CLIC-2201 for the Treatment of Relapsed/Refractory B Cell Malignancies

Phase 1

Recruiting

• Conditions: Mantle Cell Lymphoma; Primary Mediastinal Large B-cell Lymphoma (PMBCL); Non-Hodgkin's Lymphoma; Diffuse Large B Cell Lymphoma; B-Cell Leukemia; High-grade B-cell Lymphoma; B-cell Acute Lymphoblastic Leukemia; B-cell Lymphoma
• Interventions: Biological: CLIC-2201

• Registration Number: NCT06208735
• Lead Sponsor: British Columbia Cancer Agency

Brief Summary

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.

Detailed Description

This is a Phase I, first-in-human, open-label multicenter trial of CLIC-2201 CAR-T cells for participants with relapsed/refractory B cell malignancies.

This trial will be conducted in two cohorts (cohort A, including 12 adult participants with B-NHL and cohort B, including 12 paediatric/young adult participants with B-ALL).

Consented participants will undergo a series of tests to confirm eligibility. Following eligibility confirmation, participants will undergo leukapheresis, which enables CLIC-2201 manufacturing. Leukapheresis is a procedure where white blood cells are collected from the blood. The collected cells will be shipped fresh to the Conconi Family Immunotherapy Laboratory (CFIL) in Victoria, BC, where manufacturing will take place.

At the CFIL lab, the autologous T cells will be selected, activated, and transduced with lentivirus to deliver the sdCD22 CAR transgene and then expanded over a period of 8 days in an automated, closed process on the CliniMACS Prodigy.

Participants will undergo lymphodepleting chemotherapy consisting of fludarabine (40 mg/m\^2 daily x 3 days) and cyclophosphamide (500 mg/m\^2 daily x 2 days) on trial days -4 and -3. The chemotherapy will deplete the exciting immune cells and give a chance to the infused CAR-T cells to expand and grow in the body.

Infusion of the autologous CLIC-2201 will follow at least 48 hours after but within seven days of completion of the last dose of fludarabine.

The standard 3+3 design will be used for CLIC-2201 administration to guide dosing and determination of the maximum tolerated dose (MTD). At each dose level, a decision will be made by the study team to escalate (E), stay at the current dose (S), de-escalate (D), or remove that dose level from further enrollment on trial (R) based on the number of dose-limiting toxicities (DLTs) evaluable participants who experience a DLT at that level.

There is no evidence that dosing of CAR-T cells/kg is different between paediatric and adult populations; however, most CAR-T cell products for B-ALL typically used a lower dose than for B-NHL. Therefore, in this trial, each dose level would start with the accrual of one adult participant in Cohort A before enrolling paediatric participants in Cohort B at that dose level. If a dose level is seen to be too toxic in Cohort A, this dose level will not be tested in Cohort B.

Participants in each cohort will be enrolled and treated in groups of n=3. The first 3 participants (group 1) will be treated at DL1. The first participant at this dose level will be staggered for a minimum of 28 days to allow for the full assessment of DLTs. After this, the other two participants enrolled at this level will be monitored for a minimum 14-day period. The staggered intervals pattern will be repeated for each dose level.

If none of the three participants in group 1 experiences a DLT, another group of three participants will be treated at the next higher dose level (DL2).

If \>=2/3 participants experience a DLT, the dose will be de-escalated to DL-1, with de-escalation to DL-1 potentially occurring if both first 2 participants experience a DLT.

If 1/3 participants experience a DLT, an additional group of 3 more participants will be treated at the same dose level.

The dose escalation will continue until the maximum dose level (DL3) is reached without significant DLTs, or when at least 2/6 participants experience DLTs at a certain dose level (i.e., 33% of patients with a DLT at that dose level). The MTD will then be defined as the dose level just below this toxic dose level.

To receive the CLIC-2201 infusion, participants will be admitted to the in-patient unit, and they will remain at the hospital for a minimum of 7 days to be monitored closely for any complication, infection, and side effects. The participants will be discharged to the appropriate outpatient clinic if they are deemed medically stable after this time.

