Clinical Trials /

CD30 CAR for Relapsed/Refractory CD30+ T Cell Lymphoma

NCT04083495

Description:

This is a research study to determine the safety and tolerability of ATLCAR.CD30 for treating relapsed/refractory Peripheral T Cell Lymphoma. Blood samples will be collected from study participants and the immune T cells will be separated. T cells will be genetically modified in a laboratory at UNC-Chapel Hill to enable them to produce CD30 antibody. The modified T cells, called ATLCAR.CD30, will be able to target and attach to lymphoma cancer cells that carry the CD30 antigen. Once they are attached, the T cells will attack and destroy the lymphoma cancer cells. To prepare the body for the ATLCAR.CD30 cells, participants will complete lymphodepletion with two chemotherapy agents. Lymphodepletion will happen over three days prior to ATLCAR.CD30 infusion. If participants respond to this treatment, and there are sufficient unused ATLCAR.CD 30 cells, they may be eligible to receive a second infusion. The second infusion will be given after a second lymphodepletion chemotherapy. Most of the clinic visits in this research will last between 1-8 hours. Participants will be followed closely for 4 consecutive weeks after ATLCAR.CD30 infusion(s). Other follow-up visits will happen on Weeks 6 and 8, and continue every 3 months for the first year after infusion. Long-term follow up will continue annually for up to 15 years after the last ATLCAR.CD30 infusion. There are risks associated in participating in this research study. Risks of treatment include pain, fever, nausea, vomiting, and neurotoxicity. Other risks are associated with study procedures, such as biopsies, imaging, infusion, and breach of confidentiality.

Related Conditions:
  • Peripheral T-Cell Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase II Study of CD30 CAR for Relapsed/Refractory CD30+ T Cell Lymphoma
  • Official Title: Phase II Study of the Administration of T Lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) for Relapsed/Refractory CD30+ Peripheral T Cell Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: LCCC1904-ATL
  • NCT ID: NCT04083495

Conditions

  • Peripheral T Cell Lymphoma

Interventions

DrugSynonymsArms
ATLCAR.CD30 T cellsATLCAR.CD30 cells

Purpose

This is a research study to determine the safety and tolerability of ATLCAR.CD30 for treating relapsed/refractory Peripheral T Cell Lymphoma. Blood samples will be collected from study participants and the immune T cells will be separated. T cells will be genetically modified in a laboratory at UNC-Chapel Hill to enable them to produce CD30 antibody. The modified T cells, called ATLCAR.CD30, will be able to target and attach to lymphoma cancer cells that carry the CD30 antigen. Once they are attached, the T cells will attack and destroy the lymphoma cancer cells. To prepare the body for the ATLCAR.CD30 cells, participants will complete lymphodepletion with two chemotherapy agents. Lymphodepletion will happen over three days prior to ATLCAR.CD30 infusion. If participants respond to this treatment, and there are sufficient unused ATLCAR.CD 30 cells, they may be eligible to receive a second infusion. The second infusion will be given after a second lymphodepletion chemotherapy. Most of the clinic visits in this research will last between 1-8 hours. Participants will be followed closely for 4 consecutive weeks after ATLCAR.CD30 infusion(s). Other follow-up visits will happen on Weeks 6 and 8, and continue every 3 months for the first year after infusion. Long-term follow up will continue annually for up to 15 years after the last ATLCAR.CD30 infusion. There are risks associated in participating in this research study. Risks of treatment include pain, fever, nausea, vomiting, and neurotoxicity. Other risks are associated with study procedures, such as biopsies, imaging, infusion, and breach of confidentiality.

Detailed Description

      This multicenter, open-label phase 2 study will determine the efficacy and safety of
      autologous activated T lymphocytes (ATLs) expressing the chimeric antigen receptor specific
      for CD30 (ATLCAR.CD30) administered in two sequential infusions in subjects with
      relapsed/refractory CD30+ PTCL. Up to 20 subjects will receive 2 infusions of 2 × 108
      cells/m2 of ATL product expressing the CAR.CD30. Subjects will have cells procured to
      manufacture the ATLCAR.CD30 cells and during the time period required to manufacture the
      product the subjects will be able to receive standard of care bridging therapy to be
      determined by their primary local oncologist. Prior to receiving the first cell infusion,
      subjects will undergo lymphodepletion with fludarabine and bendamustine. Subjects will have
      their disease assessed at week 8 by either CT chest, abdomen and pelvis or PET/CT. Subjects
      who have stable disease (SD), partial response (PR) or complete response (CR) without
      subsequent progressive disease and meet the eligibility criteria for a second infusion, will
      receive lymphodepletion followed by a second infusion. The lymphodepletion for the second
      infusion will consist of cyclophosphamide and fludarabine.

