RPM CD19-mbIL15-CAR-T Cells in Patient With Advanced Lymphoid Malignancies
Study Details
Study Description
Brief Summary
This is an open-label Phase 1 study to determine the feasibility, safety, and the recommended maximum tolerated Dose (MTD) of a single infusion of RPM CD19 mbIL15 CAR-T cells for adult patients. Approximately 24 subjects will be enrolled and it is anticipated approximately 16 subjects will be infused at the varied doses of T cells.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Detailed Description
This is an open-label Phase 1 study to determine the feasibility, safety, and the recommended maximum tolerated Dose (MTD) of a single infusion of RPM CD19 mbIL15 CAR-T cells for adult patients. Approximately 24 subjects will be enrolled and it is anticipated approximately 16 subjects will be infused at the varied doses of T cells.
This study will very rapidly administer T cells that are genetically modified by electroporation using DNA plasmids from the SB system to co-express CD19RCD8CD28 (the CAR), mbIL15, and HER1t. The presence of mbIL15 may allow for reduced doses of CAR-T cells to be infused to reduce the risk for adverse events, such as cytokine release syndrome (CRS).
The key features of study design are listed below.
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Uncontrolled
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Blinding: open-label
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Randomized: no
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Duration of treatment: single infusion within day
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Titration: none
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Single center, Taiwan
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Infusion RPM CD19-mbIL15-CAR-T cell In this study, anti-CD19 autologous chimeric antigen receptor T-cells infusion produced by rapid personalized manufacture are used to treat patients with relapsed/refractory Advanced Lymphoid Malignancies. Route of administration: Intravenous injection. Lymphodepletion conditioning: Lymphodepletion will be conducted several days prior to RPM CD19-mbIL15-CAR-T cell infusion. A combination of fludarabine and cyclophosphamide will be used for lymphodepletion. |
Biological: RPM CD19-mbIL15-CAR-T cells
Single dose of RPM CD19-mbIL15-CAR-T cells will be infused, and a standard "3+3" design will be applied.
Drug: Fludarabine
Fludarabine is used for lymphodepletion.
Drug: Cyclophosphamide
Cyclophosphamide is used for lymphodepletion
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Outcome Measures
Primary Outcome Measures
- Maximun Tolerated Dose (MTD) of the RPM CD19- mbIL15-CAR-T [within 4 weeks after infusion]
MTD is the highest dose at which no more than 1 of 6 patients experiences a dose limiting toxicity.
Secondary Outcome Measures
- Feasibility of the product manufacturing process [day 0 to month 12]
Percentage of subjects for whom the desired dose of RPM CD19 mbIL15 CAR-T cells can be successfully manufactured.
- Adverse events related to treatment [day 0 to month 12]
The incidence and severity of AE of Cytokine Release Syndrome and neurotoxicity.
- Persistence of infused T cells [day 0 to month 12]
Duration of CAR-T cell persistence by vector copy number (VCN).
- Safety Switch Function [day 0 to month 12]
Measure the decrease of RPM CD19 mbIL15-CAR-T cells after cetuximab administration.
- Immunogenicity [day 0 to month 12]
Immnuogenicity (humoral) defined as the percent of subjects that develop anti-drug antibodies.
- Cytokine Profile [day 0 to month 12]
levels of cytokine in serum, including IL-6, IL-10, IFN-γ, TNFα concentration (pg/mL), measured by Elisa.
- Homing ability of the infused T-cells [day 0 to month 12]
Percent of subjects with measurable RPM CD19 mbIL15 CAR-T cells in bone marrow.
- Disease response after T cell infusion [day 0 to month 12]
Objective response rate (ORR), complete response (CR), Complete response with incomplete blood count recovery (CRi), partial response (PR)
- Progression-Free Survival [day 0 to month 12]
Measured from infusion of RPM CD19 mbIL15 CAR-T cells until the documentation of disease progression or death due to any cause, whichever occurs first.
- Overall Survival [day 0 to month 12]
Overall survival will be determined as time fro the start of RPM CD19-mbIL15-CAR-T cells infusion until death due to any cause.
- Emergence of CD19neg malignant B cells [day 0 to month 12]
CD19 expression of tumor tissue when tumor relapse and progress.
