A Study of KQ-2003 CAR-T Cell Therapy for Patients With Relapsed or Refractory POEMS Syndrome

A Phase 1 Study to Evaluate the Safety, Tolerability, Preliminary Efficacy, and Pharmacokinetic Characterization of KQ-2003 for Patients With Relapsed/Refractory POEMS Syndrome

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

Study Overview

• Status: Not yet recruiting
• Conditions: POEMS Syndrome
• Intervention / Treatment: Biological: KQ-2003 CAR T-cells

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.

• Study Type: Interventional
• Enrollment (Estimated): 21
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Jian Li, M.D.; Phone Number: 010-65296114; Email: lijian@pumch.cn

Study Locations

• China
  • Beijing, China, 100730
    • Chinese Academy of Medical Sciences & Peking Union Medical College Hospital
    • Contact: Jian Li, M.D.; Phone Number: 010-65296114; Email: lijian@pumch.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1a: Low dose group; Infusion of KQ-2003 CAR T-cells by single dose of 0.5×10^6 CAR-T cells/kg	Biological: KQ-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.
Experimental: Phase 1a: Medium dose group; Infusion of KQ-2003 CAR T-cells by single dose of 1.0×10^6 CAR-T cells/kg	Biological: KQ-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.
Experimental: Phase 1a: High dose group; Infusion of KQ-2003 CAR T-cells by single dose of 2.0×10^6 CAR-T cells/kg	Biological: KQ-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.
Experimental: Phase 1b: RP2D; After all subjects in the Phase 1a dose-escalation study completed DLT observation, RP2D was determined based on the analysis results for the phase 1b expansion study.	Biological: KQ-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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with dose-limiting toxicity (DLT)	For DLT evaluation, severity (grade) is classified according to common terminology criteria for adverse events version 5.0 (CTCAE v5.0).	Within 28 days of receiving KQ-2003 CAR T-cells transfusion therapy
Maximum Tolerated Dose (MTD)	At least 6 subjects in the MTD dose group must complete the DLT assessment.	Within 28 days of receiving KQ-2003 CAR T-cells transfusion therapy
Adverse Event	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).	Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1)
Recommended Phase 2 Dose (RP2D)	To determine after all subjects in the Phase 1 dose-escalation study completed DLT observation	Through study completion, an average of 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum concentration (Cmax)	Blood and bone marrow samples will be collected and used for pharmacokinetics assessments.	Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1)
Time to maximum plasma concentration (Tmax)	Blood and bone marrow samples will be collected and used for pharmacokinetics	Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1)
Levels of IL-6	Blood samples will be collected and used for pharmacodynamic to evaluate the levels about cytokine levels	Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1)
Levels of IFN-γ	Blood samples will be collected and used for pharmacodynamic to evaluate the levels about cytokine levels	Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1)
CD4+T lymphocyte count	Blood samples will be collected and used for pharmacodynamic to evaluate the levels about peripheral blood lymphocyte subsets	Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1)
CD8+T lymphocyte count	Blood samples will be collected and used for pharmacodynamic to evaluate the levels about peripheral blood lymphocyte subsets	Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1)
ADA	The trial will evaluate the positive rate, titer and duration or persistence of ADA following the administration of CAR T-Cells.	Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1)
Response of serum vascular endothelial growth factor level(VEGF)	The improvements of serum VEGF will be assessed every three months by evaluating changes from baseline and will be described descriptively.	Through study completion, an average of 2 years
Hematologic response	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.	Through study completion, an average of 2 years
Response of positron emission tomography-scan (PET-CT)	Observe the change in FDG uptake in the lesions of the subjects compared to the baseline, assessed every three months.	Through study completion, an average of 2 years
Response rate of critical organs	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.	Through study completion, an average of 2 years
Complete response rate (CRR)	The definition of CRR is the proportion of subjects achieving CR confirmed by efficacy re-assessment after a minimum interval of three months.	Through study completion, an average of 2 years
Disease-free survival (DFS)	DFS refers to time from treatment until the recurrence of disease (or death) after undergoing the study treatment.	Through study completion, an average of 2 years
Overall survival (OS)	OS is the time from the start of cell infusion to the death of the subject.	Through study completion, an average of 2 years
Levels of IL-2	Blood samples will be collected and used for pharmacodynamic to evaluate the levels about cytokine levels	Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1)
Levels of IL-10	Blood samples will be collected and used for pharmacodynamic to evaluate the levels about cytokine levels	Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1)
Levels of TNF-α	Blood samples will be collected and used for pharmacodynamic to evaluate the levels about cytokine levels	Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1)
Levels of C-reactive protein (CRP)	Blood samples will be collected and used for pharmacodynamic to evaluate the levels	Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1)
Levels of ferritin	Blood samples will be collected and used for pharmacodynamic to evaluate the levels	Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1)
CD19+B lymphocyte count	Blood samples will be collected and used for pharmacodynamic to evaluate the levels about peripheral blood lymphocyte subsets	Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1)
CD20+B lymphocyte count	Blood samples will be collected and used for pharmacodynamic to evaluate the levels about peripheral blood lymphocyte subsets	Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1)
CD3+T lymphocyte count	Blood samples will be collected and used for pharmacodynamic to evaluate the levels about peripheral blood lymphocyte subsets	Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1)

Collaborators and Investigators

• Sponsor: Novatim Immune Therapeutics (Zhejiang) Co., Ltd.

Study record dates

Study Major Dates

• Study Start (Estimated): August 31, 2024
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: July 8, 2024
• First Submitted That Met QC Criteria: July 18, 2024
• First Posted (Actual): July 24, 2024

Study Record Updates

• Last Update Posted (Actual): July 24, 2024
• Last Update Submitted That Met QC Criteria: July 18, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Immunoproliferative Disorders; Disease; Congenital Abnormalities; Hematologic Diseases; Neuromuscular Diseases; Peripheral Nervous System Diseases; Paraproteinemias; Blood Protein Disorders; Abnormalities, Multiple; Polyneuropathies; Syndrome; POEMS Syndrome
• Other Study ID Numbers: KQ-2003-BC101

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No