Study of NXC-201 CAR-T in Patients With Light Chain (AL) Amyloidosis

Study Overview
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Brief Summary
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Open-label Phase 1b Dose Escalation/Dose Expansion study exploring the safety and efficacy of NXC-201 in patients with relapsed or refractory light chain amyloidosis (AL).

Detailed Description
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Building on the prior NXC-201 results in AL amyloidosis published by Kfir-Erenfeld et. al (2022) and Asherie et. al. (2023), this study will enroll additional patients with relapsed or refractory AL amyloidosis and assess the safety and efficacy of NXC-201. Subjects with relapsed/refractory AL amyloidosis will undergo leukapheresis at least one month prior to lymphodepletion, to provide starting material for NXC-201 CART manufacture. Subjects will be treated according to the following process for lymphodepletion: Days -5, -4 and -3 Cyclophosphamide 250mg/m2, IV infusion over 30 mins, followed immediately by Fludarabine 25 mg/m2 IV infusion over 30 minutes. NXC-201 CART is administered on Day 0, after lymphodepletion. Enrolled subjects will receive a dose of NXC-201 CAR-positive (CAR+) T cells as follows: Dose Escalation phase: Cohort 1 450 × 106 CAR+ T cells with 30-45 days of safety follow-up per patient (3 patients) Cohort 2 800 × 106 CAR+ T cells with 30-45 days of safety follow-up per patient (3 patients) The dose expansion phase (Phase 1b expansion) will enroll 3 or more additional patients at the same 800 × 106 dose of CAR+ T cells if approved by DSMB.

Official Title
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Phase 1b Dose Expansion Study of NXC-201 for the Treatment of Patients With Relapsed or Refractory AL Amyloidosis

Conditions
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Light Chain (AL) Amyloidosis

Intervention / Treatment
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* Biological: NXC-201 CAR-T


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥18 years of age Voluntarily signed informed consent form (ICF) Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2 Histologically-proven systemic AL confirmed by positive Congo red staining with green birefringence on polarized light microscopy in an organ outside the bone marrow and evidence of a measurable clonal disease that requires active treatment. Relapsed disease or need for additional therapy after 1 or more prior lines of therapy as determined by the treating physician meeting one of the following criteria: Intolerant of initial therapy and has not achieved a hematologic Very good partial response (VGPR). Loss of hematologic response as defined has an increase the difference between involved and uninvolved free light chains >40 mg/DL (4 mg/L) Inadequate response to initial therapy defined as achieving at least a hematologic VGPR after at least 4 cycles of initial therapy. Relapsed AL amyloidosis post allogenic stem cell transplantation without evidence of graft versus host disease after cessation of any immunosuppressive therapy (IST) for at least one month before recruitment to the study. Subjects must have measurable disease at screening, including at least one of the criteria below: Serum M-protein greater or equal to 0.5 g/dL Serum free light chain (FLC) assay (both must be present): involved FLC level greater or equal to 50 mg/L (5 mg/dL) serum FLC ratio is abnormal Concurrent multiple myeloma is NOT excluded as long as end organ involvement with AL amyloidosis is demonstrated. Women of child-bearing potential (WCBP), must have a negative serum pregnancy test prior to treatment. All sexually active WCBP and all sexually active male subjects must agree to use effective methods of birth control throughout the study Recovery to ≤Grade 2 or baseline of any non-hematologic toxicities due to prior treatments, excluding alopecia and Grade 3 neuropathy Ability and willingness to adhere to the study visit schedule and all protocol requirements Exclusion Criteria: Any prior systemic therapy for AL amyloidosis within 14 days prior to leukapheresis Long-acting growth factors or drugs used for cell mobilization within 14 days prior to leukapheresis Short-acting growth factors or drugs used for cell mobilization within 5 days prior to leukapheresis Therapeutic doses of steroids within 3 days prior to leukapheresis Palliative radiation, if urgently needed, is allowed between screening and lymphodepletion Any prior systemic therapy for AL amyloidosis within 14 days prior to the start of lymphodepletion. Central nervous system (CNS) directed radiation within 8 weeks prior to lymphodepletion Long-acting growth factors or drugs used for cell mobilization within 14 days prior to lymphodepletion Short-acting growth factors or drugs used for cell mobilization within 3 days prior to lymphodepletion Investigational cellular therapies within 8 weeks prior to lymphodepletion Subjects with known bulky central nervous system disease Inadequate hepatic function: Alanine aminotransferase (ALT) >3 normal value Inadequate renal function: creatinine clearance (CRCL) < 20. International ratio (INR) or partial thromboplastin time (PTT) > 1.5 x ULN (Upper limit of normal), unless on a stable dose of anticoagulant for a thromboembolic event that does NOT meet exclusion criteria Inadequate bone marrow function defined by absolute neutrophil count (ANC) < 1000 cells/mm^3, platelet count < 30,000 mm^3, or hemoglobin < 8 g/dL (blood transfusions are allowed), absolute lymphocyte count < 300 cells/mm^3. Ongoing treatment with chronic immunosuppressants Presence of active infection within 72 hours prior to lymphodepletion Significant co-morbid condition or disease which in the judgment of the Investigator would place the subject at undue risk or interfere with the study Known human immunodeficiency virus (HIV) positive status subjects who have not achieved undetectable viral load on Highly active antiretroviral therapy / combination antiretroviral therapy (HAART/CAART) within 6 months of lymphodepletion Active Hepatitis B or Hepatitis C infection Subjects with a history of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication or mechanical control within 3 months. Left ventricular ejection fraction < 40% Heart failure which is, in the opinion of the investigator, related to ischemic heart disease Subjects with second malignancies in addition to myeloma, if the second malignancy has required therapy in the last 2 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 or any other malignancy in remission with the written permission from treating oncologist. Subjects who have had a venous thromboembolic event requiring anticoagulation and who meet any of the following criteria: Have been on a stable dose of anticoagulation for < 1 month (except for acute line insertion induced thrombosis) Have had a Grade 2, 3, or 4 hemorrhage in the last 30 days Are experiencing continued symptoms from their venous thromboembolic event (e.g., continued dyspnea or oxygen requirement) Pregnant or lactating women

