Trial Title:
Chimeric Antigen Receptor T Cell Therapy Redirected to CD4 (CD4CAR)as a Second Line Treatment for Chronic Myelomonocytic Leukemia, CMML.
NCT ID:
NCT06071624
Condition:
Chronic Myelomonocytic Leukemia
Conditions: Official terms:
Leukemia
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Conditions: Keywords:
Chronic Myelomonocytic Leukemia
T Cell
Cell Therapy
CAR-T
chimeric antigen
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Biological
Intervention name:
CD4CAR
Description:
CD4CAR cells transduced with a lentiviral vector to express the single-chain variable
fragment (scFv) nucleotide sequence of the anti-CD4 molecule derived from humanized
monoclonal ibalizumab and the intracellular domains of CD28 and 4-1BB co-activators fused
to the CD3ζ T-cell activation signaling domain administered by IV infusions as a single
dose
Arm group label:
Treatment
Summary:
This study is designed as a single arm open label traditional Phase I, 3+3, study of
CD4-directed chimeric antigen receptor engineered T-cells (CD4CAR) in patients with
relapsed or refractory CMML. Specifically, the study will evaluate the safety and
feasibility of CD4CAR T-cells.
Detailed description:
The study will be performed as a dose-escalation protocol. Due to the relatively low
incidence and prevalence of cluster of differentiation 4-positive (CD4+) hematological
malignancies and the associated aggressive nature of these diseases and the sequel of
treatment failure, the investigators expect to recruit 20 subjects at Indiana University
with an expected dropout rate of 25% primarily due to rapid progression or death and
screen and or manufacturing failure. Taking this into account, the investigators expect
to treat 15 patients. The study will utilize autologous CD4CAR T-cells that are
engineered to express a chimeric antigen receptor (CAR) targeting CD4 that is linked to
the cluster of differentiation 28 (CD28), 4-1BB, cluster of differentiation 3-zeta (CD3ζ)
signaling chains (third generation CAR).
At entry, disease status will be staged. Qualifying subjects will be leukapheresed to
obtain large numbers of peripheral blood mononuclear cells (PBMC) for the manufacturing.
Next, participants will receive conditioning chemotherapy. If tumor burden is
sufficiently reduced (screening step), participants will receive CD4CAR cells by infusion
on Day 0 of treatment.
If the disease progresses during the manufacturing period participants may be excluded
from the study. Minimal chemotherapy to keep the disease under control in the meanwhile
is allowed if deemed necessary by investigators.
A single dose of CD4CAR transduced T cells will consist of the cell number for the dose
level to be infused.
Post-infusion monitoring of CD4CAR T-cells: Subjects will have blood drawn for cytokine
levels, CD4CAR Transgene Copy Number (PCR) and flow cytometry in order to evaluate the
presence of CD4CAR cells on days 0, 1, 3, 5, 7, 14, and 28 following infusion (or as
clinically needed). Cytokines levels will be evaluated per schedule above in addition to
and as needed every 8 +/- 2 hours as feasible if/when CRS occurs and until resolution.
Active monitoring of fungal and viral infections during treatment while utilizing
standard prophylaxis recommended for HIV-positive patients with T-cell aplasia and those
undergoing allogeneic stem cell transplant. Investigators plan to collect data about
clinicoradiologic measurements of residual tumor burden starting on day 7 and weekly
afterward until Day 28 and then monthly for 6 months. This will be followed by quarterly
clinical evaluations for the next two (2) years with a medical history, physical
examination, and comprehensive blood testing. After these short- and intermediate-term
evaluations are performed, these patients will enter a rollover study to assess for
disease-free survival (DFS), relapse, and the development of other health problems or
malignancies where follow-up will be up to twice a year by phone and a questionnaire for
an additional thirteen (13) years. The treating physician will decide to proceed with
allogeneic or autologous transplant when needed.
