Genetically Engineered Cells (Anti-CD19/CD20/CD22 CAR T-cells) for the Treatment of Relapsed or Refractory Lymphoid Malignancies

Phase I Clinical Trial of Anti-CD19/20/22 Chimeric Antigen Receptor T Cells for Treatment of Relapsed or Refractory Lymphoid Malignancies (Non-Hodgkin Lymphoma, Acute Lymphoblastic Leukemia, Chronic Lymphocytic Leukemia, B-Prolymphocytic Leukemia)

This phase I trial tests the safety, side effects and best infusion dose of genetically engineered cells called anti-CD19/CD20/CD22 chimeric antigen receptor (CAR) T-cells following a short course of chemotherapy with cyclophosphamide and fludarabine in treating patients with lymphoid cancers (malignancies) that have come back (recurrent) or do not respond to treatment (refractory). Lymphoid malignancies eligible for this trial are: non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and B-prolymphocytic leukemia (B-PLL). T-cells (a type of white blood cell) form part of the body's immune system. CAR-T is a type of cell therapy that is used with gene-based therapies. CAR T-cells are made by taking a patient's own T-cells and genetically modifying them with a virus so that they are recognized by a group of proteins called CD19/CD20/CD22 which are found on the surface of cancer cells. Anti-CD19/CD20/CD22 CAR T-cells can recognize CD19/CD20/CD22, bind to the cancer cells and kill them. Giving combination chemotherapy helps prepare the body before CAR T-cell therapy. Giving CAR-T after cyclophosphamide and fludarabine may kill more tumor cells.

Study Overview

• Status: Recruiting
• Conditions: Recurrent B Acute Lymphoblastic Leukemia; Refractory B Acute Lymphoblastic Leukemia; Refractory Chronic Lymphocytic Leukemia; Recurrent Non-Hodgkin Lymphoma; Refractory Non-Hodgkin Lymphoma; Recurrent Acute Lymphoblastic Leukemia; Refractory Acute Lymphoblastic Leukemia; Recurrent High Grade B-Cell Lymphoma; Refractory High Grade B-Cell Lymphoma; Recurrent Chronic Lymphocytic Leukemia; Recurrent B-Cell Prolymphocytic Leukemia; Refractory B-Cell Prolymphocytic Leukemia; Recurrent Transformed Chronic Lymphocytic Leukemia; Refractory Transformed Chronic Lymphocytic Leukemia; Recurrent Indolent Non-Hodgkin Lymphoma; Refractory Indolent Non-Hodgkin Lymphoma
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: Fludarabine Phosphate; Biological: Anti-CD19/CD20/CD22 CAR T-Cells

Detailed Description

PRIMARY OBJECTIVE:

I. To determine the safety of the treatment of relapsed/refractory non-Hodgkin lymphoma, relapsed/refractory chronic lymphocytic leukemia, refractory B-prolymphocytic leukemia and relapsed/refractory acute lymphoblastic leukemia with chimeric antigen receptor T cells targeting CD19/20/22 and to find the recommended phase II dose for this cellular therapy.

SECONDARY OBJECTIVES:

I. To describe the safety profile of the infusion of CAR-T cells targeting CD19/20/22 in relapsed/refractory Non-Hodgkin lymphoma, relapsed/refractory chronic lymphocytic leukemia, refractory B-prolymphocytic leukemia and in relapsed/refractory acute lymphoblastic leukemia.

II. To describe the toxicities related to infusion of CAR-T cells targeting CD19/20/22.

III. To describe the overall response rate and complete response rate of relapsed B cell malignancies treated with CAR-T cells targeting CD19/20/22.

IV. To describe the overall and progression free survival of patients with relapsed lymphoma, CLL, B-PLL and ALL treated with anti-CD19/20/22 CAR-T cells.

EXPLORATORY OBJECTIVES:

I. To describe the persistence of anti-CD19/20/22 CAR-T cells, measured by flow cytometry and quantitative polymerase chain reaction (qPCR).

II. To describe the T cell subpopulations of the anti-CD19/20/22 CAR-T cell product before infusion.

III. To describe the changes in anti-CD19/20/22 CAR-T cells after infusion and their correlation with disease response and adverse events.

IV. To investigate the correlation between changes in cytokine plasma concentrations and changes in anti-CD19/20/22 CAR-T cell subpopulations over time.

