Clinical Trials /

Anti-CD19 Chimeric Antigen Receptor T Cells for Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma

NCT04545762

Description:

This study will assess safety and feasibility of infusing genetically modified autologous T cells transduced to express a chimeric antigen receptor targeting the B cell surface antigen Cluster of Differentiation 19 (CD19)

Related Conditions:
  • Burkitt Lymphoma
  • Diffuse Large B-Cell Lymphoma
  • Follicular Lymphoma
  • Lymphoplasmacytic Lymphoma
  • Mantle Cell Lymphoma
  • Primary Mediastinal B-Cell Lymphoma
  • Small Lymphocytic Lymphoma
  • Transformed Non-Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Anti-CD19 Chimeric Antigen Receptor T Cells for Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma
  • Official Title: A Phase 1 Clinical Trial of Anti-CD19 Chimeric Antigen Receptor T Cells for Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: 19703
  • SECONDARY ID: NCI-2020-06711
  • NCT ID: NCT04545762

Conditions

  • Refractory Non-Hodgkin Lymphoma
  • Burkitt Lymphoma
  • Mantle Cell Lymphoma
  • Follicular Lymphoma
  • Lymphoplasmacytic Lymphoma
  • Primary Mediastinal Large B Cell Lymphoma
  • Diffuse Large B Cell Lymphoma
  • Small Lymphocytic Lymphoma
  • Transformed Lymphoma

Interventions

DrugSynonymsArms
FludarabineFludarabine 30mg/m2, FludaraTreatment Regimen
CyclophosphamideCyclophosphamide 300mg/m2, Cytoxan, Endoxan, Neosar, Procytox, Revimmune, CycloblastinTreatment Regimen
anti-CD19 CAR-T cellsTreatment Regimen

Purpose

This study will assess safety and feasibility of infusing genetically modified autologous T cells transduced to express a chimeric antigen receptor targeting the B cell surface antigen Cluster of Differentiation 19 (CD19)

Detailed Description

      This is an open-label, pilot, phase 1 study to determine the safety profile of anti-CD19
      CAR-T cell infusion in participants with R/R B-cell NHL. The dose-finding cohorts in this
      study will evaluate and define the safe dose of anti-CD19 CAR-T cells. Using a "3+3" design,
      participants will be enrolled sequentially to each dose level. A dose expansion will then
      occur at the maximum tolerated dose (MTD) and dose levels that have not exceeded the MTD.

      Up to 36 participants will be enrolled and treated. Each subject will provide consent and be
      evaluated for study eligibility. Eligible subjects will undergo apheresis with collection of
      autologous peripheral blood mononuclear cells that will be used to generate CAR-T cells. The
      CAR T cells will be produced using the Miltenyi Prodigy and an FDA compliant Lentigen CD19
      targeted lentiviral vector. After successful generation of the anti-CD19 CAR-T cells (drug
      product (DP)), subjects will undergo lymphodepleting chemotherapy with fludarabine and
      cyclophosphamide followed by 2-5 days of rest. A single infusion of anti-CD19 CAR-T cells at
      the starting dose of 5 x 105 cells/kg will be given on Day=0. Following treatment with DP,
      subjects will be followed on this study for 12 months for safety, disease status, and
      survival. For long term follow-up, participants will be followed for 15 years.

      PRIMARY OBJECTIVES

        1. To evaluate the safety of administering chimeric antigen receptor T cells targeting
           CD-19 to patients with relapsed or refractory CD19+ B-cell nonHodgkin lymphoma (NHL).

        2. To determine the recommended phase 2 dose (RP2D) for this cellular therapy.

      SECONDARY OBJECTIVES

        1. To assess the safety and toxicity of cell collection and infusion of CAR-T cells
           targeting CD19 in patients with relapsed or refractory CD19+ B cell NHL.

        2. To describe the efficacy of chimeric antigen receptor T cells targeting CD-19 in
           patients with relapsed or refractory CD19+ B cell NHL.

        3. To evaluate the feasibility of CD19 CAR T cell manufacturing for patients with relapsed
           or refractory CD19+ B cell NHL of local manufacturing and ability to produce adequate
           quantities of vector positive T-cells
    

Trial Arms

NameTypeDescriptionInterventions
Treatment RegimenExperimentalApheresis (1 day): Autologous lymphocytes/ mononuclear cell collection will be collected through standard apheresis procedures as per University of California, San Francisco (UCSF) institutional practices CAR-T cell manufacturing (estimated ~13-14 days) Lymphodepleting chemotherapy: 3 days of immunosuppressive chemotherapy. Cyclophosphamide given at a dose of 300 mg/m2/IV and fludarabine given at 30 mg/m2 /IV on days -5, -4, and -3. CAR-T cell infusion (1 day): The infusion of CAR-T cells targeting CD19 will occur over 5-30 minutes.
  • Fludarabine
  • Cyclophosphamide
  • anti-CD19 CAR-T cells

Eligibility Criteria

        Inclusion Criteria:

          1. Patients must have a diagnosis of relapsed or refractory B-cell NHL:

               -  DLBCL, Mantle Cell, Follicular Lymphoma, Lymphoplasmacytic lymphoma, Small
                  Lymphocytic Lymphoma, Primary Mediastinal B-Cell Lymphoma, Burkitt Lymphoma,
                  transformed lymphoma.

