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.

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.

Eligibility Criteria:
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.