Dose of CD4CAR description: the main objective of this study is to establish a
recommended dose and/or schedule of CD4CAR. The guiding principle for dose escalation in
phase I is to avoid unnecessary exposure of patients to sub-therapeutic doses (i.e., to
treat as many patients as possible within the therapeutic dose range) while preserving
safety and maintaining rapid accrual. Investigators will use the rule-based traditional
Phase I "3+3" design for the evaluation of safety. Based on lab experience in mice the
starting dose (dose level 1) for the first cohort of three patients in phase I portion of
the study will be 8x10^5 cells. The dose escalation or de-escalation will follow a
modified Fibonacci sequence as below.
If more than one patient out of the first cohort of three patients in dose level 1
experience dose limiting toxicity (DLT), the trial will be placed on hold. If zero or one
out of three patients in the first cohort of dose level 1 experience DLT, three more
patients will be enrolled at dose level 1; the dose escalation continues until at least
two patients among a cohort of six patients experience DLT (i.e., ≥33% of patients with a
DLT at this dose level)
If one of the first three patients in dose level 1 experiences a DLT, three more patients
will be treated at dose level 1.
If none of the three patients or only one of the 6 patients in the dose level 1
experiences a DLT, the dose escalation continues to the dose level 2 If one of the first
three patients in dose level 2 experience a DLT, three more patients will be treated at
dose level 2 If none of the three patients or only one of the 6 patients in the dose
level2 experiences a DLT, the dose escalation continues to the dose level 3 If one of the
first three patients in dose level 3 experiences a DLT, three more patients will be
treated at dose level 3 If none of the three patients or only one of the 6 patients in
the dose level 3 experiences a DLT, dose level 3 will be declared the maximum tolerated
dose (MTD) and will be used as the recommended phase II dose (RP2D) for the phase II
portion of the study.
In summary, the dose escalation continues until at least two patients among a cohort of
six patients experience DLT (i.e., ≥33% of patients with a DLT at that dose level). The
recommended dose for phase II trials is defined as one dose level below this toxic dose
level. Since some grade 3 and possibly 4 toxicities are highly likely to be reversible,
grade 3 infectious, hematological and vascular toxicities will not be considered DLTs
mandating dose reduction. Also allergic or infusion-related reactions ≤ grade 3 will not
be counted as DLTs. There will be no intra-patient dose escalation or reduction.
To allow for full spectrum toxicity duration evaluation and reporting, no patients within
the same or a different cohort will be initiated on lymphodepleting chemotherapy sooner
than 28 days from the initiation date of the preceding patient.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. ≥ 18 years old at the time of informed consent
2. Ability to provide written informed consent and HIPAA authorization
3. Diagnosis of CMML that is CD4+ and is recurrent or refractory to first line standard
of care treatment.
4. Creatinine clearance of ≥ 60 ml/min (or otherwise non clinically significant, per
study investigator)
5. ALT/AST < 3 x ULN
6. Bilirubin < 2 x ULN
7. Pulmonary Function Test (PFT) with a DLCO of ≥ 60%. This will not have to be
repeated if within 45 days of initial assessment.
8. Adequate echocardiogram with EF of ≥50% This will not have to be repeated if within
45 days of initial assessment.
