients may have already received called cytarabine and daunorubicin that are now packaged together.

Another purpose of this study is to collect blood samples for special research studies. Researchers want to study how much of the CPX-351 is in the body over time. These studies are call pharmacokinetic studies or PK studies for short. PK studies require the collection of several blood samples before and after participants are given the study drug.

Cytarabine in combination with an anthracycline is a frequently used chemotherapy platform for both newly diagnosed and relapsed/refractory acute myeloid leukemia (AML) and other hematologic malignancies. Synergistic antitumor activity has been demonstrated between cytarabine and daunorubicin that is dependent upon the ratio of the drugs with the best therapeutic effect observed with a cytarabine to daunorubicin ratio of 5:1 in in vitro and in vivo models. CPX-351 is a liposomal preparation of cytarabine and daunorubicin that maintains this therapeutic drug ratio 24 hours post infusion. The altered biodistribution from encapsulation may result in a greater therapeutic effect in patients with relapsed hematologic malignancies and demonstrate greater tolerability than non-liposomal cytarabine and daunorubicin.

This is a single institution phase-I pilot study that aims to assess the pharmacokinetics, toxicity and tolerability of CPX-351 in pediatric and young adults with relapsed/refractory hematologic malignancies. Subjects will receive a single course of CPX-351 administered on Days 1, 3, and 5. The study will first open to children in a dose exploration phase, and then be available to an expanded cohort, which will be open to children and young adults once a tolerable dose has been determined.

Safety Study of CPX-351 in Children With Relapsed Leukemia or Lymphoma

A Phase I/Pilot Study of CPX-351 for Children, Adolescents and Young Adults With Recurrent or Refractory Hematologic Malignancies

Any Grade 3 or greater adverse event that can be possible/probably/or definitely attributable to CPX-351 that occurs between Day 1 and Day 56.

If 2 or more participants have dose limiting toxicities at a given dose level, the maximum tolerated dose will have been exceeded.

Blood samples will be collected on Day 5 (prior to CPX-351 infusion, 45 minutes (mid infusion), 90 minutes (immediately post-infusion), 2 hr, 5 hr, 8 hr, 12 hrs, Day 6, Day 8, and Day 10. Serum will be analyzed for drug and metabolite concentrations.

Tumor measurements will be used to assess disease response per standard response criteria for acute myeloid leukemia, acute lymphoid leukemia and lymphoma.

Jazz Pharmaceuticals

Children's Hospital Medical Center, Cincinnati

Digestive System Diseases

Intestinal Diseases

Lymphoma, Extranodal NK-T-Cell

Immunoblastic Lymphadenopathy

Enteropathy-Associated T-Cell Lymphoma

Angioimmunoblastic T-cell Lymphoma

Angioimmunoblastic Lymphadenopathy With Dysproteinemia

Enteropathy-associated T-cell Lymphoma

Antirheumatic Agents

Cyclophosphamide

Immunomodulating Agents

Immunosuppressive Agents

Immunologic Factors

All patients will be receiving starting dose: 0.3x10\^6 Chimeric Antigen Receptor (CAR)+ T cells/kg (weight based dosing) (up to a maximum dose of 18x10\^6 CAR+ T cells/kg) infuse on day 0 and Cyclophosphamide: 300 or 500 mg/m\^2 intravenous (IV) infusion over 30 minutes on days -5, -4 and -3 and Fludarabine: 30 mg/m\^2 IV infusion over 30 minutes administered immediately following the cyclophosphamide on days -5, -4, and -3

Dose-escalation trial starting dose: 0.3x10\^6 Chimeric Antigen Receptor (CAR)+ T cells/kg (weight based dosing) (up to a maximum dose of 18x10\^6 CAR+ T cells/kg) infuse on day 0

Anti-Tumor Necrosis Factor (TNF) Receptor Superfamily Member 8 (CD30) Chimeric Antigen Receptor (CAR) T cells

300 or 500 mg/m\^2 intravenous (IV) infusion over 30 minutes on days -5, -4 and -3

30 mg/m\^2 intravenous (IV) infusion over 30 minutes administered immediately following the cyclophosphamide on days -5, -4, and -3

James N Kochenderfer, M.D.

