POEMS Syndrome
Conditions
Brief summary
This is a multicenter, open-label, dose-escalation/expansion phase 1 study to evaluate the safety, tolerability, pharmacokinetic/pharmacodynamic characteristics and determine the recommended dose of KQ-2003 CAR T-cells for patients with Relapsed/Refractory POEMS Syndrome
Detailed description
The study included the phase 1a dose escalation study and the phase 1b cohort extension study. The phase 1a study is an open, dose-escalation design with 3 dose groups according to the 3+3 dose escalation rule: low dose group (0.5×10\^6 CAR T cells/kg), medium dose group (1.0×10\^6 CAR T cells/kg), high dose group (2.0×10\^6 CAR T cells/kg). After initial confirmation of maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D), a phase 1b cohort extension study will be conducted.
Interventions
BIOLOGICALKQ-2003 CAR T-cells
KQ-2003 CAR T-cell therapy involves autologous chimeric antigen receptor T-cells, capable of targeting both human B cell maturation antigen (anti-BCMA CAR) and CD19 antigen molecules (anti-CD19 CAR) simultaneously as a cellular therapy.
Sponsors
Novatim Immune Therapeutics (Zhejiang) Co., Ltd.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥18 years old, male or female; * Diagnosis of POEMS syndrome with relapsed or refractory disease; * Eastern Cooperative Oncology Group (ECOG) Performance ≤2 ; * Adequate venous access for the apheresis of peripheral blood mononuclear cell; * Vascular Endothelial Growth Factor (VEGF) ≥1200ng/L； * Overall Neuropathy Limitations Scale (ONLS) ≥ 1; * Adequate organ function; * Able and willing to comply with the study protocol and follow-up plan, and sign the informed consent form in writing.
Exclusion criteria
* Subjects who had previously received BCMA-CD19 dual-target CAR-T cell products or autologous stem cell transplantation within 12 weeks before the collection of peripheral blood mononuclear cells; * Known allergy or hypersensitivity reactions to cyclophosphamide, fludarabine, dimethyl sulfoxide (DMSO), CD19, or BCMA-targeted drugs; * Received any treatment that might influence the activity of CAR-T cells prior to the collection of peripheral blood mononuclear cells; * Have history of vaccination within the 4 weeks preceding the collection of peripheral blood mononuclear cells; * Have tested positive for cytomegalovirus and/or mycobacterium tuberculosis, or had any uncontrolled active infection within 14 days prior to the collection of peripheral blood mononuclear cells; * Subjects infected with active HBV or HCV, HIV, syphilis; * Subjects with known central nervous system disease, for example, seizure disorders, clinically significant cerebral ischemia/hemorrhage, dementia); * Subjects currently experiencing active autoimmune diseases; Diagnosed with immunodeficiency or receiving any other form of immunosuppressive therapy within 7 days prior to enrollment in this study; * Subjects with active bleeding or VTE events (such as pulmonary embolism or deep vein thrombosis) require anticoagulation; * Have following severe diseases: unstable angina, cerebrovascular accident or transient ischemic attack, myocardial infarction , New York Heart Association (NYHA) Class ≥ III, congestive heart failure, poorly controlled severe arrhythmias or other cardiac diseases requiring mechanical support; subjects with known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) \< 50% of predicted normal; subjects with known moderate or severe persistent asthma, or a history of asthma within the past 2 years, or currently having any category of uncontrolled asthma; subjects requiring oxygen to maintain adequate oxygen saturation; subjects with hypertension whose blood pressure cannot be lowered to the following range despite treatment with two or more antihypertensive medications; * Have active malignancies; * Have any non-hematologic toxicity resulting from prior treatments that cannot be restored to ≤ grade 1 or baseline, excluding alopecia and grade 2 neuropathy; * Subjects had participated in other clinical trials and used its investigational drugs within the 3 months prior to the collection of peripheral blood mononuclear cells; * History of alcohol abuse, drug addiction, substance abuse, or mental illness within the past year; * Pregnant or lactating women; * Any situation that the investigator believes may increase the risk of subjects or interfere with the results of clinical trials
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of patients with dose-limiting toxicity (DLT) | Within 28 days of receiving KQ-2003 CAR T-cells transfusion therapy | For DLT evaluation, severity (grade) is classified according to common terminology criteria for adverse events version 5.0 (CTCAE v5.0). |
| Adverse Event | Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1) | Safety will be assessed by adverse events (AEs), which include clinically significant abnormalities identified during a medical test (e.g. laboratory tests, electrocardiogram, vital signs, physical examinations). AEs will be coded by Medical Dictionary for Regulatory Activities (MedDRA) and their severity will be graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE, version 5.0). |
