Trial Summary
What is the purpose of this trial?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).
Is the treatment NXC-201 a promising treatment for amyloidosis?Yes, NXC-201 is a promising treatment for amyloidosis. It is a type of CAR T cell therapy, which is a new and exciting way to treat diseases by using the body's own immune cells. This treatment has shown positive results in reducing harmful proteins in patients with amyloidosis, leading to a strong response in the body. It offers hope for patients with this rare and challenging condition.3791011
What safety data exists for NXC-201 CAR-T treatment in amyloidosis?The research does not provide specific safety data for NXC-201 CAR-T treatment in amyloidosis. However, it mentions the use of anti-BCMA CAR T cell therapy in patients with AL amyloidosis and concurrent multiple myeloma, where patients tolerated the therapy well with manageable toxicities. This suggests that CAR T cell therapies can be safe with proper patient selection and medical optimization, but specific data for NXC-201 is not detailed in the provided research.1681011
Do I have to stop taking my current medications for the trial?The trial protocol does not specify if you must stop taking your current medications. However, you cannot have had any systemic therapy for AL amyloidosis within 14 days before leukapheresis, and there is a 4-week washout period required from previous investigational treatments. Please discuss your specific medications with the trial team.
What data supports the idea that NXC-201 CAR-T for Amyloidosis is an effective treatment?The available research shows that NXC-201 CAR-T therapy, also known as anti-BCMA CAR T cell therapy, has been used successfully in patients with AL amyloidosis who also had multiple myeloma. These patients had heart and kidney issues but tolerated the treatment well and achieved a state where no disease was detected. This suggests that the treatment can be effective for amyloidosis, especially when patients are carefully selected and their heart and kidney functions are optimized before treatment. Additionally, another study reported a case where a different type of CAR T cell therapy targeting CD19 was used for a patient with AL amyloidosis, resulting in a significant reduction in disease markers and a strong response six months after treatment. This further supports the potential effectiveness of CAR T therapies for amyloidosis.245911
Eligibility Criteria
This trial is for adults with relapsed or refractory light chain amyloidosis who have had previous treatments. They must not be pregnant, agree to birth control, and have measurable disease. People with inadequate organ function, recent other therapies, certain blood disorders, active infections or second malignancies are excluded.Inclusion Criteria
My cancer can be measured by blood tests.
I am not pregnant and agree to use birth control during the study.
My diagnosis of systemic AL amyloidosis is confirmed and requires treatment.
I am 18 years old or older.
I am able to get out of my bed or chair and move around.
Exclusion Criteria
I have had treatment for AL amyloidosis before certain medical procedures.
I have a significant brain tumor or brain metastases.
My kidney function is not normal.
I am currently on long-term immunosuppressant therapy.
I am HIV positive and my viral load is not undetectable despite treatment.
I do not have an active Hepatitis B or C infection.
My bone marrow is not functioning properly.
I have a history of heart conditions.
My liver isn't working properly.
Treatment Details
The study tests NXC-201 CAR-T cells' safety and effectiveness in treating AL amyloidosis that has returned or resisted treatment. It's an early-phase trial where the dose of NXC-201 will be increased gradually to find the right balance between efficacy and safety.
1Treatment groups
Experimental Treatment
Group I: NXC-201 CAR-TExperimental Treatment1 Intervention
The dose escalation phase will include the following doses:
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.
NXC-201 is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as NXC-201 for:
- None approved yet; under investigation for AL Amyloidosis and Multiple Myeloma
🇪🇺 Approved in European Union as NXC-201 for:
- None approved yet; under investigation for AL Amyloidosis and Multiple Myeloma
Find a clinic near you
Research locations nearbySelect from list below to view details:
Memorial Sloan Kettering Comprehensive Cancer CenterNew York, NY
University of California Davis Medical CenterSacramento, CA
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Who is running the clinical trial?