Background:

* Improved treatments for a variety of treatment-resistant, TNFRSF8 (CD30)-expressing malignancies including Hodgkin lymphoma, anaplastic large cell lymphoma, and other CD30- expressing lymphomas are needed.
* T cells can be genetically modified to express chimeric antigen receptors (CARs) that specifically target malignancy-associated antigens.
* Autologous T cells genetically modified to express CARs targeting the B-cell antigen B-lymphocyte antigen CD19 (CD19) have caused complete remissions in a small number of patients with lymphoma. These results demonstrate that CAR-expressing T cells can have anti-lymphoma activity in humans.
* CD30 expression can be easily detected by immunohistochemistry on lymphoma cells, which allows selection of CD30-expressing malignancies for treatment.
* CD30 is not known to be expressed by normal cells except for a small number of activated lymphocytes.
* We have constructed a novel fully-human anti-CD30 CAR that can specifically recognize CD30-expressing target cells in vitro and eradicate CD30-expressing tumors in mice.
* This particular CAR has not been tested before in humans.
* Possible toxicities include cytokine-associated toxicities such as fever, hypotension, and neurological toxicities. Elimination of a small number of normal activated lymphocytes is possible, and unknown toxicities are also possible.

Objectives:

Primary

-Determine the safety and feasibility of administering T-cells expressing a novel fully human anti-CD30 CAR to patients with advanced CD30-expressing lymphomas.

Eligibility:

* Patients must have anaplastic large cell lymphoma, peripheral T-cell lymphoma not otherwise specified, diffuse large B-cell lymphoma not otherwise specified, primary mediastinal B-cell lymphoma, grey zone lymphoma, enteropathy associated T-cell lymphoma, or extranodal natural killer (NK)/T-cell lymphoma, nasal type
* Patients must have malignancy that is both measurable on a computed tomography (CT) scan with a largest diameter of at least 1.5 cm and possessing increased metabolic activity detectable by positron emission tomography (PET) scan. Alternatively, patients with lymphoma detected by flow cytometry of bone marrow are eligible.
* Patients must have a creatinine of 1.6 mg/dL or less and a normal cardiac ejection fraction.
* An Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 is required.
* No active infections are allowed including evidence of active human immunodeficiency virus (HIV), hepatitis B, or hepatitis C. At the time of protocol enrollment patients must be seronegative for cytomegalovirus (CMV) by antibody testing or must have a negative blood CMV polymerase chain reaction (PCR).
* Absolute neutrophil count greater than or equal to 1000/micro L, platelet count greater than or equal to 55,000/micro L, hemoglobin greater than or equal to 8g/dL
* Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less or equal to 3 times the upper limit of the institutional normal unless liver involvement by malignancy is demonstrated.
* At least 14 days must elapse between the time of any prior systemic treatment (including corticosteroids above 5 mg/day of prednisone or equivalent corticosteroid dose) and initiation of required leukapheresis.
* Clear CD30 expression must be detected on 75% or more of malignant cells from either bone marrow or lymphoma mass by flow cytometry or immunohistochemistry. The patient s malignancy will need to be assessed for CD30 expression by flow cytometry or immunohistochemistry performed at the National Institutes of Health (NIH). If unstained, paraffin-embedded bone marrow or lymphoma sections are available from prior biopsies, these can be used to determine CD30 expression by immunohistochemistry; otherwise, patients will need to come to the NIH for a biopsy to determine CD30 expression. The sample for CD30 expression can come from a biopsy obtained at any time before enrollment, unless the patient has received a prior anti-CD30 monoclonal antibody, in which case the sample must come from a biopsy following completion of the most recent anti-CD30 monoclonal antibody treatment.
* Eligible patients with diffuse large B-cell lymphoma or primary mediastinal B-cell lymphoma must have received 2 prior treatment regimens at least 1 of which included an anthracycline and an anti-CD20 monoclonal antibody.
* Patients who have never had an allogeneic hematopoietic stem cell transplant as well as patients who have had a 9/10 or 10/10 human leukocyte antigen (HLA)-matched sibling or a 9/10 or 10/10 HLA- matched unrelated donor hematopoietic stem cell transplant are potentially eligible.
* Women who are pregnant or plan to become pregnant will be excluded.

