Final Analysis of the Phase 1a/b Study of Chimeric Fibril-Reactive Monoclonal Antibody 11-1F4 in Patients with Relapsed or Refractory AL Amyloidosis

Background: AL amyloidosis has a very poor prognosis with a variable median survival of 12 to 18 months depending largely on the severity of organ involvement. Current treatment focusing on eliminating the plasma cell clone that produces amyloidogenic light chains have improved overall survival in these patients [ Kumar 2011]. However, the risk of early mortality remains high due to multi-organ dysfunction caused by persistent, insoluble amyloid fibril deposits. To address this, amyloid fibril-reactive monoclonal antibody (mAb) 11-1F4 was designed to target amyloid deposits by directly binding to a conformational epitope present on human light-chain amyloid fibrils. The mAb was tested in a murine (Mu) and later a chimeric (Ch) form in mice with induced human AL amyloidomas; to which there was rapid destruction of amyloid fibrils without any evidence of toxicity in the animals [ Hrncic 2000; Solomon 2003 ]. Confirmation of the mAb's specificity for amyloid fibrils was further demonstrated when the I-124 labeled Mu mAb was visualized in amyloid-laden organs on PET/CT imaging in human subjects [ Wall 2010 ]. These promising results led to the development of GMP-grade amyloid fibril-reactive chimeric IgG1 mAb 11-1F4 by NCI's Biological Resource Branch. Here we report the final data from the open-label, dose-escalation phase 1a/b study of Ch IgG1 mAb 11-1F4 (NCT02245867).

Methods: Relapsed or refractory AL Amyloidosis patients who received prior anti-plasma cell treatment were enrolled. Patients received Ch mAb 11-1F4 as a single intravenous infusion (phase 1a) or a series of weekly infusions for 4 weeks (phase 1b). A dose-escalation "up and down" design was used for both phase 1a and 1b where successive doses of 0.5, 5, 10, 50, 100, 250 and 500 mg/m² were administered. The primary objective was to determine the maximum tolerated dose and to evaluate safety and tolerability of the antibody. Secondary objectives included determining pharmacokinetics and organ response based on the International Society of Amyloidosis' consensus criteria [ Pallidini 2012 ] and the renal staging and response criteria [ Pallidini 2014 ].

Results: Twenty-seven patients were treated with mAb 11-1F4. Eight patients completed phase 1a and 19 patients completed treatment in phase 1b. Twenty-six patients were evaluable for response. Median age for Phase 1a and 1b was 68. All patients tolerated the given dose of mAb 11-1F4 up to the highest dose level of 500mg/m² for both phase 1a and 1b. There were no drug-related grade 4 or 5 adverse events (AEs) or dose-limiting toxicities. Two patients developed a grade 2 rash 3-4 days after infusion. One patient developed the skin rash in phase 1a (dose level 4) and when he was retreated in phase 1b. A skin biopsy with immunohistochemical staining showed 11-1F4 mAb binding to amyloid fibrils with a concomitant neutrophilic infiltrate. Another patient developed a similar rash in phase 1b which further provides clinical evidence that 11-1F4 mAb directly binds to light-chain amyloid fibrils.Overall, 63% (5 of 8) of evaluable patients demonstrated organ response after one infusion of mAb 11-1F4 in phase 1a and 61% (11 of 18) of evaluable patients showed organ response in Phase 1b. The median time to response was 2 weeks after the start of treatment with the tendency of faster response in higher dosages. We observed organ response independent of the free light chain type.

Conclusions: We found that mAb 11-1F4 is well tolerated and safe without grade 4 or 5 AEs nor dose limiting toxicity (MTD of 500mg/m²). Moreover, we postulate that in patients with persistent organ dysfunction after plasma-cell directed therapy; mAb 11-1F4 leads to fast, early and sustained organ response. Overall, amyloid fibril targeted therapy with mAb 11-1F4 represents both a promising and innovative approach to the management of patients with AL Amyloidosis. The rapid destruction of amyloid fibrils by mAb 11-1F4 can improve organ function and, potentially improve mortality in patients with this uniformly fatal disease. Larger randomized trials to evaluate the efficacy of this mAb are planned.