Nexcella Inc.Lead Sponsor
Immix Biopharma, Inc.Industry Sponsor
References
Hematopoietic cell transplantation for primary systemic amyloidosis: what have we learned. [2019]Dose-intensive therapy with hematopoietic cell transplantation is effective at reversing AL amyloidosis but is not without risk. Guidelines have been developed for patient selection in order to maximize benefit and minimize treatment-related mortality. Identification of a patient's clonal germline light chain variable region gene may become relevant to patient selection, and development of less morbid approaches to stem cell mobilization and collection would be helpful. While there is room for discussion regarding the design of future therapeutic trials, it is reasonable to attempt to improve the complete response rate for good risk patients by continuing efforts on the phase II level. Attempts to improve outcomes for patients with symptomatic cardiac or advanced multisystem disease may require serial solid organ and stem cell transplantation as well as the development of less toxic approaches using lower doses of melphalan, improved supportive care measures and specific organ-system prophylaxis. If outcomes can be improved, issues related to clonotypic contamination of stem cells will need to be revisited.
Bortezomib-based induction for transplant ineligible AL amyloidosis and feasibility of later transplantation. [2018]Recent studies support the use of bortezomib-based therapies in light chain amyloidosis (AL). We performed a retrospective analysis of the safety, efficacy and long-term survival (median follow-up 3 years) after bortezomib-based treatment in 28 consecutive patients with de novo AL deemed ineligible at initial presentation. The first 14 patients received bortezomib and dexamethasone (VD), and the second 14 patients received cyclophosphamide, bortezomib and dexamethasone (CVD; CyBorD). Both regimens were well tolerated with no treatment-related mortality. The overall hematological response (HR) rate was 93% in both the groups. Median time to response was shorter in the CVD group (39 days vs 96 days in the VD group; P=0.002). Hematological and organ responses induced with bortezomib-based therapy enabled 8 (33%) of initially transplant ineligible patients to undergo autologous hematopoietic stem cell transplantation (AHCT), including 4 patients with cardiac stage III or IV. Seven of the eight patients (88%) who underwent subsequent AHCT achieved sustained HR at a median of 33 months posttransplant. These data suggest that bortezomib-based induction followed by AHCT is a viable therapeutic strategy for transplant-ineligible AL. Larger, multicenter prospective trials are necessary to confirm our findings.
Target Mediated Drug Disposition Model of CPHPC in Patients with Systemic Amyloidosis. [2018]The amyloid deposits that cause disease in systemic amyloidosis always contain the normal plasma protein, serum amyloid P (SAP) component. SAP is the target of a novel immunotherapy approach now being developed to eliminate amyloid deposits. The treatment is enabled by, and critically depends on, the use of the drug (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC, GSK2315698, Ro 63-8695), which depletes circulating SAP almost completely but leaves some SAP in amyloid deposits for specific recognition by subsequently administered therapeutic anti-SAP antibodies. Herein, we report a mechanistic model that predicts, with clinically acceptable precision, the exposure-response relationship for CPHPC, both in healthy individuals and in patients with systemic amyloidosis. The model covariates are gender, renal function, total amyloid load, and presence of hepatic amyloid, all of which are known at baseline. The model is being used to predict individualized dosing regimens in an ongoing, first-in-human study with anti-SAP antibodies.
Delineation of the timing of second-line therapy post-autologous stem cell transplant in patients with AL amyloidosis. [2021]Among patients with immunoglobulin light chain (AL) amyloidosis, there is little consensus on when reinstitution of chemotherapy should occur. We conducted a retrospective study to evaluate the patterns of relapse or progression (R/P) and the timing of reinitiating therapy among 235 patients initially treated with autologous stem cell transplant (ASCT) at Mayo Clinic. The median time from ASCT to second-line therapy was 24.3 months. At the time of restarting therapy, median difference of free light chain (dFLC) was 9.9 mg/dL (42% of diagnosis value), 32% had a dFLC <5 mg/dL, and 63% met criteria for organ R/P. The indications for retreatment were (1) clinical suspicion of R/P, 10%; 92) hematologic R/P only, 23%; (3) organ R/P only, 32%; (4) both hematologic and organ R/P, 31%; and (5) suboptimal response to ASCT and second-line therapy as consolidation, 4%. Patients with organ progression at the time of second-line therapy had inferior survival. Although a dFLC of >5 mg/dL at the time of reinstituting therapy was associated with risk, patients relapsing from very good partial response (VGPR) or better had a longer time to develop organ progression after hematologic R/P (24.2 vs 3.2 months, P = .007). These data suggest that the best candidates for clinical trials testing novel plasma cell-directed chemotherapy beyond first line may be those patients who are either relapsing from VGPR or better (dFLC at diagnosis was >5 mg/dL) or having inadequate response to prior therapy. This strategy should allow for hematologic response assessment while avoiding the risk of deleterious organ progression. Implementation of more stringent progression criteria may also be warranted.