      OUTLINE

      Cell Procurement Up to 300 mL of peripheral blood (in 2 - 3 collections) will be obtained
      from subjects for cell procurement. In subjects with inadequate lymphocyte count in the
      peripheral blood, a leukopheresis may also be performed to isolate sufficient T cells. The
      parameters for pheresis will be up to 2 blood volumes.

      Bridging Chemotherapy Subjects will be allowed to receive additional standard of care therapy
      (e.g., chemotherapy or radiation therapy) to stabilize their disease if the treating
      physician feels it is in the subject's best interests.

      Lymphodepleting Chemotherapy Prior to the initial cellular product administration subjects
      will receive a lymphodepleting regimen of fludarabine 30 mg/m2/day administered IV over 30
      min followed by an IV dose over 1 hour of bendamustine 70 mg/m2/day administered over 3
      consecutive days. These agents will be administered per institutional guidelines. Prophylaxis
      (e.g., hydration, antiemetics, etc.) needed prior to fludarabine and bendamustine
      chemotherapy will be provided per institutional guidelines 2-14 days prior to the second cell
      product administration.. Prior to the second infusion, subjects will receive a
      lymphodepletion regimen of cyclophosphamide 300 mg/m2 IV and fludarabine 30 mg/m2 each as a
      daily infusion for 3 days per institutional guidelines 2-14 days prior to the second cell
      product administration. Subjects whose absolute neutrophil count and/or platelet count takes
      ≥3 months to recovery to levels required to meet eligilibity for lymphodepletion (ANC ≥ 1.0 ×
      109/L and platelet count ≥ 50 × 109/L) prior to the second infusion will receive a 25% dose
      reduction in cycolophosphamide and fludarabine lymphodepletion for the second round of
      lymphodepletion.

      ATLCAR.CD30 Cell Administration The cellular product consisting of ATLCAR.CD30 cells will be
      administered by a licensed healthcare provider (oncology nurse or physician) via intravenous
      injection over 5 - 10 minutes through either a peripheral or a central line. The volume of
      infusion will depend upon the concentration of the cells when frozen and the size of the
      subject. The expected volume will be 1 - 50 mL. Post lymphodepletion, subjects who meet
      eligibility criteria for cellular therapy will receive ATLCAR.CD30 cells within 2 - 14 days
      after completing the lymphodepleting chemotherapy regimen. The recommended phase 2 dose
      (RP2D) determined in the phase 1 study of ATLCAR.CD30 will be administered to subjects (2 ×
      108 CAR-T/m2).

      If a subject only has enough ATLCAR.CD30 cells product for one infusion, they will still be
      able to receive one infusion of cells and will not have a 2nd lymphodepletion or infusion of
      cells. These subjects will be replaced for the purposes of efficacy determination.
    

Trial Arms

NameTypeDescriptionInterventions
ATLCAR.CD30 cellsExperimentalThe cellular product consisting of ATLCAR.CD30 cells will be administered via intravenous injection over 5 - 10 minutes through either a peripheral or a central line. The volume of infusion will depend upon the concentration of the cells when frozen and the size of the subject. Administration to eligible subjects will occur within 2 - 14 days after completing the lymphodepleting chemotherapy regimen
  • ATLCAR.CD30 T cells

Eligibility Criteria

        Inclusion Criteria for the Study

          1. Written informed consent and HIPAA authorization for release of personal health
             information explained to, understood by and signed by the subject or legally
             authorized representative.

          2. Age ≥ 18 years at the time of consent.

          3. Karnofsky score of >60%

          4. Histological or cytological evidence/confirmation of CD30+ peripheral T-cell lymphoma
             per the 2017 World Health Organization Classification of Haematopoietic and Lymphoid
             Tissues.