Participants will be seen at the outpatient clinic or daycare unit on days 10, 14, 21, 28, 60, 90, 180, and 365 after the CLIC-2201 infusion. They will continue with annual follow-up visits up to 15 years post-CLIC-2201 infusion.

Study Timeline

• Study First Submitted: 2023-12-20
• Study First Submitted QC: 2024-01-05
• Study First Posted: 2024-01-17
• Study Start: 2025-01-02
• Status Verified: 2025-05
• Last Update Submitted: 2025-05-07
• Last Update Posted: 2025-05-09
• Primary Completion: 2026-08-01
• Study Completion: 2027-08-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 24

Inclusion Criteria

Not provided

Exclusion Criteria

1. Any uncontrolled or serious active infection at the time of enrolment.

2. Active autoimmune disease requiring immunosuppressive therapy within 4 weeks of enrolment.

3. Live vaccine ≤6 weeks prior to enrolment

4. Active Graft Versus Host Disease (GVHD) requiring systemic immunosuppressive therapy within 4 weeks of enrolment.

5. Treatment with any of the following in the specified time period before leukapheresis:

   1. Allogeneic HCT within 3 months,
   2. Autologous HCT within 3 months,
   3. CD19 CAR-T cell infusion within 3 months,
   4. Donor lymphocyte infusion (DLI) within 3 months,
   5. Bendamustine within the last 6 months,
   6. Any investigational agent within 30 days or 5 half-lives (whichever is shorter),
   7. 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.
   8. Immunosuppressive therapies (i.e., calcineurin inhibitors, methotrexate, mycophenolate, rapamycin) within 4 weeks.
   9. 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.

6. 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.

7. 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.

8. Active (confirmed by PCR) hepatitis B or hepatitis C at time of screening confirmed by PCR.

9. Any Human Immunodeficiency Virus (HIV) infection at time of screening.

10. Hypersensitivity to fludarabine or cyclophosphamide.

11. Any allergy to gentamycin or its derivatives

12. Pregnant or nursing participants.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
CLIC-2201	CLIC-2201	A single Intravenous infusion of CLIC-2201 will be given.

Primary Outcome Measures

Name	Time	Method
Proportion of participants who experienced any grade of CRS to define the safety of CLIC-2201	Within the first 28 days of CAR-T infusion	The safety will be measured by the proportion of participants who experienced any grade of CRS, ICANS, IEC-HS, any adverse events, and any severe adverse events.
Proportion of participants who experienced any SAEs to define the safety of CLIC-2201	Within the first 28 days of CAR-T infusion	The safety will be measured by the proportion of participants who experienced any grade of CRS, any grade of ICANS, any adverse events, and any severe adverse events.
Proportion of participants who experienced any grade of ICANs to define the safety of CLIC-2201	Within the first 28 days of CAR-T infusion	The safety will be measured by the proportion of participants who experienced any grade of CRS, any grade of ICANS, any adverse events, and any severe adverse events.
Proportion of participants who experienced any grade of IEC-HS to define the safety of CLIC-2201	Within the first 28 days of CAR-T infusion	The safety will be measured by the proportion of participants who experienced any grade of CRS, any grade of ICANS, any adverse events, and any severe adverse events.
Defining the maximum tolerated dose (MTD) of CLIC-2201	Within the first 28 days of CAR-T infusion	The MTD will be measured by monitoring and recording the AEs experienced by the participant within the first 28 days after the infusion, including the treatment-related death as deemed by the investigator, grade 3 Cytokine Release Syndrome (CRS), Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS), and Immune Effector Cell-Associated Hemophagocytic Lymphocytosis-Like Syndrome (IEC-HS) lasting for more than seven days; grade 4 CRS, ICANS, and IEC-HS; grade 4 non-hematologic toxicity that is not deemed related to CRS, ICANS, IEC-HS (except for Grade 4 transaminases and isolated, asymptomatic laboratory electrolyte abnormalities for seven days or more).
Proportion of participants who experienced any grade of AEs to define the safety of CLIC-2201	Within the first 28 days of CAR-T infusion	The safety will be measured by the proportion of participants who experienced any grade of CRS, any grade of ICANS, any adverse events, and any severe adverse events.