Impact of involved free light chain (FLC) levels in patients achieving normal FLC ratio after initial therapy in light chain amyloidosis (AL). [2018]Achievement of a normal FLC ratio (FLCr) following treatment indicates hematologic response and suggests better outcomes in light chain amyloidosis (AL). We examined if elevated involved free light chain (hiFLC) impacts outcomes in patients achieving normal FLCr. We retrospectively analyzed 345 AL patients who were diagnosed within a 10-year period (2006-2015) and had 2 consecutive normal FLCr values after 1st line treatment. Among these, patients with hiFLC at 1st reading of normal FLCr (hiFLC1; n = 166; 48.1%) were compared to those who did not (n = 179; 51.9%). Patients with AL who have hiFLC1 after initial therapy had higher rates of multi-organ involvement (63.3 vs 46.4%; P = .002) and patients in advanced Mayo stage (42.9 vs 32.2%; P = .04) at diagnosis. The median progression free survival [PFS; 38.2 (95%CI; 26.4, 55.4) vs 67.1 (95%CI; 55.8, 88) months; P = .0002] and overall survival [OS; 94.4 (95%CI; 78, 107.1) vs not reached (NR, 95%CI; 116.1, NR) months; P < .0001] were lower in those who had hiFLC1. A more stringent comparison for patients with 2 consecutive hiFLC (hIFLC2; n = 111; 32.2%) versus not (n = 2234; 67.8%) showed consistent results [PFS; 27.1 (95%CI; 23, 53.8) vs 63.3 (95%CI; 55.4, 77) months; P < .0001 and OS; 78 (95% CI; 54.6, 98.8) vs NR (95%CI; NR, NR); P < .0001]. This poor prognostic impact of hiFLC on survival was independent of serum creatinine, Mayo stage, negative immunofixation status and inclusion of transplant in initial therapy on multivariate analysis. Hence, persistent elevation of iFLC predicts poor prognosis even among patients achieving normal ratio after initial therapy in AL.
High-dose melphalan and autologous peripheral blood stem cell transplantation in patients with AL amyloidosis and cardiac defibrillators. [2020]Cardiac deposition of misfolded light chains is the leading cause of morbidity and mortality in patients with immunoglobulin (AL) amyloidosis. Cardiac defibrillators can be used in the management of patients with advanced cardiac amyloidosis, but data concerning the use of these devices in patients undergoing treatment with high-dose melphalan followed by autologous peripheral blood stem cell transplantation (HDM/SCT) is limited. Herein we describe a single-institution experience of HDM/SCT in 15 patients with cardiac defibrillators. During the peri-transplant period, five of these patients (33%) had detectable cardiac arrhythmias and two patients (13%) had implantable cardiac defibrillator (ICD) discharges. Thirteen of the 14 evaluable patients (93%) achieved at least a partial hematologic response. Transplant-related mortality was 6.7% and median overall survival was 40.8 months, with multiple patients achieving an overall survival of >10 years. These data highlight the feasibility of HDM/SCT in patients with an ICD due to advanced cardiac AL amyloidosis, but highlight the need for additional research to appropriately determine which patients will benefit from this aggressive therapy.
