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

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

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)

Study Overview

• Status: Recruiting
• Conditions: Follicular Lymphoma; Burkitt Lymphoma; Mantle Cell Lymphoma; Lymphoplasmacytic Lymphoma; Diffuse Large B Cell Lymphoma; Refractory Non-Hodgkin Lymphoma; Small Lymphocytic Lymphoma; Primary Mediastinal Large B Cell Lymphoma; Transformed Lymphoma
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: Fludarabine; Biological: anti-CD19 CAR-T cells

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 Chimeric antigen receptor T cells (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.

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.

OUTLINE

Eligible participants 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 Technology, Inc., 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.

For participants whose dose does not meet the target dose, enrollment into a conforming product low-dose cohort, at minimum dose level - 1 and that has not exceeded the MTD will occur. This conforming product low-dose cohort will be evaluated for toxicity and efficacy of those lower dose levels as part of the primary safety and secondary objectives.

For participants whose CAR-T product does not meet the pre-specified release criteria, enrollment into a non-conforming product cohort, at a minimum dose level - 1 and that has not exceeded the MTD will occur. This non-conforming product cohort will be evaluated for toxicity and efficacy of the non-conforming product cohort as part of the exploratory objectives

• Study Type: Interventional
• Enrollment (Estimated): 36
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Laurel Brechtel; Phone Number: (415) 307-8418; Email: Laurel.Brechtel@ucsf.edu

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143
      • Recruiting
      • University of California, San Francisco
      • Principal Investigator: C. Babis Andreadis, MD
      • Contact: Phone Number: 877-827-3222; Email: cancertrials@ucsf.edu
      • Contact: Laurel Brechtel; Phone Number: 415-307-8418; Email: Laurel.Brechtel@ucsf.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 ((nodal or extranodal marginal zone lymphoma, 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) within 3 months of screening. Repeat testing may occur at Investigator's discretion.
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 anti-CD19 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 an evaluation of eligibility on day 1 prior to infusion of anti-CD19 CAR-T cell product. This eligibility criterion will include the inclusion and exclusion criteria required for enrollment with the following exceptions and additions:

1. No significant laboratory abnormalities. 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.
2. ECOG performance status < 2
3. No evidence of uncontrolled intercurrent illness including, but not limited to ongoing or active infection, inflammatory response, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, pulmonary abnormalities or psychiatric illness/social situations.
4. No new neurologic symptoms suggestive of an active central nervous system condition, or uncontrolled CNS involvement by lymphoma.
5. No corticosteroid use within 7 days prior to infusion (with exception of agents used for prevention of emesis during lymphodepletive chemotherapy).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment Regimen; Apheresis (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.