Background:

* Improved treatments for a variety of treatment-resistant, TNFRSF8 (CD30)-expressing malignancies including Hodgkin lymphoma, anaplastic large cell lymphoma, and other CD30- expressing lymphomas are needed.
* T cells can be genetically modified to express chimeric antigen receptors (CARs) that specifically target malignancy-associated antigens.
* Autologous T cells genetically modified to express CARs targeting the B-cell antigen B-lymphocyte antigen CD19 (CD19) have caused complete remissions in a small number of patients with lymphoma. These results demonstrate that CAR-expressing T cells can have anti-lymphoma activity in humans.
* CD30 expression can be easily detected by immunohistochemistry on lymphoma cells, which allows selection of CD30-expressing malignancies for treatment.
* CD30 is not known to be expressed by normal cells except for a small number of activated lymphocytes.
* We have constructed a novel fully-human anti-CD30 CAR that can specifically recognize CD30-expressing target cells in vitro and eradicate CD30-expressing tumors in mice.
* This particular CAR has not been tested before in humans.
* Possible toxicities include cytokine-associated toxicities such as fever, hypotension, and neurological toxicities. Elimination of a small number of normal activated lymphocytes is possible, and unknown toxicities are also possible.

Objectives:

Primary

-Determine the safety and feasibility of administering T-cells expressing a novel fully-human anti-CD30 CAR to patients with advanced CD30-expressing lymphomas.

Eligibility:

* Patients must have anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma not otherwise specified, diffuse large B-cell lymphoma not otherwise specified, primary mediastinal B-cell lymphoma, grey zone lymphoma, enteropathy-associated T-cell lymphoma, or extranodal natural killer (NK)//T-cell lymphoma, nasal type
* Patients must have malignancy that is both measurable on a computed tomography (CT) scan with a largest diameter of at least 1.5 cm and possessing increased metabolic activity detectable by positron emission tomography (PET) scan. Alternatively, patients with lymphoma detected by flow cytometry of bone marrow are eligible.
* Patients must have a creatinine of 1.6 mg/dL or less and a normal cardiac ejection fraction.
* An Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 is required.
* No active infections are allowed including evidence of active human immunodeficiency virus (HIV), hepatitis B, or hepatitis C. At the time of protocol enrollment, patients must be seronegative for cytomegalovirus (CMV) by antibody testing or must have a negative blood CMV polymerase chain reaction (PCR).
* Absolute neutrophil count greater than or equal to 1000/micro L, platelet count greater than or equal to 55,000/micro L, hemoglobin greater than or equal to 8g/dL
* Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less or equal to 3 times the upper limit of the institutional normal unless liver involvement by malignancy is demonstrated.
* At least 14 days must elapse between the time of any prior systemic treatment (including corticosteroids above 5 mg/day of prednisone or equivalent corticosteroid dose) and initiation of required leukapheresis.
* Clear CD30 expression must be detected on 75% or more of malignant cells from either bone marrow or lymphoma mass by flow cytometry or immunohistochemistry. The patient s malignancy will need to be assessed for CD30 expression by flow cytometry or immunohistochemistry performed at the National Institutes of Health (NIH). If unstained, paraffin-embedded bone marrow or lymphoma sections are available from prior biopsies, these can be used to determine CD30 expression by immunohistochemistry; otherwise, patients will need to come to the NIH for a biopsy to determine CD30 expression. The sample for CD30 expression can come from a biopsy obtained at any time before enrollment, unless the patient has received a prior anti-CD30 monoclonal antibody, in which case the sample must come from a biopsy following completion of the most recent anti-CD30 monoclonal antibody treatment.
* Eligible patients with diffuse large B-cell lymphoma or primary mediastinal B-cell lymphoma must have received 2 prior treatment regimens at least 1 of which included an anthracycline and an anti-CD20 monoclonal antibody.
* Patients who have never had an allogeneic hematopoietic stem cell transplant as well as patients who have had a 9/10 or 10/10 human leukocyte antigen (HLA)-matched sibling or a 9/10 or 10/10 HLA- matched unrelated donor hematopoietic stem cell transplant are potentially eligible.
* Women who are pregnant or plan to become pregnant will be excluded.