          5. CD30+ disease determined by biopsy after the subject's most recent anti-CD30 therapy
             prior to ATLCAR.CD30 (result can be pending at the time of cell procurement, but must
             be confirmed prior to treatment with the first infusion of ATLCAR.CD30 cells). NOTE:
             CD30+ disease requires documented CD30 expression by immunohistochemistry based on the
             institutional hematopathology standard.

          6. Subjects must have received at least two prior lines of therapy for their lymphoma. If
             transplant is given as a preplanned consolidation in first remission, it will not be
             counted as a 2nd line of therapy.

          7. Subjects relapsed after autologous or allogeneic stem cell transplant are eligible for
             this study.

          8. Female subjects of childbearing potential must have a negative serum pregnancy test
             within 72 hours prior to cell procurement. Note: Females are considered of
             childbearing potential unless they are surgically sterile (have undergone a
             hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are
             naturally postmenopausal for at least 12 consecutive months. Documentation of
             postmenopausal status must be provided.

          9. Female subjects of childbearing potential must be willing to abstain from heterosexual
             activity or to use 2 forms of effective methods of contraception from the time of
             informed consent until 6 months after study treatment discontinuation. The two
             contraception methods can be comprised of two barrier methods, or a barrier method
             plus a hormonal method or an intrauterine device that meets <1% failure rate for
             protection from pregnancy in the product label.

         10. Subject is willing and able to comply with study procedures based on the judgement of
             the investigator or protocol designee.

        Exclusion Criteria for the Study

          1. Subject is pregnant or lactating (Note: Breast milk cannot be stored for future use
             while the mother is being treated on study).

          2. Subject 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 five years.

          3. Subjects diagnosed with cutaneous T-cell lymphoma including mycosis fungoides, Sézary
             syndrome, or any other variant of cutaneous T-cell lymphoma.

          4. 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
             investigator.

          5. Active infection with HIV, HTLV, HCV (tests can be pending at the time of cell
             procurement; only those samples confirming lack of active infection will be used to
             generate transduced cells). Note: To meet eligibility subjects are required to be
             negative for HIV antibody or HIV viral load, negative for HTLV1 and 2 antibody or PCR
             negative for HTLV1 and 2, negative for HCV antibody or HCV viral load.

          6. Subjects who are positive for hepatitis B surface antigen (can be pending at the time
             of cell procurement; only those samples confirming lack of active infection will be
             used to generate transduced cells) are excluded. Subjects who are hepatitis B surface
             antigen negative but hepatitis B core antibody positive 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.

        Eligibility Criteria Prior to Cell Procurement

          1. Informed consent to undergo cell procurement understood by and signed by the subject
             or legally authorized representative; subject and/or legally authorized representative
             given a copy of informed consent form for cell procurement.

          2. Subject has life expectancy ≥ 6 weeks.

          3. Subject has evidence of adequate organ function as defined by:

               -  Hemoglobin ≥8.0 g/dL (transfusion independent for 2 weeks prior to procurement)

               -  Total bilirubin ≤ 1.5 × ULN, unless attributed to Gilbert's Syndrome

               -  AST ≤ 3 × ULN

               -  Creatinine ≤ 2 × ULN

          4. Imaging results from within 90 days prior to procurement to assess presence of active
             disease.

          5. 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.

        Eligibility Criteria Prior to Lymphodepletion

          1. Written informed consent explained to, understood by and signed by the subject or
             legally authorized representative; subject and/or legally authorized representative
             given a copy of informed consent form.

          2. Imaging results from within 10 days prior to lymphodepletion. Imaging must occur at
             least 3 weeks after most recent therapy (used as baseline measure for documentation of
             progression before the lymphodepletion) to document measurable or assessable disease.

          3. Subject must demonstrate adequate organ function prior to lymphodepletion as defined
             below. All tests must be obtained within 72 hours prior to lymphodepletion:

               -  Absolute neutrophil count ≥ 1.0 × 109/L

               -  Platelet count ≥ 50 × 109/L

               -  For Grade 4 neutropenia, Grade ≥3 febrile neutropenia, or Grade 4
                  thrombocytopenia, hold bendamustine until toxicity resolves to Grade ≤2

               -  Pulse Oximetry of >90% on room air

          4. Subject must have available autologous transduced activated T cells product that meets
             the Certificate of Analysis acceptance criteria.

