Clinical Trials Logo

Clinical Trial Details — Status: Not yet recruiting

Administrative data

NCT number NCT06208735
Other study ID # CLIC-02
Secondary ID
Status Not yet recruiting
Phase Phase 1
First received
Last updated
Start date July 1, 2024
Est. completion date August 1, 2027

Study information

Verified date April 2024
Source British Columbia Cancer Agency
Contact Kevin Hay, MD
Phone (403) 210-6191
Email kevin.hay@bccancer.bc.ca
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


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.


Recruitment information / eligibility

Status Not yet recruiting
Enrollment 24
Est. completion date August 1, 2027
Est. primary completion date August 1, 2026
Accepts healthy volunteers No
Gender All
Age group 1 Year and older
Eligibility Inclusion Criteria in Cohort A: Participants must meet the following criteria to be enrolled on the trial: 1. Participants in the cohort A must be 18 years of age or older of age at time of informed consent. 2. 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). 3. Participants must have a relapsed or refractory B cell lymphoma, including one of the following: 1. diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS), 2. high grade B cell lymphoma NOS, 3. high grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, 4. primary mediastinal large B-cell lymphoma (PMBCL), 5. aggressive B cell lymphoma transformed from an indolent lymphoma, 6. mantle cell lymphoma (MCL), 4. Participants must have refractory or relapsed disease, defined as one of the following: 1. Relapse or refractory disease after at least 2 lines of therapy, OR 2. Any relapse after autologous or allogeneic hematopoietic cell transplantation (HCT), OR 3. Any relapse after CAR-T cell therapy. 5. Participants must have adequate organ function at enrolment, defined as: 1. Left ventricular ejection fraction (LVEF) =40%, 2. Creatinine clearance using Cockcroft-Gault of > 30 mL/min, AND 3. ALP/ALT < 5X upper limit of normal (ULN), conjugated bilirubin < 2X ULN, and no evidence or history of liver cirrhosis. 6. Participants must have Eastern Cooperative Oncology Group (ECOG) performance status of = 2 or Karnofsky Score =50%. 7. 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. 8. 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. Inclusion Criteria in Cohort B: 1. Participants in the cohort B must be between 1-21 years of age at the time of consent. 2. 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). 3. Participants must have a relapsed or refractory B cell acute lymphoblastic leukemia (B-ALL). 4. Participants must have refractory or relapsed disease, defined as one of the following: 1. Relapse or refractory disease after at least 2 lines of therapy, OR 2. Any relapse after autologous or allogeneic hematopoietic cell transplantation (HCT), OR 3. Any relapse after CAR-T cell therapy. 5. 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). 6. Participants must have adequate organ function at enrolment, defined as: 1. Left ventricular ejection fraction (LVEF) =45%, 2. Creatinine clearance using Cockcroft-Gault or Schwartz equation of > 30 mL/min, AND 3. ALP/ALT < 5X upper limit of normal (ULN), conjugated bilirubin < 2X ULN, and no evidence or history of liver cirrhosis. 7. Participants must have a Karnofsky or Lansky Score =50%. 8. 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. 9. Participants willingness to undergo a bone marrow biopsy at enrolment. 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


Related Conditions & MeSH terms


Intervention

Biological:
CLIC-2201
Participants will undergo (a) lymphodepletion with cyclophosphamide and fludarabine, followed by (b) infusion of autologous CLIC-2201 CAR-T cells. All treatments will be delivered intravenously.

Locations

Country Name City State
Canada Calgary Cancer Centre Calgary Alberta
Canada The Ottawa Hospital - General Campus Ottawa Ontario
Canada Princess Margaret Cancer Centre Toronto Ontario
Canada The Hospital for Sick Children Toronto Ontario
Canada BC Children's Hospital Vancouver British Columbia
Canada Vancouver General Hospital Vancouver British Columbia

Sponsors (1)