Beyond Andromeda: Improving Therapy for Light Chain Amyloidosis. [2023]Therapy for light chain amyloidosis (AL) continues to evolve, and a new standard of care for the disease is rapidly forming. The risk of early death however, mainly from cardiac complications, remains an important benchmark yet to be definitively improved upon. This brief review explores recent advances in plasma cell directed therapy for AL, highlighting unique factors specific to these patients and AL biology driving differences in treatment strategies and clinical development compared with multiple myeloma. Improving upon proteasome inhibitor based upfront therapy combinations with the addition of anti-CD38 antibodies has shown promise with improved response rates in the ANDROMEDA (NCT03201965) study. Though depth and kinetics of achieving deep hematologic response as well as rates of biomarker defined organ response were improved with the addition of daratumumab to the combination of bortezomib, cyclophosphamide, and dexamethasone, death rates in each arm remained similar. Evaluation of other targeted and novel therapies in AL is ongoing, and we highlight efforts evaluating B-cell maturation antigen (BCMA) directed therapy, BCL-2 family inhibitors, and other novel agents in the field. We also look ahead to efforts to reimagine the clinical development of anti-fibrillar therapies after late phase study failures. Upcoming anti-amyloid fibril antibody studies explore opportunities to improve outcomes for the sickest AL patients with advanced cardiac disease, focusing on improving overall patient survival and reducing the risk of early death in this uniquely frail population.
Incidence and risk factors for pacemaker implantation in light-chain and transthyretin cardiac amyloidosis. [2022]The incidence and risk factors of pacemaker (PM) implantation in patients with cardiac amyloidosis (CA) are largely unexplored. We sought to characterize the trends in the incidence of permanent PM and to identify baseline predictors of future PM implantation in light-chain (AL) and transthyretin (ATTR) CA.
First third-generation CAR T cell application targeting CD19 for the treatment of systemic IgM AL amyloidosis with underlying marginal zone lymphoma. [2023]Light chain amyloidosis (AL) is a rare disease caused by the generalized deposition of misfolded free light chains. Patients with immunoglobulin M gammopathy (IgM) and indolent B-cell lymphoma such as marginal zone lymphoma (MZL) may in some instances develop AL amyloidosis. So far, CAR T cells for AL amyloidosis have only been reported utilizing the B cell maturation antigen as target, while CD19 has so far not been used in AL amyloidosis.We report the case of a 71-year-old male, diagnosed with systemic AL kappa amyloidosis and MZL, receiving third-generation CAR T cell therapy targeting CD19. Prior treatment included bendamustine/rituximab and cyclophosphamide/ dexamethasone with subsequent autologous stem cell transplantation. CAR T application was well tolerated despite heart and kidney amyloid manifestations, and only early low-grade procedure-specific toxicities were observed. A continuous decrease in IgM, kappa light chains and kappa-to-lambda light chain difference was observed in the patient from day + 30 on, resulting in a deep hematological response six months after treatment.In summary, we present a novel case of CAR T cell treatment with third generation CD19 directed infusion for AL amyloidosis with an underlying secretory active B cell lymphoma, showing that this is an effective treatment modality and can be applied to patients with subsequent AL amyloidosis.
The Cardiac Amyloidosis Registry Study (CARS): Rationale, Design and Methodology. [2023]CARS (Cardiac Amyloidosis Registry Study) is a multicenter registry established in 2019 that includes patients with transthyretin (ATTR, wild-type and variant) and light chain (AL) cardiac amyloidosis (CA) evaluated at major amyloidosis centers between 1997-2025. CARS aims to describe the natural history of CA with attention to clinical and diagnostic variables at the time of diagnosis, real-world treatment patterns, and associated patient outcomes in a diverse cohort that is more representative of the at-risk population than that described in CA clinical trials.
Anti-B Cell Maturation Antigen Chimeric Antigen Receptor T Cell Therapy for the Treatment of AL Amyloidosis and Concurrent Relapsed/Refractory Multiple Myeloma: Preliminary Efficacy and Safety. [2023]While immunotherapies, such as CAR T therapy and bi-specific antibodies, have revolutionized the treatment of multiple myeloma (MM), patients with AL amyloidosis have been excluded from trials with these agents due to concerns of underlying autonomic, cardiac, and renal dysfunction, leading to potentially fatal toxicities from these therapies. In this communication, we described the outcomes of two patients with AL amyloidosis and concurrent MM with underlying cardiac and/or renal dysfunction who underwent anti-BCMA CAR T cell therapy with ide-cel or cilta-cel, received cytokine release syndrome prophylaxis, and tolerated therapy well with manageable toxicities and achieved a MRD-negative state. We described the preliminary efficacy and safety of CAR T in patients with AL amyloidosis and highlighted the importance of patient selection and medical optimization of cardiac and renal function prior to CAR T.