Design:

* This is a phase I dose-escalation trial.
* Patients will undergo leukapheresis.
* T cells obtained by leukapheresis will be genetically modified to express an anti-CD30 CAR.
* Patients will receive a lymphocyte-depleting chemotherapy conditioning regimen with the intent of enhancing the activity of the infused anti-CD30 CAR-expressing T cells.
* A chemotherapy conditioning regimen of cyclophosphamide and fludarabine will be administered prior to all CAR T-Cell infusions. Fludarabine will be given on the same days as the cyclophosphamide.
* Two days after the chemotherapy ends, patients will receive an infusion of anti-CD30-CAR-expressing T cells.
* The initial dose level of this dose-escalation trial will be 0.3x10(6) CAR+ T cells/kg of recipient bodyweight for Cohort 1. The initial dose level will be 1 x 10 (6) CAR+T cells/kg for Cohort 2.
* The cell dose administered will be escalated until a maximum tolerated dose is determined.
* Following the T-cell infusion, there is a mandatory 9-day inpatient hospitalization to monitor for toxicity.
* Outpatient follow-up is planned for 2 weeks and 1, 2, 3, 4, 6, 9, and 12 months after the CAR T-cell infusion. Long-term gene-therapy follow-up consisting of yearly visits to a doctor near the patients home for 4 more years and then yearly telephone contact for 10 additional years will be required.
* As of Amendment E (Protocol version: 08/03/2018), repeat treatments consisting of the conditioning chemotherapy followed by a CAR T-cell infusion at the maximum tolerated dose (MTD) for the patients cohort are allowed for eligible patients with any best responses except continuing complete remission or progressive malignancy.
* Re-enrollment will be allowed for a small number of subjects.

T Cells Expressing a Fully-Human Anti-CD30 Chimeric Antigen Receptor for Treating CD30-Expressing Lymphomas

Anti-CD30 CAR T Cells With Fully-human Binding Domains for Treating CD30-expressing Lymphomas Including Anaplastic Large Cell Lymphomas

We will share coded, linked data in an National Institutes of Health (NIH)-funded or approved public repository. Coded, linked data in Biomedical Translational Research Information System (BTRIS).

Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

A DLT is defined as toxicities occurring within 30 days of CAR T-cell infusion. DLT's are Grade 3 or Grade 4 toxicities possibly, probably, or definitely related to either the anti-CD30 CAR T cells or the fludarabine and cyclophosphamide chemotherapy conditioning regimen and lasting more than 7 days. A DLT will only be considered in participants who have received CAR T-cell infusions.

Maximum tolerated dose is defined as the dose at which a maximum of 1 of 6 participants has a dose-limiting toxicity (DLT). A DLT is defined as toxicities occurring within 30 days of CAR T-cell infusion. DLT's are Grade 3 or Grade 4 toxicities possibly, probably, or definitely related to either the anti-CD30 CAR T cells or the fludarabine and cyclophosphamide chemotherapy conditioning regimen and lasting more than 7 days. A DLT will only be considered in participants who have received CAR T-cell infusions.

Peak percentage and the percentage 1 month after infusion of peripheral blood mononuclear cells (PBMC) that expressed the Chimeric Antigen Receptor (CAR) T-cells assessed by polymerase chain reaction (PCR).

