Trial Title:
CLIC-2201 for the Treatment of Relapsed/Refractory B Cell Malignancies
NCT ID:
NCT06208735
Condition:
B-Cell Leukemia
Non-Hodgkin's Lymphoma
B-cell Acute Lymphoblastic Leukemia
Diffuse Large B Cell Lymphoma
High-grade B-cell Lymphoma
Primary Mediastinal Large B-cell Lymphoma (PMBCL)
Mantle Cell Lymphoma
B-cell Lymphoma
Conditions: Official terms:
Lymphoma
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Lymphoma, B-Cell
Lymphoma, Mantle-Cell
Lymphoma, Large B-Cell, Diffuse
Leukemia, B-Cell
Leukemia, Lymphocytic, Chronic, B-Cell
Conditions: Keywords:
Chimeric Antigen Receptor T cells
CLIC-2201
CD22
Immunotherapy
CAR-T cell
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Intervention model description:
This is a Phase I, first-in-human, open-label multicenter trial of CLIC-2201 CAR-T cells
in participants with relapsed or refractory CD22-positive B-cell malignancies. The trial
will consist of a 3+3 dose-escalation/de-escalation method in both cohorts (Cohort A:
individuals who are 18 years or older and diagnosed with relapsed or refractory B-NHL and
Cohort B: pediatric individuals who are 1-21 years old and diagnosed with relapsed or
refractory B-ALL) to evaluate the safety and tolerability of increasing dose levels of
CLIC-2201 in order to estimate the MTD.
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Biological
Intervention name:
CLIC-2201
Description:
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.
Arm group label:
CLIC-2201
Other name:
Autologous CD22 targeting CAR-T cells
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.
Criteria for 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.
Gender:
All
Minimum age:
1 Year
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Alberta Children's Hospital
Address:
City:
Calgary
Zip:
T3B 6A8
Country:
Canada
Contact:
Last name:
Arooj Nazir
Email:
Arooj.Nazir@albertahealthservices.ca
Investigator:
Last name:
Victor Lewis, MD
Email:
Principal Investigator
Facility:
Name:
Calgary Cancer Centre
Address:
City:
Calgary
Zip:
T3E 0B4
Country:
Canada
Investigator:
Last name:
Robert Puckrin, MD
Email:
Principal Investigator
Facility:
Name:
Vancouver General Hospital
Address:
City:
Vancouver
Zip:
V5Z 1M9
Country:
Canada
Contact:
Last name:
Madeleine Cannings
Email:
madeleine.cannings@bccancer.bc.ca
Investigator:
Last name:
Hannah Cherniawsky, MD
Email:
Principal Investigator
Facility:
Name:
BC Children's Hospital
Address:
City:
Vancouver
Country:
Canada
Contact:
Last name:
Peter Subrt
Email:
psubrt@cw.bc.ca
Investigator:
Last name:
Amanda Li, MD
Email:
Principal Investigator
Facility:
Name:
The Ottawa Hospital - General Campus
Address:
City:
Ottawa
Zip:
K1H 8L6
Country:
Canada
Contact:
Last name:
Vanessa Lopez
Email:
vlopez@ohri.ca
Investigator:
Last name:
Natasha Kekre, MD
Email:
Principal Investigator
Investigator:
Last name:
Harold Atkins, MD
Email:
Sub-Investigator
Facility:
Name:
Princess Margaret Cancer Centre
Address:
City:
Toronto
Country:
Canada
Contact:
Last name:
Aidan Shair
Email:
aidan.shair@uhn.ca
Investigator:
Last name:
John Kuruvilla, MD
Email:
Principal Investigator
Facility:
Name:
The Hospital for Sick Children
Address:
City:
Toronto
Country:
Canada
Contact:
Last name:
Erilda Kapllani
Email:
erilda.kapllani@sickkids.ca
Investigator:
Last name:
Joerg Krueger, MD
Email:
Principal Investigator
Start date:
November 1, 2024
Completion date:
August 1, 2027
Lead sponsor:
Agency:
British Columbia Cancer Agency
Agency class:
Other
Source:
British Columbia Cancer Agency
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06208735