                    -  Subjects with small lymphocytic lymphoma (SLL) must have progressed after at
                       least 2 prior therapies and prior treatment with or intolerance of both
                       ibrutinib and venetoclax.

                    -  Subjects with DLBCL, primary mediastinal B- Cell lymphoma, Burkitt lymphoma
                       and transformed lymphoma must have relapsed or failed to respond to >= 2
                       prior lines of multiagent chemoimmunotherapy with prior exposure to both an
                       anti-CD20 antibody agent and an anthracycline.

                    -  Subjects with indolent lymphomas (follicular lymphoma and lymphoplasmacytic
                       lymphoma) must have relapsed after or been refractory to >=2 prior lines of
                       multi-agent chemoimmunotherapy including prior exposure to rituximab and at
                       least 2 other chemotherapy agents.

                    -  For subjects with Mantle cell lymphoma, previous lines of therapy may
                       include multiagent chemotherapy including alkylating agent or anthracycline
                       and anti CD20 antibody therapy and Bruton's tyrosine kinase (BTK) inhibitor
                       therapy.

               -  Positron Emission Tomography (PET) -positive disease according to
                  "Recommendations for Initial Evaluation, Staging, and Response Assessment of
                  Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification"

               -  At least one of the following:

                    -  Primary refractory or early relapse (first remission < 12 months) and not
                       eligible for stem cell transplant

                    -  Relapsed or refractory disease after two or more lines of systemic therapy

               -  No significant circulating disease, defined as an elevated total lymphocyte count
                  above the ULN due to the presence of malignant cells.

          2. CD19 positive by either immunohistochemistry or flow cytometry analysis on any biopsy.
             If prior anti-CD19 therapy has been administered, CD19 positivity has to be
             re-established on the most recent biopsy.

          3. Age >=18 years at the time of consent

          4. Absolute lymphocyte count > 100/ (microliter)

          5. Eastern Cooperative Oncology Group (ECOG) performance status < 2

          6. Adequate organ function, defined as:

               -  Adequate bone marrow function for apheresis and lymphodepleting chemotherapy

                    -  Hemoglobin (Hgb) >8 grams per deciliter (gm/dl) (transfusions allowed)

                    -  Platelets >50,000/microliter (uL) (transfusions allowed)

                    -  Absolute Neutrophil Count (ANC) > 500/uL

               -  Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) < 3 x
                  institutional upper limit of normal (ULN) and Total bilirubin < 1.5 mg/dl x
                  institutional ULN, except with Gilbert's syndrome

               -  Serum Creatinine < 2 x the institutional ULN

               -  Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) >
                  40% as assessed by echocardiogram or multiple uptake gated acquisition (MUGA)

          7. Adequate vascular access for leukapheresis procedure (either peripheral line or
             surgically placed line).

          8. Women of childbearing potential (defined as all women physiologically capable of
             becoming pregnant) must have a negative serum or urine pregnancy test AND agree to use
             highly effective methods of contraception for 1 year after the last dose of antiCD19
             CAR-T cells

          9. Males who have partners of childbearing potential must agree to use an effective
             barrier contraceptive method

         10. Ability to understand a written informed consent document, and the willingness to sign
             it.

        Exclusion Criteria:

          1. Autologous transplant within 6 weeks of planned CAR-T cell infusion

          2. Recipient of prior CAR-T cell therapy targeting CD19 outside of this protocol

          3. Active other malignancy, other than non-melanoma skin cancer, carcinoma in situ (e.g.,
             cervix, bladder, or breast).

          4. HIV seropositivity

          5. Serologic status reflecting active hepatitis B or C infection. Patients that are
             positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or
             hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to
             enrollment. (PCR positive patients will be excluded.)

          6. Subjects with uncontrolled intercurrent illness including, but not limited to ongoing
             or active infection, symptomatic congestive heart failure, unstable angina pectoris,
             cardiac arrhythmia, pulmonary abnormalities or psychiatric illness/social situations
             that would limit compliance with study requirements.

          7. Pregnant or breastfeeding women are excluded from this study because CAR-T cell
             therapy may be associated with the potential for teratogenic or abortifacient effects.
             Because there is an unknown, but potential risk for adverse events in nursing infants
             secondary to treatment of the mother with CAR-T cells, breastfeeding should be
             discontinued. These potential risks may also apply to other agents used in this study.
             NOTE: Women of childbearing potential must have a negative serum or urine pregnancy
             test.

