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Researchers Establish Recommended Phase 3 Dose of CAEL-101 for AL Amyloidosis

Study findings presented at the virtual 62nd American Society of Hematology (ASH) Annual Meeting and Exposition propose a recommended dose of CAEL-101 for use in combination with CyBorD in phase 3 clinical trials of patients with AL amyloidosis.

“CAEL-101 is an AL amyloid fibril reactive IgG1 monoclonal antibody with potential for therapeutic immune clearance of AL amyloid deposits in AL amyloidosis patients. Phase I study of CAEL-101 did not identify any significant toxicity at doses up to 500 mg/m2 dosed weekly for 4 weeks as a single agent. Organ responses occurred in a majority of patients,” wrote Jack Khouri, MD, Taussig Cancer Institute, Department of Hematology and Medical Oncology, Cleveland Clinic, Ohio, and colleagues, who sought to determine the recommended phase 3 dose of CAEL-101 plus bortezomib, cyclophosphamide, and dexamethasone (CyBorD) for use in a planned study of patients with AL amyloidosis stage IIIa and IIIb.

A total of 13 patients with AL amyloidosis were enrolled in a 3+3 dose escalation safety study, including 5 heart patients with Mayo stage IIIa disease and 5 with Mayo stage II disease. Patients in cohorts 1 (n = 4), 2 (n = 3), and 3 (n = 6) were given CAEL-101 500 mg/m2, 750 mg/m2 and 1000 mg/m2, respectively, over the course of 2 hours each week for 4 weeks. For the remainder of the study, patients received treatment every other week.

All patients received CyBorD weekly for 3 of 5 weeks of the first cycle and 3 of 4 weeks for up to 6 cycles. Of note, patients could have received a maximum 3 cycles of CyBorD right before enrollment, and only 3 patients had hematologic measurable disease at enrollment.

“With the longest follow up of 91 days and all 13 patients receiving at least 4 doses of CAEL-101, no dose limiting toxicity has been seen with 6 patients dosed at the maximum planned 1000 mg/m2 dose,” Dr Khouri et al wrote.

There were no reports of infusion reactions, although 3 significant adverse events occurred; 1 patient had recurrent atrial fibrillation without rapid ventricular response at the 500 mg/m2 dose and 2 patients dosed at 1000 mg/m2 were hospitalized with Clostridium difficile colitis and enlarging pleural effusion, although these effects not attributed to CAEL-101.

Among the 3 patients with hematologic measurable disease, 2 have had partial responses, whereas 1 is too early to evaluate. One of the patients who had a partial response had a response plateau after cycle 2 of CAEL and is the only patient off-study because of a required anti-plasma cell therapy change.

Of note, 2 of 7 patients evaluable for organ response have met organ response criteria in the 500 mg/m2 cohort.

“CAEL-101 dosed at 1000 mg/m2 is the recommended phase 3 dose in combination with CyBorD for upcoming randomized, double blind, phase 3 trials. Hematologic responses do not seem to be affected by concurrent use of CAEL-101 with CyBorD. Organ responses have occurred early in the course of therapy and are expected to increase over time, particularly after completion of chemotherapy and dexamethasone,” Dr Khouri et al reported.

“Longer follow up, the ongoing exposure to CAEL-101 after the conclusion of chemotherapy and planned phase III trials will provide more data on organ response, quality of life and survival,” they concluded.—Hina Porcelli

Khouri J, Anwer F, Samaras CJ, et al. Safety, Tolerability and Efficacy of Cael-101 in AL Amyloidosis Patients Treated on a Phase 2, Open-Label, Dose Selection Study to Evaluate the Safety and Tolerability of Cael-101 in Patients with AL Amyloidosis. Presented at: the 62nd ASH Annual Meeting and Exposition; December 5-8, 2020; virtual. Abstract 729.

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