| Maximum Tolerated Dose (MTD) | Within 28 days of receiving KQ-2003 CAR T-cells transfusion therapy | At least 6 subjects in the MTD dose group must complete the DLT assessment. |
| Recommended Phase 2 Dose (RP2D) | Through study completion, an average of 1 year | To determine after all subjects in the Phase 1 dose-escalation study completed DLT observation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete response rate (CRR) | Through study completion, an average of 2 years | The definition of CRR is the proportion of subjects achieving CR confirmed by efficacy re-assessment after a minimum interval of three months. |
| Disease-free survival (DFS) | Through study completion, an average of 2 years | DFS refers to time from treatment until the recurrence of disease (or death) after undergoing the study treatment. |
| Overall survival (OS) | Through study completion, an average of 2 years | OS is the time from the start of cell infusion to the death of the subject. |
| Maximum concentration (Cmax) | Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1) | Blood and bone marrow samples will be collected and used for pharmacokinetics assessments. |
| Time to maximum plasma concentration (Tmax) | Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1) | Blood and bone marrow samples will be collected and used for pharmacokinetics |
| Levels of IL-2 | Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1) | Blood samples will be collected and used for pharmacodynamic to evaluate the levels about cytokine levels |
| Levels of IL-6 | Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1) | Blood samples will be collected and used for pharmacodynamic to evaluate the levels about cytokine levels |
| Levels of IL-10 | Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1) | Blood samples will be collected and used for pharmacodynamic to evaluate the levels about cytokine levels |
| Levels of TNF-α | Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1) | Blood samples will be collected and used for pharmacodynamic to evaluate the levels about cytokine levels |
| Response of serum vascular endothelial growth factor level(VEGF) | Through study completion, an average of 2 years | The improvements of serum VEGF will be assessed every three months by evaluating changes from baseline and will be described descriptively. |
| Levels of C-reactive protein (CRP) | Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1) | Blood samples will be collected and used for pharmacodynamic to evaluate the levels |
| Levels of ferritin | Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1) | Blood samples will be collected and used for pharmacodynamic to evaluate the levels |
| CD19+B lymphocyte count | Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1) | Blood samples will be collected and used for pharmacodynamic to evaluate the levels about peripheral blood lymphocyte subsets |
| CD20+B lymphocyte count | Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1) | Blood samples will be collected and used for pharmacodynamic to evaluate the levels about peripheral blood lymphocyte subsets |
| CD3+T lymphocyte count | Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1) | Blood samples will be collected and used for pharmacodynamic to evaluate the levels about peripheral blood lymphocyte subsets |
| CD4+T lymphocyte count | Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1) | Blood samples will be collected and used for pharmacodynamic to evaluate the levels about peripheral blood lymphocyte subsets |
| CD8+T lymphocyte count | Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1) | Blood samples will be collected and used for pharmacodynamic to evaluate the levels about peripheral blood lymphocyte subsets |
| ADA | Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1) | The trial will evaluate the positive rate, titer and duration or persistence of ADA following the administration of CAR T-Cells. |
| Levels of IFN-γ | Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1) | Blood samples will be collected and used for pharmacodynamic to evaluate the levels about cytokine levels |
| Hematologic response | Through study completion, an average of 2 years | Hematologic response is also a criterion for assessing the efficacy of treatment for POEMS syndrome. The improvements of serum protein electrophoresis (SPEP) and immunofixation electrophoresis (IFE) will be assessed every three months by evaluating changes from baseline and will be described descriptively. |
| Response of positron emission tomography-scan (PET-CT) | Through study completion, an average of 2 years | Observe the change in FDG uptake in the lesions of the subjects compared to the baseline, assessed every three months. |
| Response rate of critical organs | Through study completion, an average of 2 years | Evaluate the changes in clinical symptoms compared to the baseline according to CTCAE 5.0. The assessment of clinical efficacy is conducted every three months after KQ-2003 CAR T-cells transfusion therapy. |
Countries
China
Contacts
Primary ContactJian Li, M.D.
Outcome results
None listed