Response was measured using the Cheson et al. Revised Response Criteria for Malignant Lymphoma, Journal of Clinical Oncology 2007 and Recommendations for Initial Evaluation, Staging, and Response Assessment of Non-Hodgkin Lymphoma: The Lugano Classification Journal of Clinical Oncology, 2014). Complete Response (CR) is complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. Partial Response (PR) is ≥ 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses. Progressive Disease (PD) ≥ 50% increase from nadir in the sum of the products of at least two lymph nodes, or appearance of a new lesion greater than 1.5 cm in any axis even if other lesions are decreasing in size. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

National Cancer Institute (NCI)

Principal Investigator

Participants who have not had an allogeneic hematopoietic stem cell transplant. 0.3x10\^6 Chimeric Antigen Receptor (CAR) T cells per kg of recipient bodyweight

Starting dose: 0.3x10\^6 Chimeric Antigen Receptor (CAR)+ T cells/kg (weight based dosing) infuse on day 0 and Cyclophosphamide: 300 mg/m\^2 intravenous (IV) infusion over 30 minutes on days -5, -4 and -3 and Fludarabine: 30 mg/m\^2 IV infusion over 30 minutes administered immediately following the cyclophosphamide on days -5, -4, and -3

Dose Escalation Cohort 1 Dose Level 1 - 0.3x10^6 Chimeric Antigen Receptor (CAR) T Cells Per kg

Participants who have not had an allogeneic hematopoietic stem cell transplant. 1.0x10\^6 Chimeric Antigen Receptor (CAR) T cells per kg of recipient bodyweight

1.0x10\^6 Chimeric Antigen Receptor (CAR)+ T cells/kg (weight based dosing) infuse on day 0 and Cyclophosphamide: 300 mg/m\^2 intravenous (IV) infusion over 30 minutes on days -5, -4 and -3 and Fludarabine: 30 mg/m\^2 IV infusion over 30 minutes administered immediately following the cyclophosphamide on days -5, -4, and -3

Dose Escalation Cohort 1 Dose Level 2 - 1.0x10^6 Chimeric Antigen Receptor (CAR) T Cells Per kg

Participants who have not had an allogeneic hematopoietic stem cell transplant. 3.0x10\^6 Chimeric Antigen Receptor (CAR) T cells per kg of recipient bodyweight

3.0x10\^6 Chimeric Antigen Receptor (CAR)+ T cells/kg (weight based dosing) infuse on day 0 and Cyclophosphamide: This chemotherapy dose was changed part-way through the protocol, thus 4 participants received 500 mg/m\^2 and 3 participants received 300 mg/m\^2 intravenous (IV) infusion over 30 minutes on days -5, -4 and -3 and Fludarabine: 30 mg/m\^2 IV infusion over 30 minutes administered immediately following the cyclophosphamide on days -5, -4, and -3.

Dose Escalation Cohort 1 Dose Level 3 - 3.0x10^6 Chimeric Antigen Receptor (CAR) T Cells Per kg

Participants who have not had an allogeneic hematopoietic stem cell transplant. 9.0x10\^6 Chimeric Antigen Receptor (CAR) T cells per kg of recipient bodyweight

9.0x10\^6 Chimeric Antigen Receptor (CAR)+ T cells/kg (weight based dosing) infuse on day 0 and Cyclophosphamide: 500 mg/m\^2 intravenous (IV) infusion over 30 minutes on days -5, -4 and -3 and Fludarabine: 30 mg/m\^2 IV infusion over 30 minutes administered immediately following the cyclophosphamide on days -5, -4, and -3

Dose Escalation Cohort 1 Dose Level 4 - 9.0x10^6 Chimeric Antigen Receptor (CAR) T Cells Per kg

Participants who have had an Human Leukocyte Antigen (HLA)-matched sibling or an 8/8-HLA-matched unrelated donor transplant.

1.0x10\^6 Chimeric Antigen Receptor (CAR) T cells per kg of recipient bodyweight

1.0 x10\^6 Chimeric Antigen Receptor (CAR)+ T cells/kg (weight based dosing) infuse on day 0 and Cyclophosphamide: 300 mg/m\^2 intravenous (IV) infusion over 30 minutes on days -5, -4 and -3 and Fludarabine: 30 mg/m\^2 IV infusion over 30 minutes administered immediately following the cyclophosphamide on days -5, -4, and -3

Dose Escalation Cohort 2 Dose Level 1 - 1.0x10^6 Chimeric Antigen Receptor (CAR) T Cells Per kg

Participants who have had an Human Leukocyte Antigen (HLA)-matched sibling or an 8/8 HLA-matched unrelated donor transplant.