Eligibility Criteria
Criteria
Inclusion Criteria for Enrollment:
A subject may participate in the study if all the following criteria is met:
- Patients with CD19+ malignancies that are refractory to or relapsed after current standard treatment (including allogeneic or autologous HSCT) and not suitable for other treatment options, such as second-time HSCT. CD19+ malignancies include:
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Relapsed/Refractory B-cell Acute Lymphoblastic Leukemia (ALL):
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Refractory ALL is defined as failure to achieve CR at the end of induction.
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Relapsed ALL is defined as reappearance of blasts in the blood or bone marrow (≥ 5%) or in any extramedullary site after a CR.
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Relapsed/Refractory B-cell originated Non-Hodgkin Lymphoma (NHL) including 1) de-novo diffuse large B-cell lymphoma or primary mediastinal large B-cell lymphoma, 2) large-B cell lymphoma transformed from indolent lymphomas, 3) follicular lymphoma of all grades, 4) mantle cell lymphoma, and 5) CD20(+) high-grade B-cell lymphomas. Refractory disease for lymphoma is defined as:
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Progressive disease or stable disease lasting < 6 months, as best response to most recent chemotherapy regimen; or disease progression or recurrence < 12 months after prior autologous HSCT.
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Prior therapy must have included an anti-CD20 monoclonal antibody-containing regimen and an anthracycline-containing chemotherapy regimen
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For patients with transformed follicular lymphoma (TFL), prior chemotherapy for follicular lymphoma and subsequent refractory disease after transformation to DLBCL.
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At least one measurable lesion, demonstrating that the nodal lesion is ≥ 1.5 cm in the longest diameter or the extranodal lesion is ≥ 1.0 cm in the longest diameter, according to the Lugano Classification (2014).
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Patients must have received at least 2 prior lines of therapy. HSCT (allogeneic or autologous) can be accounted as one of the prior line therapy, and the subjects must have been at least 3 months from prior HSCT.
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Karnofsky Performance Scale ≥ 60
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Patient able to provide written informed consent for participating in the study
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Age ≥ 20 years and ≤ 75 years old at the time of providing informed consent
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Patients shall be at least 3 weeks from the last cytotoxic chemotherapy before apheresis. Short-acting targeted therapies (e.g., tyrosine kinase inhibitors) must be stopped > 72 hours before apheresis.
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Monoclonal antibody use including Anti-CD20 therapy has been discontinued at least 4 weeks before leukapheresis and CAR-T cells infusion except for systemic inhibitory/stimulatory immune checkpoint therapy. Immune checkpoint therapy has been discontinued at least 3 half-lives before leukapheresis (e.g. ipilimumab, nivolumab, pembrolizumab, atezolizumab, OX40 agonists, 4-1BB agonists, etc.).
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Absolute lymphocyte count (ALC) ≥ 1.0x109/L and absolute number of CD3+ T cells (ATC) ≥ 0.3x109/L, absolute neutrophil count (ANC) ≥ 1.0 x109/L for lymphoma and ANC ≥ 0.5 x109/L for ALL, platelets ≥ 50.0 x109/L, hemoglobin ≥ 80.0 g/L within 7 days before apheresis.
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Adequate organ function demonstrated by the following:
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Renal: serum creatinine <2 x upper limit of normal (ULN)
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Hepatic: ALT/AST ≤ 2.5 x ULN or ≤ 5 x ULN if documented liver metastases, total bilirubin ≤ 1.5 mg/dL, except in subjects with Gilbert's Syndrome in whom total bilirubin must be ≤ 3.0 mg/dL.
