Description:
Background
Hairy cell leukemia (HCL) is an indolent CD22+ B-cell leukemia comprising 2% of all
leukemias. Most cases of HCL respond well to purine analog chemotherapy and harbor BRAF V600E
mutation that can be considered for targeted treatment at the time of relapse. However, there
are patients with high-risk HCL such as patients with BRAF wild type IGHV4-34 unmutated HCL
who respond poorly to chemotherapy and have poor survival.
HCL variant (HCLv), also brightly CD22+, resembles HCL morphologically but is more aggressive
and responds poorly to standard purine analog chemotherapy. Patients have fewer options of
targeted treatment partly due to wild type BRAF. We showed that the overall survival in
patients progressed after cladribine-rituximab is less than three years.
Moxetumomab pasudotox-tdfk is an anti-CD22 recombinant immunotoxin which in 2018 was
FDA-approved for adult patients with relapsed/refractory HCL. However, there are patients
with HCL and HCLv who progress after treatments with standard purine analog chemotherapy and
moxetumomab pasudotox-tdfk, and in the case of classic HCL, even after BRAF +/- MEK
inhibition. There is still an unmet need for new treatment options for those with
relapsed/refractory disease.
Adoptive cellular therapy with T-cells genetically modified using viral-based vectors to
express chimeric antigen receptors (CAR) targeting the CD22 molecule have demonstrated
dramatic clinical responses in patients with CD22+ acute lymphoblastic leukemia (ALL).
Moxetumomab pasudotox-tdfk proved that CD22 is a potent target for HCL due to its ubiquitous
expression in HCL and HCLv, and cellular therapy represents a promising target for those
patients that have progressed after other treatments options with chemotherapy, immunotherapy
and targeted therapy. This will be the first trial of anti-CD22 CAR T-cell therapy in the
treatment of relapsed/refractory HCL and HCLv.
Objectives
To assess the safety and feasibility of administering escalating doses of autologous
anti-CD22-CAR (M971BBz) engineered T-cells in subjects with HCL/HCLv following a
cyclophosphamide/fludarabine lymphodepletion regimen.
Explore whether the administration of anti-CD22-CAR engineered T-cells can mediate antitumor
effects in HCL/HCLv.
Eligibility
HCL/HCLv, after prior treatment with, ineligible for, refusal of, or inability to obtain 1)
Rituximab given concurrently with or sequentially after purine analog, 2) moxetumomab
pasudotox-tdft, and 3) BRAF-inhibition.
Need for treatment, either 1) ANC <1/nL, 2) Hgb <10g/dL, 3) Plt <100/nL, 4) HCL count >5/nL,
5) HCLv count doubling time <3 months, 6) symptomatic splenomegaly, 7) enlarging HCL mass >
2cm in short axis, 8) increasing lytic or blastic bone lesions.
> 18 years of age.
CD22 expression must be detected on greater than 15% of the malignant cells by
immunohistochemistry or greater than 80% by flow cytometry
No uncontrolled infection, cardiopulmonary dysfunction, or secondary malignancy requiring
treatment.
No chemotherapy, immunotherapy, or radiation therapy less than or equal to 3 weeks prior to
apheresis.
Design
PBMC will be obtained by leukapheresis, CD3+ cells enriched and cultured in the presence of
anti-CD3/-CD28 beads followed by lentiviral vector supernatant containing the anti-CD22
(M971BBz) CAR.
On Day -4 (cell infusion is Day 0), patients will begin induction chemotherapy comprising
fludarabine 25 mg/m2 on Days 4, 3 and 2 and cyclophosphamide 900 mg/m2 on day 2.
The CD22-CAR T-cells will be infused on Day 0, with up to a 72h delay allowed for infusion of
fresh cells or a 7 day delay if cells are cryopreserved, if needed for resolution of clinical
toxicities, to generate adequate cell numbers, or to facilitate scheduling.
A Phase I cell dose escalation scheme will be performed primarily using 2 dose levels (1 x
105 transduced T-cells/kg; 3 x 105 transduced T-cells/kg).
If 2 of 2-6 participants at dose level 1 have DLT, safety will be evaluated in a de-escalated
dose of 3 x 104 transduced T-cells/kg (plus minus 20%). Once the maximum tolerated dose (or
highest level evaluated) is reached, with 0-1 out of 6 having DLT, an additional 4
participants will be enrolled to provide further assessment of DLTs and for determining a
preliminary assessment of the efficacy of the therapy in this participant population.