V. To investigate proteomic changes in anti-CD19/20/22 CAR-T cell subpopulations over time.

VI.To investigate whether antigen escape occurs in patients treated with anti-CD19/20/22 CAR-T.

OUTLINE: This is a phase I dose-escalation study of anti-CD19/CD20/CD22 CAR-T cells. Patients with NHL with lesions =< 5 cm, indolent lymphomas, CLL (without Richter's transformation), or B-PLL are assigned to Cohort A. Patients with ALL, CLL (with Richter's transformation), NHL with lesions > 5 cm and/or lymphoblastic lymphoma, or NHL with circulating lymphoma cells are assigned to Cohort B.

COHORT A:

LYMPHODEPLETIVE REGIMEN: Patients receive cyclophosphamide intravenously (IV) over 60 minutes on day -6 and fludarabine IV over 30 minutes on days -5 to -3 in the absence of disease progression or unacceptable toxicity.

CAR T-CELL THERAPY: Patients receive anti-CD19/CD20/CD22 CAR-T cells IV over 5-30 minutes on day 0.

COHOHRT B:

LYMPHODEPLETIVE REGIMEN: Patients receive cyclophosphamide IV over 60 minutes on day -6 and fludarabine IV over 30 minutes on days -5 to -3 in the absence of disease progression or unacceptable toxicity.

CAR T-CELL THERAPY: Patients receive anti-CD19/CD20/CD22 CAR-T cells IV over 5-30 minutes on day 0 and 7.

After completion of study treatment, patients in Cohort A are followed up on days 1-7, 14, 21, 30, 60, 90, at months 6, 24, 36, 48, and 60, and then annually for 6-15 years. Patients in Cohort B are followed up on days 9, 14, 21, 30, 60, 90, at months 6, 24, 36, 48, and 60, and then annually for 6-15 years.

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

Contacts and Locations

• Study Contact: Name: The Ohio State University Comprehensive Cancer Center; Phone Number: 800-293-5066; Email: OSUCCCClinicaltrials@osumc.edu

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Recruiting
      • Ohio State University Comprehensive Cancer Center
      • Contact: Sumithira Vasu, MD; Phone Number: 614-293-8197; Email: Sumithira.Vasu@osumc.edu
      • Principal Investigator: Sumithira Vasu, MD
    • Columbus, Ohio, United States, 43203
      • Recruiting
      • Nationwide Children's Hospital
      • Contact: Kennedy Thompson; Phone Number: 614-722-5043; Email: Kennedy.thompson@nationwidechildrens.org
      • Contact: Lori Jewell, BA; Phone Number: 614-722-6576; Email: Lori.Jewell@nationwidechildrens.org
      • Principal Investigator: Margarey Lamb, MD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Subjects must have relapsed or refractory non-Hodgkin lymphoma with lesions =< 5 cm, indolent lymphomas, chronic lymphocytic leukemia without Richter's transformation, or B-prolymphocytic leukemia (Cohort A) or acute lymphoblastic leukemia, chronic lymphocytic leukemia with Richter's transformation, non-Hodgkin lymphoma with lesions > 5 cm and/or lymphoblastic lymphoma, or non-Hodgkin lymphoma with circulating lymphoma cells (Cohort B). Subjects must have been treated with at least two lines of therapy. Disease must have either progressed after the last regimen or presented failure to achieve complete remission with the last regimen. B-PLL is defined as having greater than 55% prolymphocytes in the peripheral blood
• Subjects with relapsed/refractory CLL after at least 2 prior lines of appropriate therapy and must have previously received an approved BTK inhibitor and venetoclax
• Subjects with refractory high-grade B-cell lymphoma who relapse within 12 months of autologous stem cell transplant
• Subjects with relapsed/refractory B-prolymphocytic leukemia who received at least 1- 2 prior lines of appropriate therapy and who have failed or are ineligible for allogeneic stem cell transplant
• Subjects with relapsed/refractory acute B-lymphoblastic leukemia who received at least 2 prior lines of appropriate therapy or who have failed or are ineligible for allogeneic stem cell transplant.
• The patient's lymphoid malignancy must be positive for CD19 and/or CD20 and/or CD22, either by immunohistochemistry or flow cytometry analysis on the last biopsy available or peripheral blood for circulating disease.
• Patients who received blinatumomab or inotuzumab are eligible.
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2. For patients < 16 years, Performance score Lansky >= 50
• Total bilirubin =< 1.5 times the institutional upper limit of normal
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) =< 3 X institutional upper limit of normal
• Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 X institutional upper limit of normal
• Creatinine clearance more than or equal to 50 ml/min calculated by the Cockcroft - Gault formula
• Subjects must have adequate pulmonary function as defined as pulse oximetry >= 92% on room air
• Subjects must have adequate cardiac function as defined as left ventricular ejection fraction >= 40% in the most recent echocardiogram
• Absolute lymphocyte count > 100/uL
• Subjects (or legal guardians) must have the ability to understand and the willingness to sign a written informed consent document
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a contraceptive method with a failure rate of < 1% per year during the treatment period and for at least 6 months after the Anti-CD19/20/22 CAR-T cell infusion
• A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (< 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptive s that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices
• The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm
• With female partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for at least 6 months after the Anti-CD19/20/22 CAR-T cell infusion. Men must refrain from donating sperm during this same period
• With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 6 months after the human anti-CD19 CAR-T cell infusion to avoid potential embryonal or fetal exposure. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.

