A Phase 1/2 Study to Assess Safety and Dose of Ixazomib in Combination with Cyclophosphamide and Dexamethasone in Newly Diagnosed Patients with Light Chain (AL) Amyloidosis

Introduction: AL amyloidosis is an incurable clonal plasma cell disorder characterized by tissue deposits of immunoglobulin light chain fragments leading to organ dysfunction and death. Standard treatment for newly diagnosed patients (pts) has traditionally included oral melphalan + dexamethasone as well as high-dose melphalan + ASCT. Although the combination of bortezomib, cyclophosphamide and dexamethasone (CyBorD) has activity, better tolerated treatment approaches are needed. Here we report preliminary results of a Phase 1/2, open-label, multi-institution study of ixazomib (I) in combination with cyclophosphamide (Cy) and dexamethasone (D) in newly diagnosed AL amyloidosis. Methods: Eligible pts are ≥18 years with newly diagnosed, untreated biopsy-proven AL amyloidosis according to standard criteria. A total of up to 30 pts will be enrolled, with up to 18 in the dose escalation arm (phase 1) and 12 in the maximum tolerated dose (MTD) expansion arm (phase 2) according to a classical 3+3 design. Four dose levels were evaluated in phase 1. I and Cy are given orally (PO) on days 1, 8, 15, and D 20mg PO on days 1, 8, 15, 22 of each 28-day cycle. Treatment continues for a total of 6 cycles or until disease progression, significant toxicity or withdrawal. The primary study objective in phase 1 is to establish the MTD and in phase 2 is to determine hematologic/organ response rate. Results: As of May 2019, 18 pts have been enrolled; 16 in phase 1 and 2 in phase 2. The MTD was established at dose level 3 (I 4mg and Cy 500mg). Median age is 65 years (range 46-79), 12 (67%) are male. Light chain isotype is lambda in 14 (78%). Seven pts (39%) have cardiac, 10 (56%) renal, 4 (22%) gastrointestinal, 1 (6%) hepatic, 2 (11%) soft tissue involvement, with 22% having multi-organ involvement. Four pts (22%) completed 6 cycles of therapy and 6 (33%) remain on study with a median of 3 cycles completed. Eight pts (44%) have been taken off study prior to completing 6 cycles due to no response in 5 (28%) after a median of 3.5 cycles (2-5), grade 4 hyperbilirubinemia unrelated to study drug in 1 (6%), cardiac decompensation in 1 (6%), and 1 death attributed to advanced disease. Eight of 16 pts (50%) had at least 1 drug-related adverse event (AE) (any grade), most commonly edema (19%), fatigue (19%), dizziness/lightheadedness (13%) and lymphopenia (13%). Grade 3/4 AEs were rare with grade 3 lymphopenia, anemia, and hyponatremia occurring in 13%, 6%, and 6% of pts, respectively.