Participants will be monitored for toxicity, response and T-cell persistence as well as other
biologic correlates.
Accrual ceiling will be set at 23 to allow for a few unevaluable participants and screen
failures.
Title
- Brief Title: Phase I Study of Anti-CD22 Chimeric Receptor T Cells in Patients With Relapsed/Refractory Hairy Cell Leukemia and Variant
- Official Title: Phase I Study of Anti-CD22 Chimeric Receptor T Cells in Patients With Relapsed/Refractory Hairy Cell Leukemia and Variant
Clinical Trial IDs
- ORG STUDY ID:
210019
- SECONDARY ID:
21-C-0019
- NCT ID:
NCT04815356
Conditions
- Hairy Cell Leukemia
- Hairy Cell Leukemia Variant
Interventions
Drug | Synonyms | Arms |
---|
CD22CART cell infusion | | Experimental therapy: Dose Escalation |
Purpose
Background
Hairy cell leukemia (HCL) is an indolent CD22+ B-cell leukemia comprising 2% of all
leukemias. Most cases of HCL respond well to purine analog chemotherapy and harbor BRAF V600E
mutation that can be considered for targeted treatment at the time of relapse. However, there
are patients with high-risk HCL such as patients with BRAF wild type IGHV4-34 unmutated HCL
who respond poorly to chemotherapy and have poor survival.
HCL variant (HCLv), also brightly CD22+, resembles HCL morphologically but is more aggressive
and responds poorly to standard purine analog chemotherapy. Patients have fewer options of
targeted treatment partly due to wild type BRAF. We showed that the overall survival in
patients progressed after cladribine-rituximab is less than three years.
Moxetumomab pasudotox-tdfk is an anti-CD22 recombinant immunotoxin which in 2018 was
FDA-approved for adult patients with relapsed/refractory HCL. However, there are patients
with HCL and HCLv who progress after treatments with standard purine analog chemotherapy and
moxetumomab pasudotox-tdfk, and in the case of classic HCL, even after BRAF +/- MEK
inhibition. There is still an unmet need for new treatment options for those with
relapsed/refractory disease.
Adoptive cellular therapy with T-cells genetically modified using viral-based vectors to
express chimeric antigen receptors (CAR) targeting the CD22 molecule have demonstrated
dramatic clinical responses in patients with CD22+ acute lymphoblastic leukemia (ALL).
Moxetumomab pasudotox-tdfk proved that CD22 is a potent target for HCL due to its ubiquitous
expression in HCL and HCLv, and cellular therapy represents a promising target for those
patients that have progressed after other treatments options with chemotherapy, immunotherapy
and targeted therapy. This will be the first trial of anti-CD22 CAR T-cell therapy in the
treatment of relapsed/refractory HCL and HCLv.
Objectives
To assess the safety and feasibility of administering escalating doses of autologous
anti-CD22-CAR (M971BBz) engineered T-cells in subjects with HCL/HCLv following a
cyclophosphamide/fludarabine lymphodepletion regimen.
Explore whether the administration of anti-CD22-CAR engineered T-cells can mediate antitumor
effects in HCL/HCLv.
Eligibility
HCL/HCLv, after prior treatment with, ineligible for, refusal of, or inability to obtain 1)
Rituximab given concurrently with or sequentially after purine analog, 2) moxetumomab
pasudotox-tdft, and 3) BRAF-inhibition.
Need for treatment, either 1) ANC <1/nL, 2) Hgb <10g/dL, 3) Plt <100/nL, 4) HCL count >5/nL,
5) HCLv count doubling time <3 months, 6) symptomatic splenomegaly, 7) enlarging HCL mass >
2cm in short axis, 8) increasing lytic or blastic bone lesions.
> 18 years of age.
CD22 expression must be detected on greater than 15% of the malignant cells by
immunohistochemistry or greater than 80% by flow cytometry
No uncontrolled infection, cardiopulmonary dysfunction, or secondary malignancy requiring
treatment.
No chemotherapy, immunotherapy, or radiation therapy less than or equal to 3 weeks prior to
apheresis.
Design
PBMC will be obtained by leukapheresis, CD3+ cells enriched and cultured in the presence of
anti-CD3/-CD28 beads followed by lentiviral vector supernatant containing the anti-CD22
(M971BBz) CAR.
On Day -4 (cell infusion is Day 0), patients will begin induction chemotherapy comprising
fludarabine 25 mg/m2 on Days 4, 3 and 2 and cyclophosphamide 900 mg/m2 on day 2.