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Cardiac: no clinically significant ECG findings, hemodynamically stable and LVEF ≥ 45% confirmed by echocardiogram
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Pulmonary: baseline oxygen saturation > 90% on room air
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- Not receiving anti-thymocyte globulin (ATG), alemtuzumab, or other T-cell immunosuppressive antibodies, donor-lymphocyte infusion or T-cell infusion for the past 3 weeks before apheresis;
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Negative serology for Anti-HTLV-I / HTLV-II (DHTLV I/II)
Exclusion Criteria for Enrollment
A subject who met any of the following criteria is not eligible to enter the study:
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Received previous treatment with anti-CD19 therapy;
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Is with a history of CNS malignancy and/or active CNS diseases;
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Has previous or concurrent malignancies other than CD19+ malignancies;
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Has active neurological, autoimmune, or inflammatory disorders;
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Has clinically significant cardiac diseases, or cardiac arrhythmia not controlled with medical treatment;
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Has cardiac involvement with lymphoma;
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Has any active infections, conditions, and diseases that may interfere with the assessment of safety and efficacy of the study deemed by the investigator or designee;
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Received live vaccine within 6 weeks of the screening
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Received radiation therapy within 2 weeks of the planned CAR-T cells infusion;
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Is with positive serology for HIV;
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Is with positive hepatitis B or hepatitis C infection, defined as positive HBs Ag or positive Anti-HCV Ab;
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Active graft versus host disease (GVHD) ≥ grade 2 using the CIBMTR Acute GVHD Grading
System or requiring systemic steroid therapy greater than physiologic dosing; Note:
Overall grading of GVHD is based on the criteria published by Przepiorka et al., Bone Marrow Transplant 1995; 15(6):825-8, see the GVHD Grading and Staging table at CIBMTR Forms Instruction Manual (Last updated: 2020/03/10), page 301-303 (Available at https://www.cibmtr.org/manuals/fim, accessed on 08 Apr 2020).
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Use of investigational medicinal product within 30 days before the screening;
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Positive beta HCG in female of child-bearing potential (defined as not post-menopausal for 12 months) or history of previous surgical sterilization or lactating females.
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Patients with known allergy to mouse products or cetuximab.
Inclusion Criteria for Lymphodepletion and T-Cell Infusion:
- Prior to Lymphodepletion (LD):
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Patients must have no evidence of clinically significant infection;
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No acute neurological toxicity >grade 1 (with the exception of peripheral sensory neuropathy) prior to conditioning chemotherapy;
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No clinically significant cardiac dysfunction;
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Serum creatinine < 2x ULN;
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No evidence of grade ≥2 acute GVHD;
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Pulmonary: oxygen saturation > 90% on room air;
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Adequacy of T cells apheresis products to manufacture CAR-T product.
- Prior to CAR-T cells infusion:
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Patients shall be at least 4 weeks from the last cytotoxic chemotherapy (excluding the study mandated lymphodepleting chemotherapy) before infusion. Short-acting targeted therapies (e.g., tyrosine kinase inhibitors) must be stopped > 72 hours before infusion.
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At least 4 weeks from anti-thymocyte globulin (ATG), alemtuzumab, or other T-cell immunosuppressive antibodies, donor-lymphocyte infusion or T-cell infusion;
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Steroids, if given as GVHD therapy, must be stopped >72 hours prior to infusion. However, the following physiological replacement doses of steroids are allowed: < 6-12 mg/m2/day hydrocortisone or equivalent.
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Non-hematologic toxicity grade ≥2 (CTCAE version 5) related to the lymphodepleting chemotherapy until the toxicity has resolved to grade ≤1 and the subject is afebrile;
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No grade >2 neurologic, pulmonary, cardiac, gastrointestinal, renal, or hepatic (excluding albumin) toxicity;
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Adequacy of the CAR-T cells for infusion.
Exclusion Criteria For Lymphodepletion and T-Cell Infusion:
A subject who meets any of the following criteria should not undergo LD or infusion of CAR-T cells.
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New onset of cardiac arrhythmia not uncontrolled with medications;
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Hypotension warrants the use of vasopressor;
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Active infections within 1 week prior to CAR-T infusion that necessitate the use of oral or intravenous anti-infective treatments; subjects with ongoing use of prophylactic antibiotics, antifungals, or antivirals are eligible as long as there is no evidence of active infection.
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Presence of CNS or neurological abnormalities;
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Received HSCT after screening or planned to receive HSCT during the study period;
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Any conditions not suitable for the CAR-T cells infusion in the PI or designee's judgement.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | National Taiwan University Hospital | Taipei | Taiwan |
Sponsors and Collaborators
- Eden BioCell Ltd.
- National Taiwan University Hospital
Investigators
- Principal Investigator: Shangru Wu, PhD, National Taiwan University Hospital
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- Eden 2020-01