Non-Hodgkin's Lymphoma Clinical Trial
Official title:
CLIC-02: A Phase I Trial of CLIC-2201 for the Treatment of Relapsed/Refractory B Cell Malignancies
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.
| 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. |
| 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 |
| Lead Sponsor | Collaborator |
|---|---|
| British Columbia Cancer Agency |
Canada,
| 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 |
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|---|---|---|---|
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