3.0x10\^6 Chimeric Antigen Receptor (CAR) T cells per kg of recipient bodyweight

3.0x10\^6 Chimeric Antigen Receptor (CAR)+ T cells/kg (weight based dosing) infuse on day 0 and Cyclophosphamide: 300 mg/m\^2 intravenous (IV) infusion over 30 minutes on days -5, -4 and -3 and Fludarabine: 30 mg/m\^2 IV infusion over 30 minutes administered immediately following the cyclophosphamide on days -5, -4, and -3

Dose Escalation Cohort 2 Dose Level 2 - 3.0x10^6 Chimeric Antigen Receptor (CAR) T Cells Per kg

Participants in this group were enrolled but not treated.

Cohort 1 No Level Assigned - Enrolled But Not Treated

Cohort 2 No Level Assigned - Enrolled But Not Treated

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

2 participants who had baseline data collected and were enrolled but not treated, is reported here.

Dr. James N. Kochenderfer

All participants in Dose Escalation groups Cohort 1 and Cohort 2.

All Participants

Maximum Tolerated Dose of Anti-Tumor Necrosis Factor (TNF) Receptor Superfamily Member 8 (CD30) Chimeric Antigen Receptor (CAR) in Participants With Advanced CD30-expressing Lymphomas

Participant #1 - Peak percentage of CAR+ cells among peripheral blood mononuclear cells

Participant #2 - Peak percentage of CAR+ cells among peripheral blood mononuclear cells

Participant #4 - Peak percentage of CAR+ cells among peripheral blood mononuclear cells

Participant #5 - Peak percentage of CAR+ cells among peripheral blood mononuclear cells

Participant #6 - Peak percentage of CAR+ cells among peripheral blood mononuclear cells

Participant #7 - Peak percentage of CAR+ cells among peripheral blood mononuclear cells

Participant #9 - Peak percentage of CAR+ cells among peripheral blood mononuclear cells

Participant 10 - Peak percentage of CAR+ cells among peripheral blood mononuclear cells

Participant #11 - Peak percentage of CAR+ cells among peripheral blood mononuclear cells

Participant #12 - Peak percentage of CAR+ cells among peripheral blood mononuclear cells

Participant #13 - Peak percentage of CAR+ cells among peripheral blood mononuclear cells

Participant 14 - Peak percentage of CAR+ cells among peripheral blood mononuclear cells

Participant #15 - Peak percentage of CAR+ cells among peripheral blood mononuclear cells

Participant #17 - Peak percentage of CAR+ cells among peripheral blood mononuclear cells

Participant #18 - Peak percentage of CAR+ cells among peripheral blood mononuclear cells

Participant #19 - Peak percentage of CAR+ cells among peripheral blood mononuclear cells

Participant #20 - Peak percentage of CAR+ cells among peripheral blood mononuclear cells

Participant #21 - Peak percentage of CAR+ cells among peripheral blood mononuclear cells

Participant #22 - Peak percentage of CAR+ cells among peripheral blood mononuclear cells

Participant #24 - Peak percentage of CAR+ cells among peripheral blood mononuclear cells

Participant #25 - Peak percentage of CAR+ cells among peripheral blood mononuclear cells

Participant #26 - Peak percentage of CAR+ cells among peripheral blood mononuclear cells

Participant #1 - %CAR+ cells among peripheral blood mononuclear cells 1 month after infusion

Participant #2 - %CAR+ cells among peripheral blood mononuclear cells 1 month after infusion

Participant #4 - %CAR+ cells among peripheral blood mononuclear cells 1 month after infusion

Participant #5 - %CAR+ cells among peripheral blood mononuclear cells 1 month after infusion

Participant #6 - %CAR+ cells among peripheral blood mononuclear cells 1 month after infusion

Participant #7 - %CAR+ cells among peripheral blood mononuclear cells 1 month after infusion

Participant #9 - %CAR+ cells among peripheral blood mononuclear cells 1 month after infusion

#10 - %CAR+ cells among peripheral blood mononuclear cells 1 month after infusion