The CD22-CAR T-cells will be infused on Day 0, with up to a 72h delay allowed for infusion of
fresh cells or a 7 day delay if cells are cryopreserved, if needed for resolution of clinical
toxicities, to generate adequate cell numbers, or to facilitate scheduling.
A Phase I cell dose escalation scheme will be performed primarily using 2 dose levels (1 x
105 transduced T-cells/kg; 3 x 105 transduced T-cells/kg).
If 2 of 2-6 participants at dose level 1 have DLT, safety will be evaluated in a de-escalated
dose of 3 x 104 transduced T-cells/kg (plus minus 20%). Once the maximum tolerated dose (or
highest level evaluated) is reached, with 0-1 out of 6 having DLT, an additional 4
participants will be enrolled to provide further assessment of DLTs and for determining a
preliminary assessment of the efficacy of the therapy in this participant population.
Participants will be monitored for toxicity, response and T-cell persistence as well as other
biologic correlates.
Accrual ceiling will be set at 23 to allow for a few unevaluable participants and screen
failures.
Detailed Description
Background
Hairy cell leukemia (HCL) is an indolent CD22+ B-cell leukemia comprising 2% of all
leukemias. Most cases of HCL respond well to purine analog chemotherapy and harbor BRAF V600E
mutation that can be considered for targeted treatment at the time of relapse. However, there
are patients with high-risk HCL such as patients with BRAF wild type IGHV4-34 unmutated HCL
who respond poorly to chemotherapy and have poor survival.
HCL variant (HCLv), also brightly CD22+, resembles HCL morphologically but is more aggressive
and responds poorly to standard purine analog chemotherapy. Patients have fewer options of
targeted treatment partly due to wild type BRAF. We showed that the overall survival in
patients progressed after cladribine-rituximab is less than three years.
Moxetumomab pasudotox-tdfk is an anti-CD22 recombinant immunotoxin which in 2018 was
FDA-approved for adult patients with relapsed/refractory HCL. However, there are patients
with HCL and HCLv who progress after treatments with standard purine analog chemotherapy and
moxetumomab pasudotox-tdfk, and in the case of classic HCL, even after BRAF +/- MEK
inhibition. There is still an unmet need for new treatment options for those with
relapsed/refractory disease.
Adoptive cellular therapy with T-cells genetically modified using viral-based vectors to
express chimeric antigen receptors (CAR) targeting the CD22 molecule have demonstrated
dramatic clinical responses in patients with CD22+ acute lymphoblastic leukemia (ALL).
Moxetumomab pasudotox-tdfk proved that CD22 is a potent target for HCL due to its ubiquitous
expression in HCL and HCLv, and cellular therapy represents a promising target for those
patients that have progressed after other treatments options with chemotherapy, immunotherapy
and targeted therapy. This will be the first trial of anti-CD22 CAR T-cell therapy in the
treatment of relapsed/refractory HCL and HCLv.
Objectives
To assess the safety and feasibility of administering escalating doses of autologous
anti-CD22-CAR (M971BBz) engineered T-cells in subjects with HCL/HCLv following a
cyclophosphamide/fludarabine lymphodepletion regimen.
Explore whether the administration of anti-CD22-CAR engineered T-cells can mediate antitumor
effects in HCL/HCLv.
Eligibility
HCL/HCLv, after prior treatment with, ineligible for, refusal of, or inability to obtain 1)
Rituximab given concurrently with or sequentially after purine analog, 2) moxetumomab
pasudotox-tdft, and 3) BRAF-inhibition.
Need for treatment, either 1) ANC <1/nL, 2) Hgb <10g/dL, 3) Plt <100/nL, 4) HCL count >5/nL,
5) HCLv count doubling time <3 months, 6) symptomatic splenomegaly, 7) enlarging HCL mass >
2cm in short axis, 8) increasing lytic or blastic bone lesions.
>= 18 years of age.
CD22 expression must be detected on greater than 15% of the malignant cells by
immunohistochemistry or greater than 80% by flow cytometry
No uncontrolled infection, cardiopulmonary dysfunction, or secondary malignancy requiring
treatment.
No chemotherapy, immunotherapy, or radiation therapy less than or equal to 3 weeks prior to
apheresis.
Design
PBMC will be obtained by leukapheresis, CD3+ cells enriched and cultured in the presence of
anti-CD3/-CD28 beads followed by lentiviral vector supernatant containing the anti-CD22
(M971BBz) CAR.