          5. No major surgery within 28 days prior to lymphodepletion.

          6. Negative serum pregnancy test within 72 hours prior to lymphodepleting therapy for
             female participants of childbearing potential. Note: Females are considered of
             childbearing potential unless they are surgically sterile (have undergone a
             hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are
             naturally postmenopausal for at least 12 consecutive months.

          7. Subject has not received any investigational agents or any tumor vaccines within the
             previous six weeks prior to lymphodepletion.

          8. Subject has not received anti-CD30 antibody-based therapy within the previous 4 weeks
             prior to lymphodepletion.

          9. Subject has not received chemotherapy within the previous 3 weeks prior to
             lymphodepletion.

         10. Subject does not have rapidly progressive disease, per treating oncologist's
             discretion.

         11. Subject is a good candidate for CAR T cell therapy, per treating oncologist's
             discretion.

         12. Subjects on strong inhibitors of CYP1A2 (e.g., fluvoxamine, ciprofloxacin) as these
             may increase plasma concentrations of bendamustine, and decrease plasma concentrations
             of its metabolites. See http://medicine.iupui.edu/clinpharm/ddis/ for an updated list
             of strong inhibitors of CYP1A2.

         13. Subject is not taking a prohibited or contraindicated medication prior to
             lymphodepletion.

        Eligibility Criteria Prior to Cell Product Administration

          1. Subject has no evidence of uncontrolled infection or sepsis.

          2. Negative serum pregnancy within 7 days of cell product administration (does not need
             to be repeated if pre-lymphodepletion pregnancy test is within window).

          3. Evidence of adequate organ function as defined by:

               -  Total bilirubin ≤ 2 × ULN, unless attributed to Gilbert's syndrome

               -  AST ≤ 5 × ULN

               -  ALT ≤ 5 × ULN

               -  Creatinine ≤ 3 × ULN

               -  Pulse Oximetry of >90% on room air

          4. Subject has no clinical indication of rapidly progressing disease in the opinion of
             the clinical investigator.

          5. Subject is a good candidate for treatment with ATLCAR.CD30 cell product per the
             clinical investigator's discretion.

        Eligibility Criteria Prior to Lymphodepletion for Cell Product Administration #2

          1. Imaging results from within 21 days prior to lymphodepletion to confirm that the
             subject has derived clinical benefit from the initial infusion as assessed by the
             investigator (stable disease or better after the first ATLCAR.CD30 infusion without
             subsequent progressive disease).

          2. Subjects who experienced Grade 4 CRS or Grade 4 ICANS as a result of the initial
             ATLCAR.CD30 infusion are only eligible for a second round of lymphodepletion and
             infusion if they have partial response to the initial ATLCAR.CD30 infusion.

          3. Subject must demonstrate adequate organ function prior to lymphodepletion as defined
             below. All tests must be obtained within 24 hours prior to lymphodepletion:

               -  Absolute neutrophil count ≥ 1.0 × 109/L

               -  Platelet count ≥ 50 × 109/L

               -  For Grade 4 neutropenia, Grade ≥3 febrile neutropenia, or Grade 4
                  thrombocytopenia, hold bendamustine until toxicity resolves to Grade ≤2.

               -  Total bilirubin ≤ 2 × ULN, unless attributed to Gilbert's syndrome

               -  AST ≤ 5 × ULN

               -  ALT ≤ 5 × ULN

               -  Creatinine ≤ 3 × ULN

               -  Pulse Oximetry of >90% on room air

          4. Subject must have available autologous transduced activated T cells product that meets
             the Certificate of Analysis acceptance criteria.

          5. Negative serum pregnancy test within 72 hours prior to lymphodepleting therapy for
             female participants of childbearing potential. Note: Females are considered of
             childbearing potential unless they are surgically sterile (have undergone a
             hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are
             naturally postmenopausal for at least 12 consecutive months.

          6. Subject does not have evidence of uncontrolled infection or sepsis.

          7. Subject is not receiving a prohibited medication at time of starting lymphodepletion
             up through 72 hours after the last dose of cyclophosphamide.