Secondary Outcome Measures

Name	Time	Method
Proportion of participants achieving achieving and/or maintaining Complete response (CR) or complete response with incomplete count recovery (CRi).	Within 365 days of CAR-T infusion	This would be used to measure the anti-tumour activities of the CLIC-2201 treatment within a year after the infusion. The complete response will be assessed on days 28, 90, 180, and 365.; Response for lymphoma participants will be defined by Lugano criteria and for B-ALL participants by CIBMTR response criteria.
The average number of CAR transgene copies per cell	Up to day 365	This would be used to evaluate the pharmacokinetics of the CLIC-2201 treatment.
Proportion of B-ALL participants with B with minimal residual disease (MRD) negative status by next-generation sequencing and/or high-resolution flow cytometry.	Within 365 days of CAR-T infusion	This would be used to measure the anti-tumour activities of the CLIC-2201 treatment within a year after the infusion. The partial remission will be assessed on days 28, 90, 180, and 365.
Overall survival rate	Up to 15 years of CAR-T infusion	This would be used to measure the the anti-tumor activities of the CLIC-2201 treatment within 6 months after the infusion.
Progression free survival rate	Up to 15 years of CAR-T infusion	This would be used to measure the the anti-tumor activities of the CLIC-2201 treatment within 6 months after the infusion.
Proportion of participants who fail enrollment that were successfully screened	Enrollment	This would be used to evaluate the feasibility of administering CLIC-2201 cells to participants with relapsed/refractory B Cell Malignancies.
Proportion of participants for whom CLIC-2201 manufacturing was unsuccessful that completed leukapheresis	Through manufacturing, an average of 8 days	This would be used to evaluate the feasibility of administering CLIC-2201 cells to participants with relapsed/refractory B Cell Malignancies.
Proportion of participants for whom leukapheresis failed that successfully completed trial enrollment	From date of enrollment until the date of leukapheresis, assessed up to 4 weeks	This would be used to evaluate the feasibility of administering CLIC-2201 cells to participants with relapsed/refractory B Cell Malignancies.
Median time from enrollment to CLIC-2201 infusion	From date of enrollment until the date of infusion, assessed up to 6 weeks	This would be used to evaluate the feasibility of administering CLIC-2201 cells to participants with relapsed/refractory B Cell Malignancies.
Median time from enrollment to disease progression that prevents CLIC-2201 infusion.	From date of enrollment until the date of infusion, assessed up to 6 weeks	This would be used to evaluate the feasibility of administering CLIC-2201 cells to participants with relapsed/refractory B Cell Malignancies.
Proportion of participants who fail to receive CLIC-2201 infusion for whom a CLIC-2201 was successfully manufactured	Day of CLIC-2201 infusion	This would be used to evaluate the feasibility of administering CLIC-2201 cells to participants with relapsed/refractory B Cell Malignancies.
Median time from enrollment to leukapheresis	From date of enrollment until the date of leukapheresis, assessed up to 4 weeks	This would be used to evaluate the feasibility of administering CLIC-2201 cells to participants with relapsed/refractory B Cell Malignancies.
Proportion of participants with an overall response [achieving a CR or partial remission (PR)]	Within 365 days of CAR-T infusion	This would be used to measure the anti-tumour activities of the CLIC-2201 treatment within a year after the infusion.

Trial Locations

Locations (7)

Arthur J.E. Child Comprehensive Cancer Centre; 🇨🇦 Calgary, Alberta, Canada

Alberta Children's Hospital; 🇨🇦 Calgary, Alberta, Canada

Vancouver General Hospital; 🇨🇦 Vancouver, British Columbia, Canada

BC Children's Hospital; 🇨🇦 Vancouver, British Columbia, Canada

The Ottawa Hospital - General Campus; 🇨🇦 Ottawa, Ontario, Canada

Princess Margaret Cancer Centre; 🇨🇦 Toronto, Ontario, Canada

The Hospital for Sick Children; 🇨🇦 Toronto, Ontario, Canada