CD4CAR for CD4+ Leukemia and Lymphoma
Study Details
Study Description
Brief Summary
This study is designed as a single arm open label Phase I, 3x3, multicenter study of CD4-directed chimeric antigen receptor engineered T-cells (CD4CAR) in patients with relapsed or refractory T-cell leukemia and lymphoma. Specifically, the study will evaluate the safety and tolerability of CD4CAR T-cells. Funding Source - FDA OOPD
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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Phase 1 |
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 Stony Brook 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 and investigators will determine if the subject has the minimal T cell number adequate for apheresis (screening step) and for manufacturing CD4CAR cells. 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.
For cell harvest, 12-15-liter apheresis procedure will be performed at the apheresis center with the intention to harvest at least 50x10^9-nucleated cells to manufacture CD4CAR T-cells. A portion of the pheresed cells will also be cryopreserved for FDA look-back requirements and for further research. The T-cells will be purified from the PBMC, transduced with CD4CAR lentiviral vector, expanded in vitro, and then frozen for administration. Each dose will be stored in either one or two bags. The route of administration is by IV infusion and the duration of infusion will be approximately 20 minutes. Each bag will contain an aliquot (30-50 mL) of liquid suitable for freezing, and containing the following infusible grade reagents (% v/v): 62.5cc Plasmalyte-A 5% dextrose; 7.5cc Pure dimethylsulfoxide (DMSO), 20cc of 25% Human Serum Albumin, and 10cc Dextran 40. The cell product is expected to be ready for release approximately 3-4 weeks after apheresis.
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: on days 1, 3, 5, 7, 14, and 28 following infusion of CD4CAR T-cells, evaluation of leukemic cell killing and CD4CAR Trafficking will be done. Cytokines levels will be evaluated on Day 2, 4, 7, 11, 14, 21, 28 and every 8 hours during active cytokine release syndrome (CRS). 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 6 and weekly afterward until remission 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 for annual where follow-up will 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)
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If one of the first three patients in dose level 1 experiences a DLT, three more patients will be treated at dose level 1.
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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
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If one of the first three patients in dose level 2 experience a DLT, three more patients will be treated at dose level 2
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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
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If one of the first three patients in dose level 3 experiences a DLT, three more patients will be treated at dose level 3
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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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Treatment Redirected autologous T cells transduced with the anti-CD4 lentiviral vector (referred to as "CD4CAR" cells) |
Biological: CD4CAR
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 (total dose of up to ~4x106 T Cells/KG)
|
Outcome Measures
Primary Outcome Measures
- Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 [18-24 months]
To assess the safety and feasibility of the chimeric antigen receptor T cells transduced with the anti-CD4 lentiviral vector (referred to as "CD4CAR" cells) according to CTCAE grading. The feasibility of treating those adverse events and their duration till resolution will also be described.
Secondary Outcome Measures
- Duration of in vivo survival of the CD4CAR. [18-24 months]
Persistence of CD4CAR will be monitored by measuring the CD4CAR transgene copy number at variable time points.
- Rate of manufacturing failure [18-24 months]
The number of failed manufacturing attempts of CD4 CAR, per subject and overall, in this patient population. Manufacturing failure is defined as failure to manufacture the adequate CD4CAR cell dose for the particular cohort the patient is enrolled on. Three manufacturing attempts per patient are allowed.
- Clinical Response [18-24 months]
Clinical response to T-cell infusion will be evaluated by comparing disease before and after infusion identified by: standard imaging (PET CT or PET MRI) for lymphoma patients bone marrow biopsy for leukemia patients peripheral blood cells morphology, flow cytometry panel, immunohistochemistry, and other blood molecular markers for both lymphoma and leukemia.
- trafficking of CD4CAR at tumor sites and at sites with significant toxicity [18-24 months]
Quantification of both of CD4CAR by flowcytometry and transgene copy number by polymerase chain reaction (PCR) will be measured at tumor sites in bone marrow and lymph nodes at variable time points if applicable. Same tests will be done on biopsies of organs that shows significant toxicity if need be.
- Number of participants with immune reactions against CD4CAR [18-24 months]
The absolute and relative number of subjects who develop immune reactions against the treatment over a period of 2 years. Human anti-mouse antibody (HAMA) ELISA tests will be carried out in the blood of participants at multiple times after initial treatment.