On Day -4 (cell infusion is Day 0), patients will begin induction chemotherapy comprising
fludarabine 25 mg/m2 on Days -4, -3 and -2 and cyclophosphamide 900 mg/m^2 on day -2.
The CD22-CAR T-cells will be infused on Day 0, with up to a 72h delay allowed for infusion of
fresh cells or a 7 day delay if cells are cryopreserved, if needed for resolution of clinical
toxicities, to generate adequate cell numbers, or to facilitate scheduling.
A Phase I cell dose escalation scheme will be performed primarily using 2 dose levels (1 x
10^5 transduced T-cells/kg; 3 x 10^5 transduced T-cells/kg).
If 2 of 2-6 participants at dose level 1 have DLT, safety will be evaluated in a de-escalated
dose of 3 x 10^4 transduced T-cells/kg (plus minus 20%). Once the maximum tolerated dose (or
highest level evaluated) is reached, with 0-1 out of 6 having DLT, an additional 4
participants will be enrolled to provide further assessment of DLTs and for determining a
preliminary assessment of the efficacy of the therapy in this participant population.
Participants will be monitored for toxicity, response and T-cell persistence as well as other
biologic correlates.
Accrual ceiling will be set at 23 to allow for a few unevaluable participants and screen
failures.
Trial Arms
Name | Type | Description | Interventions |
---|
Experimental therapy: Dose Escalation | Experimental | Escalating doses of autologous anti-CD22-CAR T-cells in subjects to determine the MTD | |
Experimental therapy: Dose Expansion | Experimental | Autologous anti-CD22-CAR T-cells at the MTD | |
Eligibility Criteria
- INCLUSION CRITERIA:
1. Histologically confirmed diagnosis of HCL or HCLv according to morphological and
immunophenotypic criteria of WHO classification [WHO, 2008 revised 2016] of
lymphoid neoplasm. Patients should have any of the following indications for
therapy:
- Absolute neutrophil count (ANC) <1/nL,
- Hemoglobin <10g/dL,
- Platelets<100/nL,
- Symptomatic splenomegaly,
- Enlarging HCL mass or bone lesion > 2cm in short axis,
- HCL count >5/nL,
- HCLv count doubling time <3 months,
- Increasing lytic or blastic bone lesions
Participants who have eligible blood counts within 4 weeks from the initiation of
study will not be considered ineligible if subsequent blood counts prior to
enrollment fluctuate and become ineligible up until the time of enrollment
2. HCL/HCLv, after prior treatment with, ineligible for, refusal of, or inability to
obtain 1) Rituximab given concurrently with or sequentially after purine analog,
2) moxetumomab pasudotox-tdft, and 3) BRAF-inhibition.
3. CD22 expression must be detected on greater than 80% of malignant cells by flow
cytometry.
4. Patients must have measurable or evaluable disease at the time of enrollment,
which may include any evidence of disease including minimal residual disease
detected by flow cytometry or immunohistochemistry
5. Age >18 years
6. ECOG performance <2 (Karnofsky >60%), participants are exempt from this criteria
if poor performance status is related to HCL
7. Participants must have adequate organ function as defined below: Subjects must
have recovered from the acute side effects of their prior therapy, such that
eligibility criteria are met. If participants exhibit minor lab abnormalities
that are determined to be related
to HCL (not therapy-related), then those participants will be allowed to
participate
- Total bilirubin less than or equal to 3 ULN, unless consistent with Gilbert
s (ratio between total and direct bilirubin > 5)
- AST and ALT less than or equal to 3x upper limit of normal (ULN)
- Alkaline phosphatase < 2.5 ULN
- Serum creatinine less than or equal to 1.5 mg/dL or creatinine clearance
greater than or equal to 60 mL/min/1.73 m^2 for participants with creatinine
levels above institutional normal calculated using eGFR or measured
- Serum albumin > 2 g/dL
- Prothrombin time (PT)/International Normalized Ratio < 2.5x ULN (If on
warfarin, PT/INR < 3.5x ULN; If on any other anticoagulation, Prothrombin
time (PT) < 2.5x ULN
- Fibrinogen greater than or equal to 0.5x lower limit of normal
8. Subjects with CNS disease are eligible, with exceptions
9. Participants with history of allogeneic stem cell transplantation are eligible if
at least 100 days post-transplant, if there is no evidence of active GVHD and no
longer taking immunosuppressive agents for at least 30 days prior to enrollment
10. Participants of child-bearing or child-fathering potential must use effective
contraception from the time of enrollment on this study and for four months after
receiving the preparative regimen as agents used in this study are teratogenic.
