Preliminary Safety and Tolerability of CD19x22 CAR T Cells in Adolescent and Adult R/R B-NHL Patients

• ClinicalTrials.gov Identifier: NCT05098613
• Recruitment Status: Recruiting
• First Posted: October 28, 2021
• Last Update Posted: May 16, 2024
• Sponsor: University of Colorado, Denver
• Information provided by (Responsible Party): University of Colorado, Denver

Tracking Information

• First Submitted Date: October 6, 2021
• First Posted Date: October 28, 2021
• Last Update Posted Date: May 16, 2024
• Actual Study Start Date: December 21, 2021
• Estimated Primary Completion Date: December 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 18, 2021)

• Phase 1: Overall Tolerability of CD19x22 CAR T Therapy in CAR-naive Subjects as Assessed by Type, Frequency, and Severity of Adverse Events (AEs) [ Time Frame: 12 Months Post Infusion ]
  All AEs, including laboratory abnormalities, will be graded using the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grading criteria.
• Phase 1: Determine the Phase 1b Dose Level [ Time Frame: 30 Days Post Infusion ]
  Incidence and frequency of Grade 3-5 toxicity occurring within the dose limiting toxicity (DLT) period post CD19x22 CAR T infusion. Grades 3-5 adverse events (AEs) are defined as Severe, Life-Threatening, and Fatal.
• Phase 1b: Establish Evidence of Tolerability of CD19x22 CAR T Cells in a Broader Sample of CAR-naive Subjects Versus Those who have Previously Received CD19 CAR T Cell Therapy [ Time Frame: 12 Months Post Infusion ]
  Frequency and severity of all adverse events (AEs) and serious adverse events (SAEs). All AEs and SAEs will be graded using the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grading criteria.
• Phase 1b: Evaluate the Clinical Efficacy of CD19x22 CAR T through Calculating Proportion of CR, PR, SD, and PD. [ Time Frame: 12 Months Post Infusion ]
  Efficacy of treatment will be quantified by calculating the proportion of subjects who achieved a response, such as a complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) at Day +90, 6 months, and 1 year.
• Phase 1b: Evaluate the Clinical Efficacy of CD19x22 CAR T through Reporting ORR, PFS, DOR, and OS [ Time Frame: 12 Months Post Infusion ]
  Reporting of overall response rate (ORR), progression free survival (PFS), duration of response (DOR), and overall survival (OS) at 1 year.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: October 18, 2021)

• Percentage of Patients for Whom the Desired Dose of CAR T Cells was Successfully Produced [ Time Frame: Day 0 (Infusion) ]
  The feasibility of manufacturing the desired dose of anti-CD19x22 CAR T cells will be established using the percentage of patients for whom the desired dose of CAR T cells was successfully produced.
• Evaluate Clinical Efficacy of CD19x22 CAR T [ Time Frame: 12 Months Post Infusion ]
  Clinical efficacy is defined through Lugano response criteria at Day +90, 6 months, and 1 year. Efficacy in the phase 1b portion will be stratified based on prior receipt of CD19 CAR T cell therapy.
• Percentage of Study Participants who Receive CD19x22 CAR T Cell Infusion without Infusion Reaction [ Time Frame: 30 Days Post Infusion ]

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Preliminary Safety and Tolerability of CD19x22 CAR T Cells in Adolescent and Adult R/R B-NHL Patients
• Official Title: Phase 1/1b Study of Bispecific CD19 and CD22 Chimeric Antigen Receptor Co-Expressing T Cells (CD19x22 CAR T) in Adolescent and Adult Patients With Relapsed and/or Refractory B-Non-Hodgkin's Lymphoma (B-NHL)
• Brief Summary: This open-label, single arm phase 1/1b trial aims to determine the safety and tolerability of anti-CD19 and anti-CD22 chimeric antigen receptor-expressing (CAR) T cells (CD19x22 CAR T) in adolescents and adults with relapsed/refractory (R/R) B-cell Non-Hodgkin Lymphoma (B-NHL). Phase 1 will determine the maximum tolerated dose of CD19x22 CAR T cells using a standard 3+3 trial design. Phase 1b is an expansion phase designed to evaluate the preliminary efficacy of CD19x22 CAR T in CAR-treated and CAR-naïve patients.