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: Open label single-arm clinical study of NXC-201 CAR-T will proceed sequentially through dose cohorts as follows: Cohort 1 - 450×10^6 CAR-positive (CAR+) T cells (3 patients) Cohort 2 - 800×10^6 CAR-positive (CAR+) T cells (3 patients) The dose expansion phase will include a dose of 800×10^6 CAR-positive (CAR+) T cells (3 or more patients)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NXC-201 CAR-T<br>The dose escalation phase will include the following doses: Cohort 1 - 450×10^6 CAR-positive (CAR+) T cells (3 patients) Cohort 2 - 800×10^6 CAR-positive (CAR+) T cells (3 patients) The dose expansion phase will include a dose of 800×10^6 CAR-positive (CAR+) T cells (3 or more patients) | Biological: NXC-201 CAR-T<br>* NXC-201 (formerly HBI0101) CAR-T is defined as autologous T cells transduced ex-vivo with anti-BCMA CAR retroviral vector encoding the chimeric antigen receptor (CAR) targeted to human BCMA. The NXC-201 CAR-T is provided fresh without cryopreservation.<br>* Other names: HBI0101 CAR-T;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Related Adverse Events | An adverse event (AE) can be any unfavorable and unintended sign (including an abnormal. laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not considered related to the medicinal (investigational) product. | 24 months | 
| Number of Participants with Adverse Events by Severity as Assessed by CTCAE v5.0 | An assessment of severity grade will be made according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0, with the exception of cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS). CRS and ICANS should be evaluated according to the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading. | 24 months | 
| To confirm the maximum tolerated dose (MTD) | According to Common Terminology Criteria for Adverse Events (CTCAE) criteria, version 5.0, and Cytokine release syndrome (CRS) and Immune effector cell-associated neurotoxicity syndrome (ICANS) per American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading | 24 months | 
| To confirm the recommended phase 2 dose (RP2D) | According to Common Terminology Criteria for Adverse Events (CTCAE) criteria, version 5.0, and Cytokine release syndrome (CRS) and Immune effector cell-associated neurotoxicity syndrome (ICANS) per American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants with hematologic and organ response | According to consensus recommendations for AL amyloidosis treatment response criteria in AL (Palladini, 2012) | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Relapsed refractory AL amyloidosis, R/R AL amyloidosis