          8. Subject is a good candidate for CAR T cell therapy, per treating oncologist's
             discretion.

          9. Current use of systemic corticosteroids at doses ≥10 mg prednisone daily or its
             equivalent

        Eligibility Criteria Prior to Cell Product Administration #2

          1. Subject has no evidence of uncontrolled infection or sepsis.

          2. Negative serum pregnancy within 7 days of cell product administration (does not need
             to be repeated if pre-lymphodepletion pregnancy test is within window).

          3. Evidence of adequate organ function as defined by:

               -  Total bilirubin ≤ 2 × ULN, unless attributed to Gilbert's syndrome

               -  AST ≤ 5 × ULN

               -  ALT ≤ 5 × ULN

               -  Creatinine ≤ 3 × ULN

               -  Pulse Oximetry of >90% on room air

          4. Subject has no clinical indication of rapidly progressing disease in the opinion of
             the clinical investigator.

          5. Subject is a good candidate for treatment with ATLCAR.CD30 cell product per the
             clinical investigator's discretion.
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression free survival (PFS) after administration of the ATLCAR.CD30 in subjects with relapsed/refractory CD30+ peripheral T cell lymphoma
Time Frame:2 years
Safety Issue:
Description:PFS is defined from day of initial lymphodepletion administration of the first ATLCAR.CD30 product infusion to the date of disease progression per the Revised Lugano Criteria or death as a result of any cause. Subjects who do not meet criteria for progression by the analysis data cut-off date will be censored at their last evaluable disease assessment date.

Secondary Outcome Measures

Measure:Best overall response rate (BOR) mediated by the ATLCAR.CD30 product administered in subjects with relapsed/refractory CD30+ peripheral T cell lymphoma
Time Frame:2 years
Safety Issue:
Description:The best overall response rate (BOR) will be defined as the best response recorded from the first administration of the ATLCAR.CD30 product to the date of disease progression per the Revised Lugano Criteria or death as a result of any cause.
Measure:Objective response rate (ORR) mediated by the first infusion of the ATLCAR.CD30 product administered in patients with relapsed/refractory CD30+ peripheral T cell lymphoma.
Time Frame:8 weeks
Safety Issue:
Description:The objective response rate (ORR) will be defined as the rate of complete responses (CR) + partial responses (PR) by 8 weeks from the date of first lymphodepletion prior to the first administration of the ATLCAR.CD30 product per the Revised Lugano Criteria.
Measure:Responses improved by the second infusion of the ATLCAR.CD30 product administered in subjects wwith either partial response or stable disease following the first infusion of ATLCAR.CD30
Time Frame:8 weeks
Safety Issue:
Description:The percentage of subjects who have an improvement in their response after the second administration of ATLCAR.CD30 product will be defined at 8 weeks after the second administration of the ATLCAR.CD30 product per the Revised Lugano Criteria. Subjects entering the second infusion in a complete response will be reported as continued CR (CCR) but will not be included in percentage of improved responses after the second infusion.
Measure:Safety and tolerability of administering two sequential infusions of the ATLCAR.CD30 product in subjects with relapsed/refractory CD30+ peripheral T cell lymphoma
Time Frame:8 weeks
Safety Issue:
Description: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 CRS Grading Criteria and Management Guidelines Version 3.0 (March 14, 2019). ICANS toxicity will be graded according to the ICANS Grading Criteria for Management of Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) for CAR T-Cell Therapy.
Measure:Overall survival (OS) after administration of the ATLCAR.CD30 administered to subjects with relapsed/refractory CD30+ peripheral T cell lymphoma
Time Frame:2 years
Safety Issue:
Description:Overall survival will be measured from the date of initial ATLCAR.CD30 product administration to date of death.
Measure:Comparison of the expansion and persistence of ATLCAR.CD30 in peripheral blood when infused after a single infusion of ATLCAR.CD30 cells and after two infusions with ATLCAR.CD30 cells
Time Frame:1 year
Safety Issue:
Description:Persistence and expansion of ATLCAR.CD30 in peripheral blood after a single infusion and after two infusions will be determined by quantitative polymerase chain reaction (PCR) and flow cytometry in sample of peripheral blood. Feasibility is defined as ability of subjects to receive 2 sequential infusions taking into account manufacturing and any other limiting factors to receiving a second infusion of ATLCAR.CD30

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:UNC Lineberger Comprehensive Cancer Center

Trial Keywords

  • lymphoma
  • CD30
  • peripheral T cell lymphoma

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