Lead Sponsor Collaborator
British Columbia Cancer Agency

Country where clinical trial is conducted

Canada, 

Outcome

Type Measure Description Time frame Safety issue
Other Serum cytokine levels before and after CAR-T cell infusion (Mesoscale) This would be used to evaluate the biomarkers of CLIC-2201 treatment within 28 days after the infusion. Up to day 28 after the infusion
Other Proportion of participants with B-cell aplasia assessed by flow cytometry (BTNK panel) This would be used to evaluate the biomarkers of CLIC-2201 treatment within a year after the infusion. This would be assessed on days 28, 60, 90, 180, and 365. Within 365 days after the infusion
Other Measurement (quantitative and qualitative) of circulating tumour DNA in peripheral blood. This would be used to evaluate the biomarkers of CLIC-2201 treatment within a year after the infusion. Within 365 days after the infusion
Other Molecular profiling of tumour tissue to explore mechanisms of efficacy and resistance prior to CLIC-2201 infusion and on relapse. This would be used to evaluate immune and tumour cells at baseline and relapse for biomarkers of response or toxicity of CLIC-2201 treatment. At the time of enrollment and if relapsed (assessed up to 1 year post infusion)
Other Total CD3, CD4 and CD8 absolute numbers and relative percentages (BTNK panel) This would be used to evaluate immune and tumour cells at baseline and relapse for biomarkers of response or toxicity of CLIC-2201 treatment. Up to 365 days after the infusion
Other Phenotypic analysis of CLIC-2201 infusion product and cells in peripheral blood after CLIC-2201 infusion, as assessed by flow cytometry This would be used to characterize the phenotype and gene expression profile of CLIC-2201 cells. Within 4 hours prior to infusion
Other Clonal typing and gene expression profiling of the CLIC-2201 infusion product. (Single cell RNA-sequencing) This would be used to to characterize the phenotype and gene expression profile of CLIC-2201 cells. Within 4 hours prior to infusion
Other Evaluating the health-related quality of life In Cohort A: EuroQol 5 Dimension 5 Level (EQ-5D-5L) will assess participants' quality of life across five domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The questionnaire follows a five-level ranking system that ranges from no problems to extreme problems.
In Cohort B:
For participants aged 16 or older: EQ-5D-5L will be used as above.
For participants aged 8 to 15: EQ-5D-Y will be used, which is the child-friendly version of the questionnaire above in five domains and a three-level ranking system that ranges from no problems to a lot of problems.
For participants aged 4 to 7, the proxy version of EQ-5D-Y will be used. In the proxy version, parent, caregiver, or informant will be asked to respond to the questionnaire by providing their own impression of participant's health status.
Participants aged 1 to 3 will not have a quality-of-life assessment.
Up to 365 days after the infusion
Other Evaluating the quality of life The EORTC Core Quality of Life questionnaire (EORTC C-30) will be used to assess physical, psychological, and social functions among participants in CLIC-2201 study. This questionnaire consists of 30 items organized into several multi-item scales and single-item measures.
For the multi-item scale questions, the questionnaire uses a Likert scale format, with response options ranging from "Not at all" to "Very much," allowing patients to indicate the extent to which they have experienced each symptom or difficulty over the past week.
The single-item questions focus on overall health and overall quality of life and the participants could circle a number between 1(very poor) to 7 (Excellent) to indicate how they felt during the past week.
Up to 365 days after the infusion
Other Frequency of antibody responses against the single domain antibody (sdAb) portion of the CLIC-2201 CAR transgene This would be used to evaluate the immunogenicity of the CLIC-2201 treatment. This would be assessed on days 28, 90, 180, and 365. Within 365 days of CAR-T infusion
Other Frequency of cellular immune responses against CLIC-2201 cells by ELISpot This would be used to evaluate the immunogenicity of the CLIC-2201 treatment. This would be assessed on days 28, 90, 180, and 365. Within 365 days of CAR-T infusion
Primary Defining the maximum tolerated dose (MTD) of CLIC-2201 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). Within the first 28 days of CAR-T infusion
Primary Proportion of participants who experienced any grade of CRS to define the safety of CLIC-2201 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. Within the first 28 days of CAR-T infusion
Primary Proportion of participants who experienced any grade of ICANs to define the safety of CLIC-2201 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. Within the first 28 days of CAR-T infusion
Primary Proportion of participants who experienced any grade of IEC-HS to define the safety of CLIC-2201 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. Within the first 28 days of CAR-T infusion
Primary Proportion of participants who experienced any grade of AEs to define the safety of CLIC-2201 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. Within the first 28 days of CAR-T infusion
Primary Proportion of participants who experienced any SAEs to define the safety of CLIC-2201 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. Within the first 28 days of CAR-T infusion
Secondary Proportion of participants achieving achieving and/or maintaining Complete response (CR) or complete response with incomplete count recovery (CRi). 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.
Within 365 days of CAR-T infusion