9. Adequate venous access for apheresis and no other contraindications for
leukapheresis
Exclusion Criteria:
1. CD4 negative CMML
2. Pregnant or lactating women. The safety of this therapy on unborn children is not
known. Female study participants of reproductive potential (see definition below)
must have a negative serum or urine pregnancy test prior to initiation of
conditioning chemotherapy, per research sites' clinical policy
3. Uncontrolled active infection necessitating systemic therapy
4. Active hepatitis B or hepatitis C infection. Active hepatitis C is defined as the
hepatitis C antibody is positive while quantitative HCV RNA results exceed the lower
detection limit
Note the following subjects will be eligible:
- Subjects with a history of hepatitis B but have received antiviral therapy and
have non-detectable viral DNA for 6 months prior to enrollment are eligible
- Subjects seropositive for HBS antibodies due to hepatitis B virus vaccine with
no signs or active infection (Negative HBs Ag, HBc and HBe Ags) are eligible
- Subjects who had hepatitis C but have received antiviral therapy and show no
detectable hepatitis C virus (HCV) viral RNA for 6 months are eligible
- If hepatitis C antibody test is positive, then patients must be tested for the
presence of antigen by reverse transcription-polymerase chain reaction (RT-PCR)
and be hepatitis C virus ribonucleic acid (HCV RNA) negative
5. Concurrent use of systemic glucocorticoids in greater than replacement doses or
steroid dependency defined in rheumatological and pulmonary diseases as
uninterrupted corticosteroid intake for more than a year at a dosage of 0.3
mg/kg/day or greater, and where the underlying disease worsens on temporary stoppage
of steroid therapy, with symptoms of steroids withdrawal (eg, lethargy, headache,
weakness, pseudo rheumatism, emotional disturbances, etc) precipitated by the
temporary stoppage unless tapering can occur safely without compromising the
underlying disease, the withdrawal tolerance and can happen in a timeframe
appropriate to enroll in this trial without safety concerns
Subjects who receive daily corticosteroids in replacement doses can be included in
the study. The replacement doses are defined as following:
1. Hydrocortisone 25mg/day or less
2. Prednisone 10mg/day or less
3. Dexamethasone 4mg or less - Note: Recent or current use of inhaled
glucocorticoids is not exclusionary, as this route pertains extremely minimal
systemic penetration
6. Any previous treatment with any gene therapy products
7. Any uncontrolled active medical disorder that would preclude participation as
outlined in the opinion of the treating investigator and/or Principal Investigator
8. HIV infection
9. Subjects who have received or will receive live vaccines within 30 days before the
first experimental cell treatment. Inactivated seasonal flu vaccination is allowed
10. Subjects with active autoimmune diseases who need systematic treatments (such as
disease modifying agents, corticosteroids and immunosuppressive drugs) during the
last year Note: Replacement therapy (thyroxine, insulin or physiological
corticosteroid replacement therapy (up to10 mg of oral daily prednisone or
equivalent in hydrocortisone and dexamethasone) to treat adrenal dysfunction or
pituitary dysfunction) is not considered as systematic therapy. Subjects who need
inhalation corticosteroid therapy can be included in this trial. Subjects with
vitiligo or in long-term remission of pediatric asthma or allergic diseases can be
included in this trial
11. Subjects with a history of mental disorders or drug abuse that may influence
treatment compliance
12. Active malignancy not related to CMML that has required therapy in the last 3 years
or is not in complete remission. Exceptions to this criterion include successfully
treated non-metastatic basal cell or squamous cell skin carcinoma, or prostate
cancer that does not require therapy. Other similar malignant conditions may be
discussed with and permitted by the Principal Investigator
Eligibility for cd4CAR Infusion
1. Afebrile and not receiving antipyretics, and no evidence of active infection. If
fever is attributed to underlying disease, it will not disqualify.
2. Specific organ function criteria for cardiac, renal, and liver function must be
similar to initial inclusion values. Tests such as echocardiogram and PFTs need not
be repeated if within 45 days of initial assessment
3. Negative pregnancy testing (if applicable)
4. If previous history of corticosteroid chemotherapy, subject must be off all but
adrenal replacement doses 3 days before the CD4CAR infusion
5. Planned infusion dose was successfully manufactured and met release criteria
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Indiana University Melvin and Bren Simon Comprehensive Cancer Center
Address:
City:
Indianapolis
Zip:
46202
Country:
United States
Status:
Recruiting
Contact:
Last name:
Tara Haney, RN
Phone:
317-278-4184
Email:
tnhaney@iu.edu
Contact backup:
Last name:
Huda Salman, MD, PhD
Phone:
317-278-9504
Email:
hsalman@iu.edu
Start date:
February 21, 2024
Completion date:
December 2043
Lead sponsor:
Agency:
Huda Salman
Agency class:
Other
Collaborator:
Agency:
iCell Gene Therapeutics
Agency class:
Industry
Collaborator:
Agency:
The Leukemia and Lymphoma Society
Agency class:
Other
Source:
Indiana University
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06071624