Exclusion Criteria:

• Autologous transplant within 6 weeks of planned CAR-T cell infusion
• Allogeneic stem cell transplant or donor lymphocyte infusion within 2 months of planned CAR-T cell infusion and patients must be off immunosuppressive agents. Patients with live vaccines given 28 days prior to lymphodepletion (LD) chemotherapy will be excluded
• Active graft versus host disease
• Active central nervous system or meningeal involvement by lymphoma or leukemia. Subjects with untreated brain metastases/central nervous system (CNS) disease will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Patients with a history of CNS or meningeal involvement must be in a documented remission by CSF evaluation and contrast-enhanced magnetic resonance imaging (MRI) imaging for at least 90 days prior to registration
• Active malignancy, other than non-melanoma skin cancer or carcinoma in situ (e.g.cervix, bladder, breast). Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial (e.g.

Low Gleason score prostate Cancer)

• A minimum of 28 days must have elapsed between prior treatment with investigational agent(s) and the day of lymphocyte collection
• Human immunodeficiency virus (HIV)-seropositive patients are allowable, however must be on effective anti-retroviral therapy with undetectable viral load within 6 months of enrollment to be eligible for this trial
• 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
• 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. Women of childbearing potential must have a negative serum pregnancy test. 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
• Evidence of myelodysplasia or cytogenetic abnormality indicative of myelodysplasia on any bone marrow biopsy prior to initiation of therapy
• Patients with a positive hepatitis B core antibody or surface antigen are at high risk for hepatitis B virus (HBV) reaction and will require entecavir/tenofivir prophylaxis or serial hepatitis B (Hep B) PCR monitoring at the direction of an infectious disease specialist. Duration of prophylaxis to correspond with detection of Anti-CD19/20/22 CAR T cells/viral vector copies in serum or continued evidence of B-cell aplasia such as reduced intravenous immunoglobulin therapy (IVIG) levels. No antiviral prophylaxis is indicated with hepatitis C positivity with negative PCR
• Patients with history of clinically relevant CNS pathology such as epilepsy, seizure disorders, paresis, aphasia, uncontrolled cerebrovascular disease, severe brain injuries, dementia and Parkinson's disease
• History of autoimmune disease (i.e. rheumatoid arthritis, systemic lupus erythematosus) with requirement of immunosuppressive medication within 6 months
• Live vaccines given in 28 days prior to lymphodepleting chemotherapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort A (lymphodepletion; anti-CD19/CD20/CD22 CAR-T cells); LYMPHODEPLETIVE REGIMEN: Patients receive cyclophosphamide IV over 60 minutes on day -6 and fludarabine IV over 30 minutes on days -5 to -3 in the absence of disease progression or unacceptable toxicity. CAR T-CELL THERAPY: Patients receive anti-CD19/CD20/CD22 CAR-T cells IV over 5-30 minutes on day 0.	Drug: Cyclophosphamide; Given IV; Other Names: Cytoxan; CTX; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamide Monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; Drug: Fludarabine Phosphate; Given IV; Other Names: 2-F-ara-AMP; Beneflur; Fludara; 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-; SH T 586; Biological: Anti-CD19/CD20/CD22 CAR T-Cells; Given IV; Other Names: Anti-CD19/20/22 Chimeric Antigen Receptor T-Cells; CD19/CD20/CD22-targeted CAR-T Cells
Experimental: Cohort B (lymphodepletion, anti-CD19/CD20/CD22 CAR-T cells); LYMPHODEPLETIVE REGIMEN: Patients receive cyclophosphamide IV over 60 minutes on day -6 and fludarabine IV over 30 minutes on days -5 to -3 in the absence of disease progression or unacceptable toxicity. CAR T-CELL THERAPY: Patients receive anti-CD19/CD20/CD22 CAR-T cells IV over 5-30 minutes on day 0 and 7.	Drug: Cyclophosphamide; Given IV; Other Names: Cytoxan; CTX; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamide Monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; Drug: Fludarabine Phosphate; Given IV; Other Names: 2-F-ara-AMP; Beneflur; Fludara; 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-; SH T 586; Biological: Anti-CD19/CD20/CD22 CAR T-Cells; Given IV; Other Names: Anti-CD19/20/22 Chimeric Antigen Receptor T-Cells; CD19/CD20/CD22-targeted CAR-T Cells