Drug: Cyclophosphamide; Given intravenously (IV); Other Names: Cytoxan; Endoxan; Cycloblastin; Neosar; Revimmune; Procytox; Cyclophosphamide 300mg/m2; Drug: Fludarabine; Given intravenously (IV); Other Names: Fludara; Fludarabine 30mg/m2; Biological: anti-CD19 CAR-T cells; Single infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of participants with treatment-emergent adverse events (AEs)	Subjects treated with conforming product who received the target doses of 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).	From initiation of study treatment to 12 months following CAR-T infusion, approximately 15 months
Proportion of participants who experience a dose-limiting toxicity (DLT)	A DLT includes AEs graded according to CTCAE version 5.0, with the exceptions of CRS and neurotoxicity, which are graded using CRS and ICANS criteria. DLTs must 1) be suspected to be secondary to CAR-T cell infusion, 2) occur during the first 30 days after infusion and 3) meet the following criteria: 1. Grade 3 or 4 non-hematologic toxicities of any duration, with following exceptions: Grade 3 laboratory abnormalities without associated symptomatology or clinical consequence that resolve in < 7 days; AEs associated with Grade <= 2 CRS; Toxicities associated with Grade 3 CRS (except cardiac or pulmonary organ toxicity) that improves to grade <= 2 within 3 days of intervention; isolated renal or hepatic grade 3 organ toxicity that does not resolve within 7 days; Laboratory abnormalities compatible with tumor lysis syndrome; Grade 4 hematological toxicity that persists at grade >= 3 despite maximum supportive care for >21 days.	From initiation of study treatment to 30 days following CAR-T infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of participants with delayed infusion due to study-related adverse events	The proportion of participants who have their infusion delayed due to and AE will be reported.	From T-cell collection to end of infusion, approximately 18 days
Table of adverse events related to collection and infusion of CAR-T cells	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	From T-cell collection to end of infusion, approximately 18 days
Overall Response rates over time	Overall response rates will be reported as proportions at different time points across the study	From initiation of study treatment to 12 months after getting CAR-T infusion, approximately 15 months
Complete Response rates over time	Complete response rates will be reported as proportions at different time points across the study	From initiation of study treatment to 12 months after getting CAR-T infusion, approximately 15 months
Partial Response rates over time	Partial response rates will be reported as proportions at different time points across the study	From initiation of study treatment to 12 months after getting CAR-T infusion, approximately 15 months
Duration of response	This is measured, only in responders, from the documented beginning of response (CR or PR) to the time of relapse	From initiation of study treatment to 12 months after getting CAR-T infusion, approximately 15 months
Progression-free survival (PFS)	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.	From initiation of study treatment to 12 months after getting CAR-T infusion, approximately 15 months
Overall Survival	Defined as the time from entry onto study until death from any cause	Up to 15 years
Proportion of subjects for whom CD19 CAR T-cell therapy is manufactured	Feasibility will be assessed by the proportion of subjects for whom the ability to produce adequate quantities of vector.	From initiation of CD19 CAR T-cell manufacturing to end of infusion, approximately 18 days
Proportion of participants who complete study treatment	Feasibility will be assessed by the proportion of subjects who complete the study regimen	From initiation of CD19 CAR T-cell manufacturing to end of infusion, approximately 18 days

Collaborators and Investigators

• Sponsor: C. Babis Andreadis
• Collaborators: University of California, Davis
• Investigators: Principal Investigator: C. Babis Andreadis, MD, University of California, San Francisco

Publications and helpful links

General Publications

• Ernst M, Oeser A, Besiroglu B, Caro-Valenzuela J, Abd El Aziz M, Monsef I, Borchmann P, Estcourt LJ, Skoetz N, Goldkuhle M. Chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory diffuse large B-cell lymphoma. Cochrane Database Syst Rev. 2021 Sep 13;9(9):CD013365. doi: 10.1002/14651858.CD013365.pub2.

Study record dates

Study Major Dates

• Study Start (Actual): September 11, 2020
• Primary Completion (Estimated): October 31, 2024
• Study Completion (Estimated): October 31, 2024

Study Registration Dates

• First Submitted: August 31, 2020
• First Submitted That Met QC Criteria: September 10, 2020
• First Posted (Actual): September 11, 2020

Study Record Updates

• Last Update Posted (Estimated): December 14, 2023
• Last Update Submitted That Met QC Criteria: December 13, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Non-Hodgkin Lymphoma; Anti-CD19 autologous CAR-T cells
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Virus Diseases; Infections; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; DNA Virus Infections; Tumor Virus Infections; Neoplasms, Plasma Cell; Leukemia, Lymphoid; Leukemia; Epstein-Barr Virus Infections; Herpesviridae Infections; Leukemia, B-Cell; Chronic Disease; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Burkitt Lymphoma; Lymphoma, Mantle-Cell; Waldenstrom Macroglobulinemia; Leukemia, Lymphocytic, Chronic, B-Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide; Fludarabine; Fludarabine phosphate
• Other Study ID Numbers: 19703; NCI-2020-06711 (Registry Identifier: NCI Clinical Trials Reporting Program (CTRP))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No