Phase 1/1b Pharmacokinetic (PK) and Safety Study of the Investigational Oral Proteasome Inhibitor (PI) Ixazomib in Relapsed/Refractory Multiple Myeloma (RRMM) Patients (Pts) with Severe Renal Impairment or End-Stage Renal Disease (ESRD) Requiring Hemodialysis
Authors: Gupta Neeraj , Hanley Michael J , Harvey R. Donald , Badros Ashraf Z , Lipe Brea C. , Kukreti Vishal , Berdeja Jesus G. , Yang Huyuan , Hui Ai-Min , Zhang Xiaoquan , Venkatakrishnan Karthik , Chari Ajai 
Published: October 2019

Abstract
Background
Renal impairment (RI) is a major complication of MM. The oral PI ixazomib is currently under phase 3 investigation in MM. PK data from pts with mild or moderate RI (creatinine clearance [CrCl] ≥30 mL/min) suggest no ixazomib dose modification is needed in these pts (Gupta et al BJCP 2015). Hence, this study (NCT01830816) aimed to characterize the PK of ixazomib in pts with severe RI or ESRD requiring hemodialysis to provide posology recommendations in these pt populations.
Methods
Pts with RRMM or advanced malignant solid tumors were enrolled in the normal (N, CrCl ≥90 mL/min), severe (S, CrCl<30 mL/min) and ESRD requiring hemodialysis groups. CrCl was calculated using two blood samples according to the Cockcroft-Gault method. Pts received a single dose of ixazomib 3 mg. Blood samples were collected after the single dose, at multiple time points over 15 days, to characterize the plasma PK of ixazomib. For ESRD pts, pre- and post-dialyzer plasma samples were also collected hourly during the first 4-hour dialysis session 24−28 hrs after dosing. An additional pre-dose blood sample was collected for in vitro estimation of ixazomib plasma protein binding. After completion of PK sampling, pts could continue to receive ixazomib (at the higher dose of 4 mg if 3 mg was well tolerated) on days 1, 8, and 15 of 28-day cycles (part B of the study). Geometric mean ratios and 90% confidence intervals (CIs) of unbound PK parameters in the RI groups vs the normal group were calculated using an ANOVA model. Adverse events (AEs) were assessed using NCI CTCAE version 4.03.
Results
41 pts were enrolled (20, 14, and 7 to the N, S, and ESRD groups); 61% female, and 66% Caucasian and 29% African American. Mean age was 61.7 years (range 40-82) and mean weight was 83.3 kg (range 46-147). 37 pts had RRMM, and 4 had advanced solid tumors (2 colon, 1 liver, 1 thyroid). 38 pts had reportable PK parameters (Cmax or AUC) and were PK-evaluable (18 N, 14 S, 6 ESRD) (Table). Following a 3 mg dose, ixazomib was rapidly absorbed in all 3 renal function groups, with a median Tmaxof 1.0 to 1.25 hours. Ixazomib was highly bound to plasma proteins with a similar mean fraction bound of approximately 99% in all 3 renal function groups. Unbound systemic exposures (AUC) of ixazomib were 38% higher in pts with severe RI or ESRD. PK profiles were similar in solid tumor and MM pts. Ixazomib concentrations were similar in pre- and post-dialyzer samples collected hourly from ESRD pts during the 4-hour hemodialysis.
In the safety population (N=41), most pts (95%) experienced at least 1 AE; the most common were diarrhea (37%), nausea (32%), fatigue (29%), vomiting (29%), and anemia (20%). The incidence of these AEs was generally similar among renal function groups with the exception of anemia, which was more common in patients in the S and ESRD groups (5%, 36%, and 29% in the N, S, and ESRD groups, respectively). Although the incidences of the most common AEs were generally similar among renal function groups, the incidences of grade 3/4 AEs and serious AEs were greater in the S and ESRD groups versus the N group (79% and 43% vs 35%, and 43% and 57% vs 10%, respectively). In part B of the study, AEs resulting in dose reductions and discontinuations were more common in the S versus N groups (36% vs 25%, and 29% vs 10%, respectively); no pt had an AE leading to dose reduction or discontinuation in the ESRD groups. Relative ixazomib dose intensities were 93.8%, 79.6%, and 61.6% in the N, S, and ESRD groups. There were 3 on-study deaths (2 in the S group and one in the ESRD group). One MM pt in the S group died due to acute hypoxemic respiratory failure considered related to study treatment.
Conclusions
Compared with pts with normal renal function,unbound systemic exposures of ixazomib were 38% higher in pts with severe RI or ESRD requiring dialysis. Therefore, a reduced starting dose of 3 mg is recommended for pts with severe RI or ESRD requiring dialysis. Ixazomib is not dialyzable and can be administered without regards to the timing of dialysis.
Table 1. Renal Function Group Geometric mean (%CV) PK Parameters Severe RI or ESRD vs Normal Least-squares Geometric Mean Ratio (90% CI) Unbound Cmax(ng/mL) Unbound AUC (ng.hr/mL) Unbound Cmax Unbound AUC Normal (n=18) 0.30 (66) 6.64 (61) N/A N/A Severe RI (n=14) 0.478 (86) 9.25 (55) 1.60 (0.99-2.58) 1.39 (0.88-2.20) ESRD (n=6) 0.213 (57) 8.93 (55) 0.71 (0.38-1.34) 1.34 (0.78-2.31) Severe RI/ ESRD (Combined) (n=20) 0.375 (98) 9.13 (54) 1.25 (0.79-1.98) 1.38 (0.93-2.04)

Disclosures
Gupta: Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Off Label Use: Investigational proteasome inhibitor ixazomib. Hanley:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Harvey:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kukreti:Lundbeck: Honoraria; Ortho: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Berdeja:Abbvie: Research Funding; Takeda: Research Funding; BMS: Research Funding; Array: Research Funding; Acetylon: Research Funding; Novartis: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Onyx: Research Funding; Curis: Research Funding; MEI: Research Funding. Yang:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Hui:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Zhang:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Venkatakrishnan:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Chari:Novartis: Consultancy, Research Funding; Biotest: Other: Institutional Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Consultancy, Research Funding; Array Biopharma: Consultancy, Other: Institutional Research Funding, Research Funding; Millennium/Takeda: Consultancy, Research Funding.