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

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).

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.

Eligibility Criteria:
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 exclusion criteria.
13. Inadequate bone marrow function prior to leukapheresis or lymphodepletion, without transfusion or growth factor support within 5 days prior defined by absolute neutrophil count (ANC) \<1000 cells/mm3, platelet count \<50,000/mm3, or hemoglobin \<8 g/dL (blood transfusions are allowed), absolute lymphocyte count \< 300 cells/mm3.
14. Presence of active infection within 72 hours prior to lymphodepletion.
15. Significant co-morbid condition/s or disease/s which in the judgment of the Investigator would place the subject at undue risk or interfere with the study.
16. Known human immunodeficiency virus (HIV) positive status subjects who have not achieved undetectable viral load on highly active anti-retroviral therapy/combination anti-retroviral therapy (HAART/cART) within 6 months of lymphodepletion (previously treated HIV with undetectable viral load can be included)
17. Patients with active Hepatitis B or Hepatitis C with detectable viral load (previously treated Hepatitis B or Hepatitis C with undetectable viral load can be included)
18. Subjects with a history of stroke, unstable angina, or myocardial infarction requiring medication or mechanical control within 3 months.
19. Evidence of clinically significant ventricular arrhythmias on 7-day Zio® patch (or equivalent device) monitoring despite anti-arrhythmic treatment, except if a pacemaker or automated implantable cardioverter defibrillator (AICD) has been implanted.
20. Stage IIIb patients:

    1. NT-proBNP \>8500 ng/L and
    2. hs-troponin I ≥100 ng/L or troponin I ≥0.1 mcg/L or troponin T ≥ 0.035 mcg/L or hs-troponin T ≥50 ng/L
21. Left ventricular ejection fraction \<35%.
22. Heart failure which is, in the opinion of the Investigator, related to ischemic heart disease.
23. Presence of other active malignancy that requires treatment with the exception of non-melanoma skin cancer, cervical cancer, treated early-stage prostate cancer provided that prostate specific antigen is within normal limit, or any completely resected carcinoma in situ; other indolent/completely resected malignancies may be discussed with the Principal Investigator (PI) and/or Co-PI.
24. Subjects who have had a venous thromboembolic event requiring anticoagulation and who meet any of the following criteria:

    1. Have been on a stable dose of anticoagulation for \< 1 month (except for acute line insertion induced thrombosis).
    2. Have had a Grade 2, 3, or 4 hemorrhage in the last 30 days.
    3. Are experiencing continued symptoms from their venous thromboembolic event (e.g., continued dyspnea or oxygen requirement).
25. Presence of non-AL amyloidosis.
26. AL amyloidosis with isolated soft tissue involvement.
27. Supine systolic blood pressure \<100 mmHg or postural symptoms despite medical therapy.
28. Subject is a woman who is pregnant, or breast-feeding, or planning to become pregnant.
29. Subjects with known/underlying medical conditions that, in the investigator's opinion would make the administration of the study drug hazardous (i.e., chronic obstructive pulmonary disease, persistent asthma, uncontrolled diabetes or uncontrolled coronary artery disease).
30. Chronic atrial fibrillation with uncontrolled heart rate.
31. Unwillingness to practice effective birth control.
32. Inability to comply with other requirements of the protocol.