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Recommended phase II dose of anti-CD19/CD20/CD22 CAR-T cells for each study group (Cohort A and Cohort B)	Up to 30 days after CAR T-cell infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events	Will be evaluated with descriptive statistics for the frequencies of adverse events of different grades.	Up to 12 months after completion of study treatment
Overall response rate	Will be evaluated with descriptive statistics with proportions used to describe response rates.	Up to 15 years
Complete response rate	Will be evaluated with descriptive statistics with proportions used to describe response rates.	Up to 15 years
Overall survival	Will be calculated using Kaplan Meier method, comparisons between groups will be done using the log rank test.	Up to 15 years
Progression-free survival	Will be calculated using Kaplan Meier method, comparisons between groups will be done using the log rank test.	From entry onto study until lymphoma progression or death from any cause, assessed up to 15 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation between cytokine serum concentrations and disease response	Will be analyzed with descriptive statistics, including evaluations of median, minimum and peak values. Area under the curve (AUC) will be used as a measure of cytokine secretion. Comparisons will be done between responding and non-responding patients using the Mann - Whitney test for quantitative variables and Fisher's exact test for categorical variables. The Wilcoxon test will be used to evaluate the changes in cytokine concentrations. Correlations between quantitative variables will be done with Spearman's correlation test, whereas correlation between categorical variables will be done using Fisher's exact test.	Up to 15 years
Presence of measurable CAR-T cells	Will be analyzed with descriptive statistics, including evaluations of median, minimum and peak values. Area under the curve (AUC) will be used as a measure of CAR-T cell expansion and persistence. Comparisons will be done between responding and non-responding patients using the Mann - Whitney test for quantitative variables and Fisher's exact test for categorical variables. The Wilcoxon test will be used to evaluate CAR-T cell expansion and changes in T cell phenotype over time. Correlations between quantitative variables will be done with Spearman's correlation test, whereas correlation between categorical variables will be done using Fisher's exact test.	Up to 12 months
Correlation between CD19/20/22 expression on disease response	Will be analyzed with descriptive statistics, including evaluations of median, minimum and peak values. Correlations between quantitative variables will be done with Spearman's correlation test, whereas correlation between categorical variables will be done using Fisher's exact test.	Up to 15 years

Collaborators and Investigators

• Sponsor: Sumithira Vasu
• Investigators: Principal Investigator: Sumithira Vasu, MD, Ohio State University Comprehensive Cancer Center

Publications and helpful links

Helpful Links

• The Jamesline

Study record dates

Study Major Dates

• Study Start (Actual): June 30, 2022
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: May 16, 2022
• First Submitted That Met QC Criteria: June 10, 2022
• First Posted (Actual): June 14, 2022

Study Record Updates

• Last Update Posted (Actual): March 7, 2024
• Last Update Submitted That Met QC Criteria: March 6, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Hematologic Diseases; Leukemia, B-Cell; Chronic Disease; Lymphoma; Lymphoma, B-Cell; Leukemia; Recurrence; Lymphoma, Non-Hodgkin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Leukemia, Prolymphocytic; Leukemia, Prolymphocytic, 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: OSU-21170; NCI-2022-02972 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

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