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Study Description

 This study is eligible for STEP-1 funding. Find more information here. 

This is a phase I dose-finding trial of an autologous CD22 targeting chimeric antigen receptor (CAR)-T cell product, called CLIC-2201, for participants with relapsed/refractory B cell malignancies. In the proposed trial, eligible enrolled participants will undergo leukapheresis for autologous T cell collection to enable CLIC-2201 manufacturing, followed by lymphodepletion with cyclophosphamide and fludarabine, then intravenous infusion of the autologous CLIC-2201 product. The trial will use the 3+3 design to escalate or de-escalate the dose level of CLIC-2201 administered. Participants will be monitored for safety and tolerability up to day 365 following CLIC-2201 infusion.

The primary objective is to evaluate the safety and tolerability of CLIC-2201 and estimate the maximum tolerated dose (MTD) of CLIC-2201 in B-cell malignancies.

The secondary objectives are to evaluate the (i) feasibility; (ii) anti-tumour activity of CLIC-2201; (iii) and characterize the pharmacokinetic (PK) profile of CLIC-2201.

Exploratory objectives will include: i) characterizing the cellular and humoral immune responses against CLIC-2201 up to 1 year following infusion of CLIC-2201; (ii) characterizing the phenotype and gene expression profile of CLIC-2201 cells; (iii) evaluating immune and tumour cells at baseline and relapse for biomarkers of response or toxicity; (iv) evaluating serum cytokines, circulating tumour DNA (ctDNA) and B cell aplasia as biomarkers of clinical outcomes; and (v) assessing the quality of life.

Inclusion Criteria

Cohort A (B cell lymphoma):

• Participants in the cohort A must be 18 years of age or older of age at time of informed consent.
• Participants must provide written informed consent. The investigator is responsible for obtaining written informed assent/consent for the subject after adequate explanation of the study design, anticipated benefits and the potential risks. Subjects should sign the most current REB approved assent/consent prior to any study specific activity or procedure is performed. (Sites will follow their REB board requirements for consenting).
• Participants must have a relapsed or refractory B cell lymphoma, including one of the following:
  • diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS)
  • high grade B cell lymphoma NOS
  • grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements
  • primary mediastinal large B-cell lymphoma (PMBCL)
  • aggressive B cell lymphoma transformed from an indolent lymphoma
  • mantle cell lymphoma (MCL)
• Participants must have refractory or relapsed disease, defined as one of the following:
  • Relapse or refractory disease after at least 2 lines of therapy, OR
  • Any relapse after autologous or allogeneic hematopoietic cell transplantation (HCT), OR
  • Any relapse after CAR-T cell therapy
• Participants must have adequate organ function at enrolment, defined as:
  • Left ventricular ejection fraction (LVEF) ≥40%,
  • Creatinine clearance using Cockcroft-Gault of > 30 mL/min, AND
  • ALP/ALT < 5X upper limit of normal (ULN), conjugated bilirubin < 2X ULN, and no evidence or history of liver cirrhosis.
• Participants must have Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 or Karnofsky Score ≥50%.
• Females of child-bearing potential and sexually active males must agree to use a highly effective contraception method (see section 5.4) through to at least one year following administration of the CLIC-2201 product.
• Participants with accessible disease, willingness to undergo a tumour biopsy at enrolment. For participants with a recent (within 3 months) tumor biopsy, access to the archival biopsy is acceptable.

Cohort B (B-ALL):

• Participants in the cohort B must be between 1-21 years of age at the time of consent.
• Parent or legal guardian of the participant signed the informed consent and the participant's assent/consent is obtained (if applicable). The investigator is responsible for obtaining written informed assent/consent for the subject or legally acceptable representative (e.g. parent, legal guardian) after adequate explanation of the study design, anticipated benefits and the potential risks. Subjects should sign the most current REB approved assent/consent prior to any study specific activity or procedure is performed. (Sites will follow their REB board requirements for consenting).
• Participants must have a relapsed or refractory B cell acute lymphoblastic leukemia (B-ALL)
• Participants must have refractory or relapsed disease, defined as one of the following:
  • Relapse or refractory disease after at least 2 lines of therapy, OR
  • Any relapse after autologous or allogeneic hematopoietic cell transplantation (HCT), OR
  • Any relapse after CAR-T cell therapy.
• Participants in cohort B and/or those who have received CD22 targeted therapy must have documentation of CD22 tumour expression within the 6 months prior to study screening, and after any prior CD22 directed therapy (if applicable).
• Participants must have adequate organ function at enrolment, defined as:
  • Left ventricular ejection fraction (LVEF) ≥45%,
  • Creatinine clearance using Cockcroft-Gault or Schwartz equation of > 30 mL/min, AND
  • ALP/ALT < 5X upper limit of normal (ULN), conjugated bilirubin < 2X ULN, and no evidence or history of liver cirrhosis.
• Participants must have a Karnofsky or Lansky Score ≥50%.
• Participants in reproductive age must agree to use a highly effective contraception method (see section 5.4) through to at least one year following administration of the CLIC-2201 product.
• Participants willingness to undergo a bone marrow biopsy at enrolment.

Publications

Both Cohorts A and B

• Any uncontrolled or serious active infection at the time of enrolment.
• Active autoimmune disease requiring immunosuppressive therapy within 4 weeks of enrolment.
• Live vaccine ≤6 weeks prior to enrolment
• Active Graft Versus Host Disease (GVHD) requiring systemic immunosuppressive therapy within 4 weeks of enrolment.
• Treatment with any of the following in the specified time period before leukapheresis:
  • Allogeneic HCT within 3 months,
  • Autologous HCT within 3 months,
  • CD19 CAR-T cell infusion within 3 months,
  • Donor lymphocyte infusion (DLI) within 3 months,
  • Bendamustine within the last 6 months,
  • Any investigational agent within 30 days or 5 half-lives (whichever is shorter),
  • Systemic administration of therapeutic dose corticosteroids (>20 mg/day prednisone or equivalent for adults and ≥ 12 mg/m2/day for paediatric participants) within 7 days prior to leukapheresis.
  • Immunosuppressive therapies (i.e., calcineurin inhibitors, methotrexate, mycophenolate, rapamycin) within 4 weeks.
  • Oral chemotherapy agents (i.e., venetoclax) within 5 half-lives. An exception to this is that bruton tyrosine kinase (BTK) inhibitors like ibrutinib can be continued in participants with mantle cell lymphoma throughout the trial period.
• Other concurrent malignancy or a prior malignancy treated within the past 2 years, except carcinoma in situ of the skin or cervix treated with curative intent and with no evidence of active disease.
• Concomitant genetic syndrome associated with bone marrow failure such as Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure or immunodeficiency syndrome.
• Active (confirmed by PCR) hepatitis B or hepatitis C at time of screening confirmed by PCR.
• Any Human Immunodeficiency Virus (HIV) infection at time of screening.
• Hypersensitivity to fludarabine or cyclophosphamide.
• Any allergy to gentamycin or its derivatives
• Pregnant or nursing participants.