- Serum cytokines levels [18-24 months]
Serum cytokine levels will be evaluated on Day 2, 4, 7, 11, 14, 21, 28 in addition to planned monitoring during CRS every 8 hours and until resolution. These cytokines include interleukin-6 (IL-6), interferon-γ, tumor necrosis factor, IL-2, IL-2-receptor-a, IL-8, and IL-10
- determine CD4CAR cell subsets during proliferation [18-24 months]
Participants' blood will be tested by flow cytometry to determine the relative abundance of cellular subsets that may result from CD4CAR T cells upon their proliferation. These subsets include Tcm, Tem, and Tregs.
Eligibility Criteria
Criteria
Inclusion Criteria
In order to be eligible to participate in this study, an individual will be enrolled if they meet the following criteria:
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Patients must voluntarily sign and date informed consent forms that state his or her willingness to comply with all study procedures and availability for the duration of the study.
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Subjects with documented CD4+ hematologic malignancies. Male and female subjects with CD4+ T-cell malignancies with either relapsed or refractory disease (including those patients who have undergone a prior transplant and patients with an inadequate response after 4-6 cycles of standard chemotherapy)
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Patients who present with CD4+ Leukemia. Either relapsed disease or minimal residual disease (MRD); any of the following are eligible:
3.1 Peripheral T-cell leukemia, NOS 3.2 T-cell prolymphocytic leukemia 3.3 Adult T-cell leukemia 3.4 T-cell large granular lymphocytic leukemia 3.5 T cell acute lymphoblastic leukemia (T-ALL)
- For patients with CD4+ Lymphoma. Either relapsed or refractory disease; any of the following are eligible:
4.1 Peripheral T-cell lymphoma, not otherwise specified (NOS) 4.2 Sezary syndrome/cutaneous T-cell lymphoma 4.3 Angioimmunoblastic T-cell lymphoma 4.4 Adult T-cell lymphoma
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Age 18 years old or older
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Creatinine clearance of > 60 ml/min
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Liver enzymes < 3 x upper limit of normal
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Bilirubin < 2.0 mg/dL
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Serum albumin of ≥ 3gms/dl
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Pulmonary Function Test (PFT) with diffusing capacity of lung for carbon monoxide (DLCO) of ≥ 60%.
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Adequate echocardiogram with ejection fraction (EF) of ≥50%
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Adequate venous access for apheresis and no other contraindications for leukapheresis Eligibility for CD4CAR infusion
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No evidence of an active or uncontrolled infection for at least 72 hours
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Afebrile and not receiving antipyretics
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If previous history of corticosteroid chemotherapy, subject must off all but adrenal replacement doses
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Repeat baseline indicates presence of disease but not rapidly progressing disease.
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Specific organ functional criteria for cardiac, renal, and liver function similar to initial inclusion are met. Tests such as echocardiogram and PFTs need not be repeated if within 6 weeks of initial assessment
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Negative pregnancy testing (if applicable)
Screen Failure
First point screen failure: Inadequate T- lymphocytes for apheresis defined as T cell count at screening that does not meet the requirement of ≥ 107-135/µ/L
Second point screen failure: Failure of cytoreduction with conditioning chemotherapy and persistence of clinical high disease burden defined as extensive lymph node enlargement that is not reduced at least by 50% of original size, presence of central nervous system (CNS) disease or bone marrow replacement with ≥50% malignant cells.
Exclusion Criteria
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Pregnant or lactating women. The safety of this therapy on unborn children is not known. Female study participants of reproductive potential must have a negative serum or urine pregnancy test performed within 48 hours before infusion.
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Uncontrolled active infection.
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Active hepatitis B or hepatitis C infection.
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Concurrent use of systemic glucocorticoids in greater than replacement doses. Recent or current use of inhaled glucocorticoids is not exclusionary
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Previously treatment with any gene therapy products.
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Feasibility assessment during screening demonstrates < 30% transduction of target lymphocytes, or insufficient expansion (< 5-fold) in response to cluster of differentiation 3 (CD3)/CD28 costimulation. A total of three attempts will be carried out before deemed inadequate manufacturing
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Any uncontrolled active medical disorder that would preclude participation as outlined.
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HIV infection.
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Steroid dependency for any reason as well as the potential need to treat concomitant illnesses with steroids during the trial period, examples are patients with chronic obstructive pulmonary disease (COPD) and asthma known to require steroids to abort acute exacerbation.
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Patients declining to consent for treatment
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Indiana University Melvin and Bren Simon Comprehensive Cancer Center | Indianapolis | Indiana | United States | 46202 |
Sponsors and Collaborators
- Huda Salman
- iCell Gene Therapeutics
Investigators
- Study Chair: Huda Salman, MD, Indiana University
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- CTO-IUSCCC-ICG122-101
- FD-R-006820-01