Anti-CD19, Dual Co-stimulatory (4-1BB, CD3ζ) Chimeric Antigen Receptor T-cells in Patients With Relapsed/Refractory Aggressive Lymphoma or Acute Lymphoblastic Leukemia (ALL) (ACIT001/EXC002)

A Phase 1b/2 Multi-center, De-centralized, Dose Selection Study of Autologous CD19-directed Chimeric Antigen Receptor (CAR) T-cells in Patients With Relapsed/Refractory Aggressive Lymphoma or Acute Lymphoblastic Leukemia (ALL)

Autologous, unselected CD3+ lymphocytes collected from apheresis, transfected with a lentiviral vector containing a 2nd generation chimeric antigen receptor (CAR) consisting of a scFv recognizing CD19 and dual co-stimulatory intracellular signaling domains (4-1BB and CD3ζ).

Study Overview

• Status: Recruiting
• Conditions: Relapsed Non Hodgkin Lymphoma; Relapsed Pediatric ALL; Relapsed Adult ALL
• Intervention / Treatment: Biological: autologous CD19-directed chimeric antigen receptor (CAR) T-cells

Detailed Description

Anti-CD19/4-1BB/CD3ζ CAR T-cell: autologous, unselected CD3+ lymphocytes collected from whole blood or apheresis, transfected with a lentiviral vector containing a 2nd generation chimeric antigen receptor (CAR) consisting of a scFv recognizing CD19 and dual co-stimulatory intracellular signaling domains (4-1BB and CD3ζ). All patients will receive lymphodepleting, conditioning chemotherapy in the form of cyclophosphamide (500 mg/m2/day) and fludarabine (30 mg/m^2/day) on Days -5, -4, and -3 prior to a CAR T-cell intravenous, single dose administration on Day 0.

Phase 1b: Dose Finding/Escalation Dose Level 1: 0.5 x 10^6/kg Dose Level 2: 1.0 x 10^6/kg Dose Level 3: 2.0 x 10^6/kg

Phase 2: Expansion Patients will receive lymphodepleting chemotherapy as indicated prior to receiving the CAR T-cell intravenous, single dose administration on Day 0 at the RP2D as identified during Phase 1b.

• Study Type: Interventional
• Enrollment (Estimated): 63
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Zack Breckenridge; Phone Number: 7803917687; Email: zackariah.breckenridge@ahs.ca

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N2T9
      • Not yet recruiting
      • Foothills Medical Centre
      • Contact: Dr. Andrew Daly, MD
    • Calgary, Alberta, Canada, T2N4N2
      • Not yet recruiting
      • Tom Baker Cancer Centre
      • Contact: Dr. Peter Duggan, MD
    • Calgary, Alberta, Canada, T3B6A8
      • Not yet recruiting
      • Alberta Children's Hospital
      • Contact: Dr. Victor Lewis, MD
    • Edmonton, Alberta, Canada, T6G1Z2
      • Recruiting
      • Cross Cancer Institute
      • Contact: Dr. Michael P Chu, MD
    • Edmonton, Alberta, Canada, T6G2B7
      • Recruiting
      • University of Alberta Hospital
      • Contact: Dr. Peng Wang, MD
    • Edmonton, Alberta, Canada, T6G2B7
      • Not yet recruiting
      • Stollery Children's Hospital
      • Contact: Dr. Sunil Desai, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 70 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Have given written informed consent prior to any study-specific procedures; children (defined as 17 years of age or less) require guardian consent.
2. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2; or Karnofsky > 50%.
3. Age of 2 to 70 years at time of screening.
4. A histologically or cytologically documented, CD19+ non-hodgkin's lymphoma or ALL.
5. At least 1 measurable lesion or FDG-avid disease by positron-emission tomography/computed tomography (PET/CT) for lymphoma patients; quantifiable evidence of ALL in either peripheral blood or bone marrow aspirate.
6. Tumor tissue (archival or recent acquisition) must be available for correlative laboratory studies (such as immunohistochemistry, and others).
7. At least 2 prior systemic therapies and patient must not be eligible for potentially curative standard-of-care therapy.
8. Adequate renal function (defined as Cockroft-Gault creatinine clearance > 50 mL/min) and hepatic function (total bilirubin < 1.5x ULN; and AST/ALT < 3x ULN) unless directly related to malignant disease being treated for on study as demonstrated either by PET/CT imaging or by biopsy and histopathologic confirmation.
9. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 90 days after the last dose of study treatment. 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, established proper use of hormonal contraceptives 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.
10. Male participants should agree to not donate sperm during study period (i.e. up to 2 years following CAR T-cell administration).
11. Male participants with reproductive potential must agree to use medical approved contraceptives during the study and for 90 days following the last dose of study treatment.
12. Are reliable and willing to make themselves available for the duration of the study, and are willing to follow study procedures.

