Rationale and Design of the SENECA (StEm cell iNjECtion in cAncer survivors) Trial

Abstract

Objectives: SENECA (StEm cell iNjECtion in cAncer survivors) is a phase I, randomized, double-blind, placebo-controlled study to evaluate the safety and feasibility of delivering allogeneic mesenchymal stromal cells (allo-MSCs) transendocardially in subjects with anthracycline-induced cardiomyopathy (AIC).

Background: AIC is an incurable and often fatal syndrome, with a prognosis worse than that of ischemic or nonischemic cardiomyopathy. Recently, cell therapy with MSCs has emerged as a promising new approach to repair damaged myocardium.

Methods: The study population is 36 cancer survivors with a diagnosis of AIC, left ventricular (LV) ejection fraction ≤40%, and symptoms of heart failure (NYHA class II-III) on optimally-tolerated medical therapy. Subjects must be clinically free of cancer for at least two years with a ≤ 30% estimated five-year risk of recurrence. The first six subjects participated in an open-label, lead-in phase and received 100 million allo-MSCs; the remaining 30 will be randomized 1:1 to receive allo-MSCs or vehicle via 20 transendocardial injections. Efficacy measures (obtained at baseline, 6 months, and 12 months) include MRI evaluation of LV function, LV volumes, fibrosis, and scar burden; assessment of exercise tolerance (six-minute walk test) and quality of life (Minnesota Living with Heart Failure Questionnaire); clinical outcomes (MACE and cumulative days alive and out of hospital); and biomarkers of heart failure (NT-proBNP).

Conclusions: This is the first clinical trial using direct cardiac injection of cells for the treatment of AIC. If administration of allo-MSCs is found feasible and safe, SENECA will pave the way for larger phase II/III studies with therapeutic efficacy as the primary outcome.

Trial registration: ClinicalTrials.gov NCT02509156.

Figure 1.

Flowchart of subject participation timepoints.

Figure 2.

The polar map displayed shows unipolar voltage (UniV) values present on the endocardial surface of the left ventricle. The UniV is displayed according to the color spectrum shown (color legend) with lower values in red and higher values displayed in yellow, green and blue. The data points that constitute the map are depicted by white dots (n=75) and the sites of transendocardial injection are depicted by black dots (n=20). Characteristically, voltage maps in nonischemic cardiomyopathy are heterogeneous suggesting that the fibrotic process that takes place secondary to the underlying pathology is not uniform. A large area of fibrosis (lower UniV) is noted throughout the septum and relatively higher UniV is present in the inferior wall. UniV values serve as the basis for selection of the target injection areas. The overriding cell injection strategy for the SENECA trial is to distribute injections broadly throughout the myocardium and deliver product to areas that demonstrate intermediate level UniV (4 to 8mV). This range can be expanded to include areas with UniV of up to 12mV, if necessary. Each of the 20 injections contains either 0.4 ml of cell suspension with 5 million allo-MSCs per injection site for the active cell treatment arm or 0.4 ml of cell-free Buminate solution for the placebo group.