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ATLCAR.CD30.CCR4 with or without ATLCAR.CD30 in Treating Patients with Relapsed or Refractory CD30+ Hodgkin Lymphoma or Cutaneous T-cell Lymphoma

Trial Status: Active

This phase I trial studies best dose and how well autologous CCR4-CD30CAR-CD28-CD3zeta-expressing T-Lymphocytes (ATLCAR.CD30.CCR4) with or without autologous CD30CAR-CD28-CD3zeta-expressing T-Lymphocytes (ATLCAR.CD30) works in treating patients with CD30+ Hodgkin lymphoma or cutaneous T-cell lymphoma that has come back (relapsed) or that does not respond to treatment (refractory). T cells or 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. Modified T-cells called autologous T lymphocyte chimeric antigen receptor cells targeted against the CD30 antigen (ATLCAR.CD30) and autologous T lymphocyte chimeric antigen receptor cells targeted against the CD30 antigen with CCR4 (ATLCAR.CD30.CCR4) may help the cells move to regions in the body where the cancer is present and may improve the body's ability to fight Hodgkin lymphoma or cutaneous T-cell lymphoma.

Inclusion Criteria

  • Written informed consent and Health Insurance Portability and Accountability Act (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 chimeric antigen receptor (CAR) T-cell therapy trial must be obtained prior to lymphodepletion.
  • Subjects must have one of the following diagnoses by World Health Organization (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 diffuse large B-cell lymphoma (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%.
  • For Subjects in the Expansion Cohort: 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.
  • PRIOR TO PROCUREMENT: Hemoglobin (Hgb) >= 8.0 g/dL (transfusion independent for 2 weeks prior to enrollment).
  • PRIOR TO PROCUREMENT: 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 x ULN).
  • PRIOR TO PROCUREMENT: Aspartate aminotransferase (AST) =< 3 times ULN.
  • PRIOR TO PROCUREMENT: Serum creatinine =< 1.5 times ULN.
  • PRIOR TO PROCUREMENT: Creatinine clearance (CrCl) > 60mL/min per Cockcroft and Gault.
  • PRIOR TO PROCUREMENT: Pulse oximetry of > 90% on room air.
  • PRIOR TO PROCUREMENT: 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).
  • PRIOR TO PROCUREMENT: 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.
  • PRIOR TO PROCUREMENT: Subject has no clinical indication of rapidly progressing disease in opinion of treating physician.
  • PRIOR TO PROCUREMENT: Subject has adequate cardiac function, defined as: * No electrocardiogram (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.
  • PRIOR TO LYMPHODEPLETION: Presence of active disease. Imaging results from within 7 days prior to lymphodepletion to confirm presence of active disease. Subjects 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).
  • PRIOR TO LYMPHODEPLETION: Adequate bone marrow function (absolute neutrophil count (ANC) > 1000 cells/mm^3 and platelets > 75,000/mm^3). Subjects cannot have received platelet transfusion within 7 days of lymphodepletion.
  • PRIOR TO 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 x ULN).
  • PRIOR TO LYMPHODEPLETION: AST =< 3 times ULN.
  • PRIOR TO LYMPHODEPLETION: Serum creatinine =< 1.5 times ULN.
  • PRIOR TO LYMPHODEPLETION: Creatinine clearance (CrCl) > 60 mL/min per Cockcroft and Gault.
  • PRIOR TO LYMPHODEPLETION: Pulse oximetry of > 90% on room air.
  • PRIOR TO LYMPHODEPLETION: Negative serum pregnancy test within 72 hours prior to lymphodepletion 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.
  • PRIOR TO LYMPHODEPLETION: Subjects must have autologous transduced activated T-cells that meet the Certificate of Analysis (CofA) acceptance criteria.
  • PRIOR TO LYMPHODEPLETION: Has not received any investigational agents or received any tumor vaccines within the previous six weeks prior to lymphodepletion.
  • PRIOR TO LYMPHODEPLETION: Has not received anti-CD30 antibody-based therapy within the previous 4 weeks prior to lymphodepletion.
  • PRIOR TO LYMPHODEPLETION: Has not received chemotherapy or radiation therapy within the previous 3 weeks prior to lymphodepletion.
  • 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).
  • PRIOR TO LYMPHODEPLETION: Subjects who are hepatitis B virus (HBV) core antibody positive and HBV viral load negative prior to lymphodepletion must have initiated anti-HBV prophylaxis prior to lymphodepletion.