          8. Patients with history of clinically relevant central nervous system (CNS) pathology
             such as epilepsy, seizure disorders, paresis, aphasia, uncontrolled cerebrovascular
             disease, severe brain injuries, dementia and Parkinson's disease.

          9. History of autoimmune disease (e.g., rheumatoid arthritis, systemic lupus
             erythematosus) with requirement of immunosuppressive medication within 6 months.

         10. Body weight <40 kilograms(kg)

        Eligibility for Infusion of Investigational Product:

        Subjects will undergo a second evaluation of eligibility on day -2 or -1 prior to infusion
        of antiCD19 CAR-T cell product. This eligibility criterion will include the inclusion and
        exclusion criteria required for enrollment with the following exceptions and additions

        Inclusion criteria exceptions:

          1. Hematologic function parameters will not be included as a pre-infusion eligibility
             criterion (because lymphodepletive chemotherapy is expected to cause pancytopenia).

          2. Laboratory result abnormalities that are considered not clinically significant by the
             principal investigator AND are not the result of a demonstrated active infection or an
             active central nervous system condition.

        Exclusion criteria additions:

          1. Use of corticosteroids within 7 days prior to infusion (with exception of agents used
             for prevention of emesis during lymphodepletive chemotherapy).

          2. Neurologic symptoms suggestive of an active central nervous system condition.

          3. Signs or laboratory markers of active infection or systemic inflammatory response.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Proportion of participants with treatment-emergent adverse events (AEs)
Time Frame:From initiation of study treatment to 12 months following CAR-T infusion, approximately 15 months
Safety Issue:
Description:All subjects enrolled in this phase I study who actually received study drug (anti-CD19 CAR-T infusion) will be included in the analysis. Proportion of participants with treatment-emergent adverse events of CAR-T in B-cell NHL, as graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 5.0), revised Cytokine Release Syndrome (CRS) grading criteria, and American Society for Transplantation and Cellular Therapy (ASTCT) immune effector cell (IEC) -associated neurotoxicity syndrome (ICANS) Consensus Grading for Adults (for neurotoxicity grading).

Secondary Outcome Measures

Measure:Proportion of participants with delayed infusion due to study-related adverse events
Time Frame:From T-cell collection to end of infusion, approximately 18 days
Safety Issue:
Description:The proportion of participants who have their infusion delayed due to and AE will be reported.
Measure:Table of adverse events related to collection and infusion of CAR-T cells
Time Frame:From T-cell collection to end of infusion, approximately 18 days
Safety Issue:
Description:Frequency and severity for each adverse event of collection and infusion of CAR-T cells targeting CD19 in participants with relapsed B cell Non-Hodgkins Lymphoma
Measure:Response rates over time
Time Frame:From initiation of study treatment to 12 months after getting CAR-T infusion, approximately 15 months
Safety Issue:
Description:Response rates will be categorized by overall, partial, and complete and will be reported as proportions at different time points across the study
Measure:Best response rates
Time Frame:From initiation of study treatment to 12 months after getting CAR-T infusion, approximately 15 months
Safety Issue:
Description:Best overall, best partial, and best complete response rates will be calculated for the study overall. These will be reported cumulatively across the study population and across disease subtypes in a table format. Any comparisons will be hypothesis-generating and will be performed using Fisher's exact or the Chi-square test.
Measure:Duration of response
Time Frame:From initiation of study treatment to 12 months after getting CAR-T infusion, approximately 15 months
Safety Issue:
Description:This is measured, only in responders, from the documented beginning of response (CR or PR) to the time of relapse
Measure:Progression-free survival (PFS)
Time Frame:From initiation of study treatment to 12 months after getting CAR-T infusion, approximately 15 months
Safety Issue:
Description:PFS is defined as the time from entry onto study until lymphoma progression or death from any cause at 12 months after receiving CAR-T infusion.
Measure:Overall Survival
Time Frame:Up to 15 years
Safety Issue:
Description:Defined as the time from entry onto study until death from any cause
Measure:Proportion of subjects for whom CD19 CAR T-cell therapy is manufactured
Time Frame:From initiation of CD19 CAR T-cell manufacturing to end of infusion, approximately 18 days
Safety Issue:
Description:Feasibility will be assessed by the proportion of subjects for whom the ability to produce adequate quantities of vector.
Measure:Proportion of participants who complete study treatment
Time Frame:From initiation of CD19 CAR T-cell manufacturing to end of infusion, approximately 18 days
Safety Issue:
Description:Feasibility will be assessed by the proportion of subjects who complete the study regimen

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:C. Babis Andreadis

Trial Keywords

  • Non-Hodgkin Lymphoma
  • Anti-CD19 autologous CAR-T cells

Last Updated

September 10, 2020