11. Ability of subject to understand and the willingness to sign a written informed
consent document.
EXCLUSION CRITERIA:
1. Pregnant or breast-feeding females
2. Systemic chemotherapy, immunotherapy, or radiation therapy less than or equal to 3
weeks prior to apheresis; with the following exception:
- Subjects receiving steroids may be enrolled, provided there has been no increase
in dose for at least 1 week prior to starting apheresis;
- For radiation therapy: Radiation therapy must have been completed at least 3
weeks prior to enrollment (including CNS radiation), with the exception that
there is no time restriction if the volume of bone marrow treated is less than
10% and also the subject has measurable/evaluable disease outside the radiation
port.
3. Other anti-neoplastic investigational agents, or antibody based therapies currently or
within 2 weeks prior to apheresis
4. Subjects taking warfarin
5. Prior CAR therapy within 30 days prior to apheresis or prior CAR therapy at any time
with evidence for persistence of CAR T-cells in blood samples (circulating levels of
genetically modified cells of greater than or equal to 5% by flow cytometry)
6. HIV/HBV/HCV Infection:
- Seropositive for HIV antibody. (Patients with HIV are at increased risk of lethal
infections when treated with marrow-suppressive therapy. Appropriate studies will
be undertaken in participants receiving combination antiretroviral therapy in the
future should study results indicate effectiveness.)
- Seropositive for hepatitis C or positive for Hepatitis B surface antigen (HbsAG).
Participants who convert to negative will not be excluded for history of positive
test.
7. Uncontrolled, symptomatic, intercurrent illness including but not limited to
infection, congestive heart failure, unstable angina pectoris, cardiac arrhythmia,
asthma, chronic obstructive pulmonary disease, psychiatric illness, or social
situations that would limit compliance with study requirements or in the opinion of
the PI would pose an unacceptable risk to the subject
8. Second malignancy other than in situ carcinoma of the cervix, unless the tumor was
treated with curative intent at least two years previously and subject is in remission
9. History of severe, immediate hypersensitivity reaction attributed to compounds of
similar chemical or biologic composition to any agents used in study or in the
manufacturing of the cells (i.e., gentamicin)
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | safety and feasibility |
Time Frame: | end of treatment |
Safety Issue: | |
Description: | Fraction of participants at each dose level who experience a toxicity along with the grades and types of toxicity and which can successfully manufacture the targeted dose number |
Secondary Outcome Measures
Measure: | expansion and persistence |
Time Frame: | every year for 5 years |
Safety Issue: | |
Description: | Measure expansion and persistence of adoptively-transferred anti-CD22-CAR-transduced T-cells in the blood and, where possible, the bone marrow |
Measure: | MRD negative CR |
Time Frame: | every year for 15 years |
Safety Issue: | |
Description: | Fraction of HCL patients who achieve MRD negative CR following treatment with anti-CD22-CAR engineered T-cells |
Measure: | duration of response |
Time Frame: | every year for 15 years |
Safety Issue: | |
Description: | The time between the initial response to therapy and subsequent disease progression or relapse |
Measure: | progression free-survival |
Time Frame: | every year for 15 years |
Safety Issue: | |
Description: | Duration of time from the start of treatment until time of disease relapse from PR, disease progression, or death, whichever occurs first |
Measure: | event free survival |
Time Frame: | every year for 15 years |
Safety Issue: | |
Description: | Duration of time from the start of treatment until time of disease relapse, disease progression, alternative therapy given (such as radiation), or death, whichever occurs first. |
Measure: | overall survival |
Time Frame: | every year for for 15 years or until death |
Safety Issue: | |
Description: | Overall survival (OS) will be determined as the time from the start of the CD22CART infusion until death |
Measure: | time to next treatment |
Time Frame: | every year for 15 years |
Safety Issue: | |
Description: | Duration of time from the start of administration of anti-CD22-CAR engineered T-cells to next line of treatment. |
Details
Phase: | Phase 1 |
Primary Purpose: | Interventional |
Overall Status: | Not yet recruiting |
Lead Sponsor: | National Cancer Institute (NCI) |
Trial Keywords
- CD-22 Expressing Tumor
- Chimeric Antigen Receptor
- Adoptive Immunotherapy
Last Updated
August 27, 2021