Detailed Description

Phase 1: To determine the safety and tolerability of infusing CD19x22 CAR T, generated using a bicistronic vector, in adolescents and adults with R/R B-NHL, and to determine the Phase 1b recommended dose.

Phase 1b (expansion phase): To acquire additional evidence of safety and efficacy of-CD19x22 CAR T infusion in CAR-treated and CAR-naïve R/R B-NHL patients.

Secondary objectives for all subjects in Phase 1 and Phase 1b include: 1) Feasibility of manufacturing and infusion, 2) Safety of infusion and 3) Efficacy: Descriptive characterization of complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) at Day +90. As well, progression-free survival (PFS), overall survival (OS), duration of remission (DOR) and overall response rate (ORR) will be determined. Efficacy will be descriptively stratified based on prior receipt of CAR-T cell therapy.

• Study Type: Interventional
• Study Phase: Phase 1

Study Design

Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:

The study is a prospective single-arm Phase 1/1b with four dose levels. Phase 1 will determine the maximum tolerated dose of CD19x22 CAR T cells using a standard 3+3 trial design in CAR-naïve and CAR-treated patients. Phase 1b is an expansion phase designed to evaluate the preliminary efficacy of CD19x22 CAR T.

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Non-Hodgkin Lymphoma

Intervention

Drug: CD19x22 CAR T Cells

Autologous peripheral blood mononuclear cells transduced with CD19x22 CAR T lentiviral vector.

Study Arms

Experimental: CD19x22 CAR T Cell Infusion

Lymphodepleting chemotherapy following by infusion of CD19x22 CAR T Cells

Intervention: Drug: CD19x22 CAR T Cells

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: October 18, 2021): 20
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 2025
• Estimated Primary Completion Date: December 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Age: ≥ 16 years of age with no upper age limit. (NOTE: the first three subjects on this trial must be ≥ 18 years of age.)

2. Histologically confirmed aggressive B-cell NHL including the following types defined by World Health Organization (WHO) 2008:

   1. Diffuse Large B-Cell Lymphoma (DLBCL) not otherwise specified; T cell/histiocyte rich large B cell lymphoma; DLBCL associated with chronic inflammation; Epstein Barr Virus (EBV)+ DLBCL of the elderly; OR
   2. Primary mediastinal (thymic) large B cell lymphoma; OR
   3. Transformation to DLBCL; OR
   4. Mantle Cell Lymphoma (MCL).

1. Results of all tests conducted on the tissue at initial diagnosis and/or relapse, including, but not limited to, the MCL subtype (classic and blastoid), Ki-67 proliferation index, and TP53 mutation status should be provided if done. e. Subjects must not have signs or symptoms of CNS disease or detectable evidence of CNS disease on magnetic resonance imaging (MRI) at screening; subjects who have been previously treated for CNS disease, but have no evidence of disease at screening are eligible.

3. Subjects must have disease progression confirmed by either flow cytometry or immunohistochemistry (IHC), disease stabilization, or disease recurrence after at least two lines of therapy.

a. For DLBCL, the two lines of prior therapy must include an anthracycline and anti-CD20 monoclonal antibody treatment.

b. For MCL, the two lines of prior therapy include any combination of the agents below:

1. an anti-CD20-directed therapy
2. BTK inhibitor
3. Anthracycline or Bendamustine c. Relapse or refractory after single antigen targeting CAR T cell therapy.
4. Must have evaluable or measurable disease according to the revised International Working Group (IWG) Response Criteria for Malignant Lymphoma;34 lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy. MCL patients without measurable nodal or extranodal disease by IWG criteria are eligible if they have bone marrow involvement of MCL.
5. Subjects who have undergone autologous stem cell transplantation (SCT) with disease progression or relapse are eligible.

6. Subjects who have undergone allogeneic SCT will be eligible if, in addition to meeting other eligibility criteria, are:

   1. At least 100 days post-transplant,
   2. Do not have graft versus host disease (GVHD)
7. At least 14 days or 5 half-lives, whichever is shorter, must have elapsed since any prior systemic therapy (including radiation therapy) at the time the subject is planned for leukapheresis, except for systemic inhibitory/stimulatory immune checkpoint therapy, which requires 5 half-lives.
8. At least 7 days must have elapsed since any prior steroid use (dexamethasone or prednisone) prior to apheresis. Physiological replacement doses are allowable with no washout period. Topical or inhaled steroids for localized GVHD is allowable.
9. Peripheral blood CD3 count must be >0.15 x 106 cells/mL within 14 days prior to proceeding with apheresis.
10. Toxicities from prior therapy must be stable and recovered to ≤ grade 1 (exceptions include non-clinically significant toxicities such as alopecia and the organ function definitions provided in inclusion criteria 12).
11. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, or Karnofsky ≥ 80%.

