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

Background: Mortality in patients with AL Amyloidosis remains high due to progressive organ damage from amyloid deposition. Current therapies eliminate the plasma cell clone that produces amyloidogenic light chains. However, there are no approved therapies that directly target amyloid deposits, a major culprit of progressive multi-organ dysfunction. To address this, a murine (Mu) amyloid fibril-reactive monoclonal antibody (mAb) 11-1F4 was developed that binds to a conformational epitope present on human light-chain amyloid fibrils and initiates cell-mediated phagocytosis. In vivo testing of the Mu mAb and later its chimeric (Ch) form in mice with induced human AL amyloidomas resulted in rapid amyloidolysis without any evidence of toxicity [Hrncic 2000; Solomon 2003]. Subsequent evaluation of an I-124 labeled Mu mAb confirmed that it specifically bound to amyloid-laden organs as evidenced by PET/CT imaging [Wall 2010]. Because of these favorable results, GMP-grade amyloid fibril-reactive Ch IgG1 mAb 11-1F4 was produced by NCI's Biological Resource Branch for a phase 1a/b trial. An analysis of Phase 1a was presented at the American Society of Hematology's 2015 annual meeting. Here we report data from the phase 1a/b trial.

Methods: Patients with relapsed or refractory AL Amyloidosis were enrolled in this open-label, dose-escalation phase 1a/b study of Ch IgG1 mAb 11-1F4 (NCT02245867). The primary objective was to determine safety and tolerability of the antibody when given as a single intravenous infusion (phase 1a) or as a series of weekly infusions for 4 weeks (phase 1b). Secondary objectives included pharmacokinetics and efficacy as evidenced by organ response. For both phase 1a and 1b, a dose-escalation "up and down" design was used where sequential doses of 0.5, 5, 10, 50, 100, 250 and 500 mg/m² were administered to successive patients. Assessment of organ response was based on the International Society of Amyloidosis' revised consensus criteria [Pallidini 2012] and the clinically validated renal staging and response criteria [Pallidini 2014].

Results: As of July 15th, 2016, 8 (2 κ and 6 λ) patients completed phase 1a and 11 (4 κ and 7 λ) patients commenced treatment in phase 1b. Median age was 67 years (range: 34 - 77) and median number of organs involved was 2 (range: 1 - 4) with heart and kidney being the most common. All patients received prior anti-plasma cell systemic treatment and achieved at least partial hematologic response. All patients tolerated the given dose of mAb 11-1F4. The maximum tolerated dose (MTD) was 500mg/m² for phase 1a and 1b. There were no grade 4 or 5 adverse events (AEs) related to the drug. In phase 1a, one patient at dose level 4 developed a grade 2 rash 4 days after infusion. Skin biopsy revealed a so far undiagnosed cutaneous amyloidosis and immunohistochemical staining showed the mAb surrounding amyloid fibrils with an accompanying neutrophilic infiltrate. The same patient and another patient developed a similar rash during treatment in phase 1b suggesting mAb 11-1F4 binding. Although the primary objective of the trial was to evaluate safety, 63% of patients (5 of 8) with measurable disease burden demonstrated organ response after one infusion of mAb 11-1F4 in phase 1a. In phase 1b, 83% of patients (5 of 6 who completed follow up) showed organ response. At the time of presentation, we will report a complete analysis of the phase 1a and 1b clinical trial.

Conclusions: Treatment with mAb 11-1F4 is well tolerated and safe without grade 4 or 5 AEs or dose limiting toxicity up to an MTD of 500mg/m². Clinical efficacy data shows early and sustained organ response when the mAb is administered as a single infusion or as a weekly infusion for 4 weeks. Based on these very encouraging results, a phase 2 SWOG trial for patients with newly diagnosed AL Amyloidosis will be launched. Overall, we posit that amyloid fibril-specific 11-1F4 mAb represents a novel and promising adjunct to the treatment of AL Amyloidosis by safely promoting amyloid resolution and subsequent improvement in organ function. This may result in improved outcomes for patients with this devastating disease.