In a phase 1 a/b clinical trial, researchers evaluated the sue of the monoclonal antibody (mAb) CAEL-101 in treatment of systemic light-chain (AL) amyloidosis. The results of the study were reported in the journal Blood.
In AL amyloidosis, deposits of amyloid fibrils consisting of immunoglobulin light chains appear in various organs. Multi-organ dysfunction is a possible outcome, with cardiac involvement being the biggest prognostic factor in terms of mortality. CAEL-101 is a chimeric form of a murine mAb, 11-1F4, and it binds to misfolded human immunoglobulin light chains, aiding in phagocytosis and possible removal of these deposits.
This open-label, dose-escalation trial (ClinicalTrials.gov Identifier: NCT02245867) recruited patients with previously treated AL amyloidosis who did not have seriously limited cardiac, renal, or hepatic function, uncontrolled infection, or significant comorbidities. In phase 1a of this trial, patients received single doses of CAEL-101 that were administered at higher dosage levels in subsequent patients unless dose-limiting toxicities (DLTs) occurred. Phase 1b involved 4 infusions per patient, with increased dosages across subsequent patients, until the maximum tolerated dose (MTD) was achieved.
The trial evaluated tolerance, safety, pharmacokinetics, and possible clinical benefit with CAEL-101. Treatment responses were estimated by organ-specific serum biomarkers or imaging methods. The primary study objective was determining the MTD and safety features of CAEL-101.
A total of 8 patients were enrolled into the phase 1a portion of the trial, and 19 patients were enrolled in phase 1b. No DLTs were reported up to the dosage level of 500 mg/m2 in either phase of the trial, and the MTD was not reached.
CAEL-101 in serum demonstrated a terminal half-life of 10 to 16 days following multiple doses. Exposure was reportedly proportional to dosage when dosed at more than 10 mg/m2 in phase 1a and at 5 mg/m2 or more in phase 1b. In phase 1b, the peak CAEL-101 level was reached after the third dose of 500-mg/m2.
Organ response was evaluated in 24 patients who had organ involvement. A therapeutic response to CAEL-101 was seen in 15 patients (63%) of these patients. The median time to response was 3 weeks after CAEL-101 infusion, and responses were seen at CAEL-101 dosages above 5 mg/m2.
There were no drug-related fatalities reported in this trial. In phase 1a, the most common treatment-related adverse events (AEs) were of grades 1 to 2, including nausea, diarrhea, rash, pruritis, and hyperuricemia. Grade 3 or 4 pruritis occurred in 1 patient (12.5%). In phase 1b, the most common AEs were reported to be grades 1 or 2 diarrhea, rash, and elevation of aspartate transaminase levels, with each of these occurring in 3 patients (15.8%). One patient (5.3%) developed grade 3 pericardial effusion, which was attributed to advanced cardiac amyloidosis.
“The findings of this phase 1a/b study confirm that treatment with mAb CAEL-101 is well tolerated with the potential to improve biomarkers associated with organ dysfunction in patients with AL amyloidosis,” the study investigators wrote in their report.
Disclosures: Some authors have declared affiliations with or received grant support from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.
Edwards CV, Rao N, Bhutani D, et al. Phase 1a/b study of monoclonal antibody CAEL-101 (11-1F4) in patients with AL amyloidosis. Blood. 2021;138(25):2632-2641. doi:10.1182/blood.2020009039