12. Adequate organ function as defined by:

    1. Absolute neutrophil count (ANC) ≥ 750/μL for DLBCL and ≥ 500/μL for MCL.
    2. Platelet count ≥ 50,000/ μL.
    3. Renal: Creatinine ≤ 2 mg/dL OR creatinine clearance (as estimated by Cockcroft Gault equation) ≥ 60 mL/min.
    4. Hepatic: Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 2.5 upper limit of normal (ULN).
    5. Total bilirubin ≤ 1.5 mg/dl, except in subjects with Gilbert's syndrome where a bilirubin <3.0 will be acceptable.
    6. Cardiac: Ejection fraction ≥ 45%, no evidence of physiologically significant pericardial effusion as determined by an echocardiogram (ECHO), and no clinically significant electrocardiogram (ECG) findings within 6 weeks of apheresis.
    7. Pulmonary: No clinically significant pleural effusion and;

1. Baseline oxygen saturation must be > 92% on room air and; 2. For screening only and within 6 weeks of apheresis: Pulmonary Function Test: Diffuse capacity of the lungs for carbon monoxide (DLCO), forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) are all ≥50% of predicted by spirometry after correcting for hemoglobin.

a) Post apheresis: If participant has received bridging therapy or develops a significant illness, retest may be performed per investigator discretion.

13. Females of childbearing potential must have a negative serum pregnancy test (females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential). 14. Subjects of childbearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study and for 12 months after receiving the CD19x22 infusion; females of childbearing potential must have a negative pregnancy test.

15. Must be able to give informed consent; subjects unable to give informed consent will not be eligible for this study.

16. Be able to consent to long-term follow-up protocol (#20-0188). Exclusion Criteria Subjects meeting any of the following criteria are not eligible for participation in the study.

1. Age < 16 years of age.
2. Signs or symptoms of active CNS disease or detectable evidence of CNS disease on MRI at the time of screening. Subjects who have been previously treated for CNS disease, but have no evidence of disease at screening are eligible.
3. History of other malignancies, unless they have been disease free for at least 3 years. Exceptions include non-melanoma skin cancer or carcinoma in situ.
4. Uncontrolled fungal, bacterial, viral, or other infection requiring antimicrobials for management; simple urinary tract infection (UTI) and uncomplicated bacterial pharyngitis are permitted if responding to active treatment.
5. Known history of infection with human immunodeficiency virus (HIV) or hepatitis B (hepatitis B surface antigen [HBsAg] positive) or hepatitis C.
6. History of known myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months of enrollment or have cardiac atrial or cardiac ventricular lymphoma involvement.
7. Venous thrombosis or embolism not managed on a stable regimen of anticoagulation.
8. Any medical condition that in the judgement of the sponsor is likely to interfere with assessment of safety or efficacy of study treatment.
9. History of severe immediate hypersensitivity reaction to any of the agents used in this study.
10. Pregnancy (serum pregnancy test must be obtained at time of enrollment for females of childbearing potential and to be repeated 72 hours prior to lymphodepleting chemotherapy regimen); females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be childbearing potential.
11. Lactating.
12. In the investigator's judgment, the subject is unlikely to complete all protocol required study visits or procedures, including follow up visits, or comply with the study requirements for participation.
13. May not have primary immunodeficiency or history of autoimmune disease (e.g., Crohn's Disease, rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years.
14. Unwilling to participate in long-term follow-up protocol that is required if CAR T cell therapy is administered at CU-AMC (#20-0188).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 16 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Derek Schatz; 7208480628; derek.schatz@cuanschutz.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT05098613
• Other Study ID Numbers: 21-2578.cc
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: University of Colorado, Denver
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Colorado, Denver
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Manali Kamdar, MD; University of Colorado, Denver

• PRS Account: University of Colorado, Denver
• Verification Date: May 2024