  • PRIOR TO LYMPHODEPLETION: Subject has no clinical indication of rapidly progressing disease in the opinion of the treating physician.
  • PRIOR TO LYMPHODEPLETION: Subject is a good candidate for treatment with ATLCAR.CD30.CCR4 with and without ATLCAR.CD30 per the investigator’s discretion.
  • PRIOR TO CELL INFUSION AFTER LYMPHODEPLETION: No evidence of uncontrolled infection or sepsis.
  • PRIOR TO CELL INFUSION AFTER LYMPHODEPLETION: Bilirubin =< 2 times the upper limit of normal (ULN) unless attributed to Gilbert’s syndrome.
  • PRIOR TO CELL INFUSION AFTER LYMPHODEPLETION: AST =< 3 times ULN.
  • PRIOR TO CELL INFUSION AFTER LYMPHODEPLETION: Alanine aminotransferase (ALT) =< 3 times ULN.
  • PRIOR TO CELL INFUSION AFTER LYMPHODEPLETION: Creatinine clearance (CrCl) > 60 mL/min per Cockcroft and Gault.
  • PRIOR TO CELL INFUSION AFTER LYMPHODEPLETION: Pulse oximetry of > 90% on room air.
  • PRIOR TO CELL INFUSION AFTER LYMPHODEPLETION: Subject has no clinical indication of rapidly progressing disease in the opinion of the treating physician.
  • PRIOR TO CELL INFUSION AFTER LYMPHODEPLETION: Subject is a good candidate for treatment with ATLCAR.CD30.CCR4 with and without ATLCAR.CD30 per the investigator’s discretion.
  • PRIOR TO LYMPHODEPLETION FOR OPTIONAL REINFUSION: Karnofsky score > 60%
  • PRIOR TO LYMPHODEPLETION FOR OPTIONAL REINFUSION: 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, or 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.
  • PRIOR TO LYMPHODEPLETION FOR OPTIONAL REINFUSION: Must not be pregnant or lactating.
  • PRIOR TO LYMPHODEPLETION FOR OPTIONAL REINFUSION: Must not have tumor in a location where enlargement could cause airway obstruction.
  • PRIOR TO LYMPHODEPLETION FOR OPTIONAL REINFUSION: Must not have current use of systemic corticosteroids at doses >= 10 mg prednisone daily or its equivalent; those receiving < 10 mg daily may be enrolled at discretion of the Investigator.
  • PRIOR TO LYMPHODEPLETION FOR OPTIONAL REINFUSION: ANC > 1000 cells/mm^3. Subjects cannot have received platelet transfusion within 7 days of lymphodepletion. Note: Subjects may receive a second infusion without prior lymphodepletion or with a 25-50% dose reduction in bendamustine if they meet all other eligibility criteria at the time of infusion.
  • PRIOR TO LYMPHODEPLETION FOR OPTIONAL REINFUSION: Platelets > 75,000/mm^3. Subjects cannot have received platelet transfusion within 7 days of lymphodepletion. Note: Subjects may receive a second infusion without prior lymphodepletion or with a 25-50% dose reduction in bendamustine if they meet all other eligibility criteria at the time of infusion.
  • PRIOR TO LYMPHODEPLETION FOR OPTIONAL REINFUSION: 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 x ULN)
  • PRIOR TO LYMPHODEPLETION FOR OPTIONAL REINFUSION: AST =< 3 times ULN.
  • PRIOR TO LYMPHODEPLETION FOR OPTIONAL REINFUSION: Serum creatinine =< 1.5 times ULN.
  • PRIOR TO LYMPHODEPLETION FOR OPTIONAL REINFUSION: Creatinine clearance (CrCl) > 60 mL/min per Cockcroft and Gault
  • PRIOR TO LYMPHODEPLETION FOR OPTIONAL REINFUSION: Pulse oximetry of > 90% on room air.
  • PRIOR TO LYMPHODEPLETION FOR OPTIONAL REINFUSION: Negative serum pregnancy test within 72 hours prior to lymphodepletion 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.
  • PRIOR TO LYMPHODEPLETION FOR OPTIONAL REINFUSION: 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.
  • PRIOR TO LYMPHODEPLETION FOR OPTIONAL REINFUSION: Subject is a good candidate for treatment with ATLCAR.CD30.CCR4 with ATLCAR.CD30 per the investigator’s discretion.
  • PRIOR TO INFUSION OF OPTIONAL REINFUSION: No evidence of uncontrolled infection or sepsis.
  • PRIOR TO INFUSION OF OPTIONAL REINFUSION: Bilirubin =< 2 times the upper limit of normal (ULN) unless attributed to Gilbert’s syndrome.
  • PRIOR TO INFUSION OF OPTIONAL REINFUSION: AST =< 3 times ULN.
  • PRIOR TO INFUSION OF OPTIONAL REINFUSION: ALT =< 3 times ULN.
  • PRIOR TO INFUSION OF OPTIONAL REINFUSION: Creatinine clearance (CrCl) > 60 mL/min per Cockcroft and Gault.
  • PRIOR TO INFUSION OF OPTIONAL REINFUSION: Pulse oximetry of > 90% on room air.
  • PRIOR TO INFUSION OF OPTIONAL REINFUSION: Subject has no clinical indication of rapidly progressing disease in the opinion of the treating physician.
  • PRIOR TO INFUSION OF OPTIONAL REINFUSION: Subject is a good candidate for treatment with ATLCAR.CD30.CCR4 with ATLCAR.CD30 per the investigator’s discretion.

