Jason Valent, MD of the Cleveland Clinic speaks about the ASH 2020 abstract – 729 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.
Context:
CAEL-101 is an IgG1 monoclonal AL amyloid fibril reactive antibody with the potential for therapeutic immune clearance of AL amyloid deposits in patients with AL amyloidosis (AL). No major toxicity was found in the phase I analysis of CAEL-101 at doses of up to 500 mg/m2 IV administered weekly for 4 weeks as a single agent. A majority of patients experienced organ responses. The primary objective of this current dose-escalation study (NCT04304144) is to provide a recommended phase III dose of CAEL-101 when administered in conjunction with bortezomib, cyclophosphamide, and dexamethasone (CyBorD) for the proposed randomized trial in patients with Mayo phase IIIa and IIIb AL.
Methodology:
In a 3+3 dose-escalation safety trial, 13 AL patients (7 cardiac, 3 kidney, 3 both were enrolled, allowing for an additional patient in each cohort if available. Five heart patients with the remaining 5 Mayo stage II were Mayo stage IIIa patients. Cohort 1 (n=4), 2 (n=3), and 3 (n=6) received CAEL-101 IV over 2 hours at 500 mg/m2, 750 mg/m2, and 1000 mg/m2 respectively, all weekly for 4 weeks, and for the remainder of the study every other week. Premedication was administered 30 minutes prior to each infusion of CAEL-101 with diphenhydramine 25 mg po and acetaminophen 1 gram po. Separately, pharmacokinetic and anti-drug antibody data will be published. Both patients were treated with CyBorD on a weekly basis, 3 weeks out of 5 in the first cycle to comply with CAEL-101 therapy, and 3 weeks out of 4 for up to 6 cycles. Immediately prior to enrollment, patients were allowed to undergo up to 3 cycles of CyBorD. Just 3 of the 13 patients had the detectable hematologic disorder at the time of admission. Consensus criteria were used to test hematologic and organ response data on assessable patients.
Outcomes:
With the longest follow-up of 91 days and all 13 patients receiving at least 4 doses of CAEL-101, 6 patients receiving the highest expected dose of 1000 mg/m2 did not see any dose-limiting toxicity. Infusion reactions did not occur. There were three serious adverse incidents. At the 500 mg/m2 dose level not attributed to CAEL-101, one patient experienced intermittent atrial fibrillation without rapid ventricular response. Clostridium difficile colitis and enlarging pleural effusion, not due to CAEL-101 were hospitalized in two other patients dosed at 1000 mg/m2. Of the 3 patients with the detectable hematologic disease, 2 PRs have been identified, and 1 is too early to assess. After cycle 2 of CAEL, one patient with PR had a response plateau and is the only patient out of the study because of the need to modify anti-plasma cell therapy. Of the 7 patients currently assessable for organ response, 2 in the 500 mg/m2 cohort met organ response requirements (1 heart by NT pro BNP and 1 kidney by 24-hour urine protein). Tracking of organ responses is continuing and revised data will be discussed at the meeting.
Findings:Â
The suggested phase 3 dose in conjunction with CyBorD for the forthcoming randomized, double-blind, phase 3 trials is CAEL-101, dosed at 1000 mg/m2. The concurrent use of CAEL-101 with CyBorD does not seem to affect hematologic responses. In the early course of therapy, organ responses have occurred and are expected to increase over time particularly after completion of chemotherapy and dexamethasone. Longer follow-up, continuing exposure to CAEL-101 will provide more data on organ response, quality of life, and survival following completion of chemotherapy and expected phase III studies.