Participant #11 - %CAR+ cells among peripheral blood mononuclear cells 1 month after infusion

Participant #12 - %CAR+ cells among peripheral blood mononuclear cells 1 month after infusion

Participant #13 - %CAR+ cells among peripheral blood mononuclear cells 1 month after infusion

Participant #14 - %CAR+ cells among peripheral blood mononuclear cells 1 month after infusion

Participant #15 - %CAR+ cells among peripheral blood mononuclear cells 1 month after infusion

Participant #17 - %CAR+ cells among peripheral blood mononuclear cells 1 month after infusion

Participant #18 - %CAR+ cells among peripheral blood mononuclear cells 1 month after infusion

Participants #19 - %CAR+ cells among peripheral blood mononuclear cells 1 month after infusion

Participant #20 - %CAR+ cells among peripheral blood mononuclear cells 1 month after infusion

Participant #21 - %CAR+ cells among peripheral blood mononuclear cells 1 month after infusion

Participants #8, and 23 were not assigned to a dose level since they didn't receive chemo or cells. Participant # 5 first enrolled as #3 did not result in cell infusion and was re-enrolled with a new number for cell infusion. This is the same for #18 who was first enrolled as #16.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study of CAR-T Cells Expressing CD30 and CCR4 for r/r CD30+ HL and CTCL	NCT03602157	Lymphoma Immune System D... Immunoprolifera... Lymphatic Disea... Lymphoprolifera... Neoplasms Cutaneous Lymph... Cutaneous Anapl... Mycosis Fungoid... Sezary Syndrome Lymphomatoid Pa... Cutaneous T Cel... Gray Zone Lymph...	ATLCAR.CD30.CCR... ALTCAR.CD30 cel... Bendamustine Fludarabine	18 Years -	UNC Lineberger Comprehensive Cancer Center
Safety Study of CPX-351 in Children With Relapsed Leukemia or Lymphoma	NCT01943682	Acute Myeloid L... Acute Lymphobla... Burkitt Lymphom... Diffuse Large C... Gray Zone Lymph... Lymphoblastic L... Anaplastic Larg... Hodgkin Lymphom...	CPX-351	12 Months - 30 Years	Children's Hospital Medical Center, Cincinnati
T Cells Expressing a Fully-Human Anti-CD30 Chimeric Antigen Receptor for Treating CD30-Expressing Lymphomas	NCT03049449	Lymphoma, Large... Enteropathy-Ass... Lymphoma, Large... Lymphoma, Extra... Lymphoma, T-Cel...	Anti-Tumor Necr... Cyclophosphamid... Fludarabine	18 Years - 73 Years	National Institutes of Health Clinical Center (CC)
Dose-Adjusted EPOCH Chemotherapy and Rituximab (CD20+) in Previously Untreated Aggressive Non-Hodgkin's Lymphoma	NCT00001337	Diffuse Large B... Primary Mediast... Burkitt Lymphom... Anaplastic Larg... Gray Zone Lymph...	EPOCH Rituximab	12 Years -	National Institutes of Health Clinical Center (CC)
T Cells Expressing a Fully-Human Anti-CD30 Chimeric Antigen Receptor for Treating CD30-Expressing Lymphomas	NCT03049449	Lymphoma, Large... Enteropathy-Ass... Lymphoma, Large... Lymphoma, Extra... Lymphoma, T-Cel...	Anti-Tumor Necr... Cyclophosphamid... Fludarabine	18 Years - 73 Years	National Institutes of Health Clinical Center (CC)
Haploidentical BMT With Post-Transplant Cyclophosphamide and Bendamustine	NCT02996773	Acute Lymphobla... Acute Myelogeno... Myelodysplastic... Chronic Myeloge... Lymphoma,Non-Ho... Lymphoma, Hodgk... Lymphoma, Folli... Marginal Zone L... Large Cell Lymp... Mantle-Cell Lym... Gray Zone Lymph... Burkitt Lymphom... High Risk Undif...	Bendamustine Cyclophosphamid...	4 Years - 30 Years	University of Arizona

Spots Global Cancer Trial Database for gray zone lymphoma