Exclusion Criteria

  • Pregnant or lactating.
  • Tumor in a location where enlargement could cause airway obstruction.
  • Current use of systemic corticosteroids at doses >= 10 mg prednisone daily or its equivalent; those receiving < 10 mg daily may be enrolled at discretion of the investigator.
  • Active infection with human immunodeficiency virus (HIV), human T-lymphotropic virus (HTLV), 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, negative HTLV1 and 2 antibody, and negative HCV antibody or viral load.
  • Active infection with HBV. Subjects are required to have a negative Hepatitis B surface Antigen. In addition, subjects 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.
  • Has a known additional malignancy that is active and/or progressive requiring treatment; exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder cancer, or other cancer for which the subject has been disease-free for at least three years.
  • A history of intolerance to fludarabine. Subjects with an intolerance to bendamustine may be allowed to enroll at the discretion of the clinical investigator if he/she thinks that the subject is a candidate for lymphodepletion with cyclophosphamide and fludarabine
  • Subject is not a good candidate for treatment with ATLCAR.CD30.CCR4 with and without ATLCAR.CD30 per investigator’s discretion.

North Carolina

Chapel Hill
UNC Lineberger Comprehensive Cancer Center
Status: ACTIVE
Contact: Natalie S. Grover
Phone: 919-843-5968

PRIMARY OBJECTIVE:

I. To establish a safe dose (i.e., number cells/m^2) of ATLCAR.CD30.CCR4 with and without ATLCAR.CD30 to infuse after lymphodepletion with bendamustine hydrochloride (bendamustine) and fludarabine phosphate (fludarabine) in subjects with CD30+ refractory/relapsed Hodgkin lymphoma (HL) and cutaneous T-cell lymphoma (CTCL).

SECONDARY OBJECTIVES:

I. To estimate 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.

II. To estimate median overall survival (OS) in subjects with CD30+ relapsed/refractory HL and CTCL after administration of ATLCAR.CD30.CCR4 with and without ATLCAR.CD30.

III. To estimate the 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.

IV. To estimate the differential infiltration of ATLCAR.CD30.CCR4 versus (vs.) ATLCAR.CD30 cells in tumor biopsies in subjects who received both ATLCAR.CD30.CCR4 and ATLCAR.CD30 cellular products.

V. To measure the expansion and persistence of ATLCAR.CD30.CCR4 vs. ATLCAR.CD30 in peripheral blood in subjects who received both ATLCAR.CD30.CCR4 and ATLCAR.CD30 cellular products.

EXPLORATORY OBJECTIVES:

I. To compare median progression free survival (PFS) in subjects with CD30+ relapsed/refractory HL and CTCL after infusion of ATLCAR.CD30.CCR4 with and without ATLCAR.CD30.

II. To compare median overall survival (OS) in subjects with CD30+ relapsed/refractory HL and CTCL after administration of ATLCAR.CD30.CCR4 with and without ATLCAR.CD30.

III. To compare the best overall response rate in subjects with CD30+ relapsed/refractory HL and CTCL after infusion of ATLCAR.CD30.CCR4 with and without ATLCAR.CD30.

IV. To use molecular and immunohistochemistry analysis to assess for potential causes for loss of response to ATLCAR.CD30.CCR4 with or without ATLCAR.CD30 therapy.

V. To determine whether there are correlations between CAR T cell behavior and the integration locations of CAR.CD30 or CAR.CD30.CCR4.

OUTLINE: This is a dose-escalation study of autologous CCR4-CD30CAR-CD28-CD3zeta-expressing T-lymphocytes.

Patients receive bendamustine hydrochloride intravenously (IV) and fludarabine phosphate IV for 3 days for lymphodepletion prior to cell infusion (patients with intolerance to bendamustine may receive cyclophosphamide IV instead). Beginning 2-14 days after completion of lymphodepletion chemotherapy, patients receive autologous CCR4-CD30CAR-CD28-CD3zeta-expressing T-lymphocytes IV over 1-10 minutes alone or with autologous CD30CAR-CD28-CD3zeta-expressing T-lymphocytes IV given within 3 hours. Patients in the expansion phase may receive a second infusion of autologous CCR4-CD30CAR-CD28-CD3zeta-expressing T-lymphocytes and autologous CD30CAR-CD28-CD3zeta-expressing T-lymphocytes.

After completion of study treatment, patients are followed up on day 1 of weeks 1-4 and week 6, 3, 6, 9, and 12 months, every 6 months for 4 years and then yearly for up to 15 years.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
UNC Lineberger Comprehensive Cancer Center

Principal Investigator
Natalie S. Grover

  • Primary ID LCCC1606-ATL
  • Secondary IDs NCI-2018-01904
  • Clinicaltrials.gov ID NCT03602157