Light Chain (AL) Amyloidosis
Conditions
Keywords
Relapsed refractory AL amyloidosis, R/R AL amyloidosis
Brief summary
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
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. Dose escalation and expansion will be guided by safety review committee.
Interventions
BIOLOGICALNXC-201 CAR-T
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.
Sponsors
Nexcella Inc.
Immix Biopharma, Inc.
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open label single-arm clinical study of NXC-201 CAR-T will proceed sequentially through dose cohorts as follows: Cohort 1 - 150×10\^6 CAR-positive (CAR+) T cells (3 patients) Cohort 2 - 450×10\^6 CAR-positive (CAR+) T cells (3 patients) The dose expansion phase will then proceed.
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
1. ≥18 years of age. 2. Voluntarily signed informed consent form (ICF). 3. Eastern Cooperative Oncology Group (ECOG) performance status 0-2. 4. Histologically proven systemic AL amyloidosis 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 plasma cell disease that requires active treatment. 1. An underlying plasma cell disorder can be identified by one of the following: clonal plasma cells in the BM, monoclonal protein in the serum or urine, or abnormal free light chain ratio. 2. Because AL amyloidosis may present with low volumes of bone marrow plasma cells, prior biopsies demonstrating clonal plasma cell populations may be used to determine eligibility. 3. Measurable hematologic disease: difference between involved and uninvolved FLC \> 20 mg/L (or 2mg/dl) with an abnormal k/l ratio; or M-spike \> 0.5mg/dl. 5. Patients should have received at least one line of therapy with a CD38 monoclonal antibody and a proteosome inhibitor and not be in VGPR or CR at the time of inclusion. Patients who did not reach VGPR after two cycles of initial therapy or patients who did achieve VGPR or better but with a hematological relapse can be included. 6. Symptomatic organ involvement (heart, kidney, liver/GI tract, peripheral nervous system). 7. 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. 8. Recovery to ≤Grade 2 or baseline of any non-hematologic toxicities due to prior treatments, excluding alopecia and Grade 3 neuropathy. 9. Absence of any psychological, familial, sociological, or geographical conditions potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before trial entry. 10. Able to swallow pills.
Exclusion criteria
1. Prior treatment with CAR T therapy directed at any target. 2. Any therapy that is targeted to BCMA. 3. Stroke or seizure within 6 months of signing ICF. 4. Bone marrow plasma cells \>30% and clinically symptomatic multiple myeloma with end organ damage (i.e. lytic bone lesions). 5. New York Heart Association Heart Failure Class III or Class IV. 6. Any prior systemic therapy for AL amyloidosis within 14 days prior to leukapheresis. 7. Therapeutic doses of steroids within 2 weeks prior to leukapheresis (Physiological replacement doses of steroids are allowed up to 12 mg/m2/d hydrocortisone or equivalent). 8. Any prior systemic therapy for AL amyloidosis within 14 days of leukapheresis. 9. Wash-out period of at least 4 weeks from previous investigational treatment prior to leukapheresis. 10. Inadequate hepatic function: 1. Aspartate aminotransferase (AST \[SGOT\] or alanine aminotransferase (ALT \[SGPT\]) \>3 x upper limit of normal (ULN) value 2. Alkaline phosphatase \>2 times ULN 3. Serum direct bilirubin \>2 times ULN 11. Inadequate renal function: creatinine clearance (CRCL) \<20 mL/min. 12. International ratio (INR) or partial thromboplastin time (PTT) \>1.5 x ULN, unless on a stable dose of anticoagulant for a thromboembolic event that does NOT meet
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Related Adverse Events | 24 months | 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. |
| Number of Participants with Adverse Events by Severity as Assessed by CTCAE v5.0 | 24 months | 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. |
| To confirm the maximum tolerated dose (MTD) | 24 months | 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 |
| To confirm the recommended phase 2 dose (RP2D) | 24 months | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of participants with hematologic and organ response | 24 months | According to consensus recommendations for AL amyloidosis treatment response criteria in AL (Palladini, 2012) |
Countries
United States
Outcome results
None listed