Secondary Proportion of participants with an overall response [achieving a CR or partial remission (PR)] This would be used to measure the anti-tumour activities of the CLIC-2201 treatment within a year after the infusion. Within 365 days of CAR-T infusion
Secondary Proportion of B-ALL participants with B with minimal residual disease (MRD) negative status by next-generation sequencing and/or high-resolution flow cytometry. 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. Within 365 days of CAR-T infusion
Secondary Overall survival rate This would be used to measure the the anti-tumor activities of the CLIC-2201 treatment within 6 months after the infusion. Up to 15 years of CAR-T infusion
Secondary Progression free survival rate This would be used to measure the the anti-tumor activities of the CLIC-2201 treatment within 6 months after the infusion. Up to 15 years of CAR-T infusion
Secondary The average number of CAR transgene copies per cell This would be used to evaluate the pharmacokinetics of the CLIC-2201 treatment. Up to day 365
Secondary Proportion of participants who fail enrollment that were successfully screened This would be used to evaluate the feasibility of administering CLIC-2201 cells to participants with relapsed/refractory B Cell Malignancies. Enrollment
Secondary Proportion of participants for whom leukapheresis failed that successfully completed trial enrollment This would be used to evaluate the feasibility of administering CLIC-2201 cells to participants with relapsed/refractory B Cell Malignancies. From date of enrollment until the date of leukapheresis, assessed up to 4 weeks
Secondary Proportion of participants for whom CLIC-2201 manufacturing was unsuccessful that completed leukapheresis This would be used to evaluate the feasibility of administering CLIC-2201 cells to participants with relapsed/refractory B Cell Malignancies. Through manufacturing, an average of 8 days
Secondary Proportion of participants who fail to receive CLIC-2201 infusion for whom a CLIC-2201 was successfully manufactured This would be used to evaluate the feasibility of administering CLIC-2201 cells to participants with relapsed/refractory B Cell Malignancies. Day of CLIC-2201 infusion
Secondary Median time from enrollment to leukapheresis This would be used to evaluate the feasibility of administering CLIC-2201 cells to participants with relapsed/refractory B Cell Malignancies. From date of enrollment until the date of leukapheresis, assessed up to 4 weeks
Secondary Median time from enrollment to CLIC-2201 infusion This would be used to evaluate the feasibility of administering CLIC-2201 cells to participants with relapsed/refractory B Cell Malignancies. From date of enrollment until the date of infusion, assessed up to 6 weeks
Secondary Median time from enrollment to disease progression that prevents CLIC-2201 infusion. This would be used to evaluate the feasibility of administering CLIC-2201 cells to participants with relapsed/refractory B Cell Malignancies. From date of enrollment until the date of infusion, assessed up to 6 weeks
See also
  Status Clinical Trial Phase
Active, not recruiting NCT03844048 - An Extension Study of Venetoclax for Subjects Who Have Completed a Prior Venetoclax Clinical Trial Phase 3
Completed NCT01878890 - Phase I Dose Escalation Trial of Efavirenz in Solid Tumours or Non-Hodgkin Lymphoma in Therapeutic Failure. Phase 1
Completed NCT04152148 - A Phase I Clinical Trial of BAT4306F on Safety, Tolerability and Pharmacokinetics for Patients Phase 1
Recruiting NCT05096234 - 18F-F-AraG PET Imaging to Evaluate Immunological Response to CAR T Cell Therapy in Lymphoma Phase 2
Recruiting NCT05191225 - Ultrafast Truxima Infusion in Non-Hodgkin's Lymphoma: Txagorapid Study Phase 4
Recruiting NCT05623982 - Phase Ib/II Study of GNC-038 Injection in Patients With Relapsed or Refractory Non-Hodgkin's Lymphoma Phase 1/Phase 2
Active, not recruiting NCT03664635 - MB-CART20.1 Lymphoma Phase 1/Phase 2
Recruiting NCT02356159 - Study of Palifermin (Kepivance) in Persons Undergoing Unrelated Donor Allogeneic Hematopoietic Cell Transplantation Phase 1/Phase 2
Terminated NCT01699581 - Assessment of Impact Nutritional Program During Autologous Stem Cell Transplant Phase 2
Completed NCT01763398 - Analysis of the Risk Factors for the Neutropenic Fever in the High Risk NHL Patients for Developing Febrile Neutropenia Who Received 3-weekly CHOP-like Chemotherapy With Primary G-CSF Prophylaxis; Prospective Multicenter Observation Study N/A
Completed NCT01205503 - Trial of Mesna to Prevent Doxorubicin-induced Plasma Protein Oxidation and Tumor Necrosis Factor Alpha (TNF-α) Release Phase 2
Completed NCT00969462 - Doxorubicin Pharmacokinetics and Response in Non Hodgkin's Lymphoma Phase 4
Completed NCT00975975 - Basiliximab #2: In-Vivo Activated T-Cell Depletion to Prevent Graft-Versus_Host Disease (GVHD) After Nonmyeloablative Allotransplantation for the Treatment of Blood Cancer Phase 2
Completed NCT00659425 - CAT-8015 in Children, Adolescents and Young Adults With Acute Lymphoblastic Leukemia or Non-Hodgkin's Lymphoma Phase 1
Completed NCT00608907 - An Open-Label Study to Assess the Effect of CYP3A4 Induction on the Pharmacokinetics of VELCADE (Bortezomib) Phase 1
Terminated NCT00475332 - Study to Treat Relapsed Follicular Non-Hodgkin's Lymphoma With Radiation and Bexxar Phase 2
Completed NCT00533728 - Safety of Soluble Beta-Glucan (SBG) in Treatment of Patients With Non-Hodgkin's Lymphoma Phase 1
Withdrawn NCT00577161 - Fludarabine, Pixantrone and Rituximab vs Fludarabine and Rituximab forRelapsed or Refractory Indolent NHL Phase 3
Completed NCT00581646 - Study of Psychosexual Impact of Cancer-Related Infertility in Women: Third Party Reproductive Assistance N/A
Completed NCT00430352 - MAXIMA Study: A Study of Maintenance Therapy With MabThera (Rituximab) in Patients With Non-Hodgkin's Lymphoma. Phase 4