Exclusion Criteria:

1. Prior treatment with immunotherapy directly targeting T-cells (except anti-thymocyte globulin [ATG]), CD19-directed antibody-based therapies (except blinatumomab), or other gene therapy products.
2. Received any investigational drug/anti-cancer therapy within 30 days.
3. Concurrent participation in another therapeutic clinical trial.
4. Therapeutic doses of corticosteroids (defined as > 20 mg/day prednisone or equivalent) within 7 days prior to blood collection for CAR T-cell product manufacture.
5. Donor lymphocyte infusion (DLI) within 4 weeks prior to leukapheresis.
6. Salvage or debulking chemotherapy within 1 week prior to blood collection for CAR T-cell product manufacture.
7. Prior central nervous system (CNS) involvement.
8. Unresolved acute toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 Grade >1 (or baseline, whichever is greater) from prior anticancer therapy. Alopecia and other nonacute toxicities are acceptable.
9. An uncontrolled intercurrent illness including but not limited to ongoing or active infection (including fever within 48 hours of screening), symptomatic congestive heart failure (i.e., New York Heart Association [NYHA] Class 3 or 4), unstable angina pectoris, clinically significant and uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
10. Major surgical procedure within 30 days.
11. Known history of human immunodeficiency virus (HIV) or active infection requiring therapy, or positive tests for hepatitis B surface antigen or hepatitis C ribonucleic acid (RNA).
12. Any vaccination against infectious diseases (e.g., influenza, varicella) within 4 weeks (28 days) of initiation of study treatment.
13. A woman who is pregnant or breastfeeding.

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: CAR T cells; Patients with relapsed/refractory B-cell ALL or NHL.

Biological: autologous CD19-directed chimeric antigen receptor (CAR) T-cells; Anti-CD19/4-1BB/CD3ζ CAR T-cell: autologous, unselected CD3+ lymphocytes collected from whole blood or apheresis, transfected with a lentiviral vector containing a 2nd generation chimeric antigen receptor (CAR) consisting of a scFv recognizing CD19 and dual co-stimulatory intracellular signaling domains (4-1BB and CD3ζ). All patients will receive lymphodepleting, conditioning chemotherapy in the form of cyclophosphamide (500 mg/m2/day) and fludarabine (30 mg/m2/day) on Days -5, -4, and -3 prior to a CAR T-cell intravenous, single dose administration on Day 0.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number and type of treatment-related adverse events.	3 years
Number of dose limiting toxicities of anti-CD19 CAR T-cells	3 years
Maximum concentration (Cmax).	3 years
Time to maximum concentration (Tmax).	3 years
Area-Under-the-Concentration-vs-time curve (AUC) in peripheral blood and/or bone marrow.	3 years
Overall objective response rate (ORR: proportion of patients with confirmed responses of complete [CR] or partial [PR])	3 years

Collaborators and Investigators

• Sponsor: University of Alberta
• Collaborators: Alberta Cancer Foundation; Canadian Cancer Trials Group
• Investigators: Principal Investigator: Dr. Michael P Chu, MD, Cross Cancer Institute

Study record dates

Study Major Dates

• Study Start (Actual): March 3, 2021
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: April 30, 2019
• First Submitted That Met QC Criteria: May 2, 2019
• First Posted (Actual): May 6, 2019

Study Record Updates

• Last Update Posted (Actual): July 25, 2023
• Last Update Submitted That Met QC Criteria: July 21, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia; Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid
• Other Study ID Numbers: ACIT001/EXC002

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