Daratumumab-based therapies in transplant-ineligible patients with untreated multiple myeloma and hepatic dysfunction: A systematic review of subgroup analyses

Introduction There is subgroup analysis suggesting a lack of benefit of daratumumab use in multiple myeloma (MM) and hepatic disease (HD). The objectives of this study were to conduct a systematic review and interpretation of daratumumab-based regimen efficacy in transplant-ineligible patients with untreated MM and HD. Methods A systematic search in Pubmed® database about randomized clinical trials (RCTs) with subgroup analysis regarding hepatic function for overall survival (OS) or progression-free survival (PFS) were developed. Two methodologies were applied. One of them considered statistical interaction, prespecification, biological support and consistency of subgroup results. Second methodology was two-part validated tool: preliminary questions to reject subset analysis without minimal relevance, and a checklist relating a recommendation for applicability in clinical practice. Results It was included three records. About first methodology, statistical interaction among subgroups was found for PFS in one RCT. Subsets were prespecified in all RCTs. Biological support of efficacy differences could be reasonable. Inconsistent results were found. Second methology directly rejected applicability of subset analysis in two records. Checklist recommended “null” application of results in the remaining RCT. Conclusions No consistent heterogeneity for daratumumab-based regimen efficacy was observed among subgroups regarding hepatic function in transplant-ineligible patients with untreated MM. Patients with normal hepatic function and HD could benefit from these treatments.

982. Effect of Hepatic Impairment on the Safety and Pharmacokinetics of Rezafungin

Background Rezafungin (RZF) is a novel echinocandin antifungal being developed for treatment of candidemia and invasive candidiasis, and for prevention of invasive fungal diseases among immunosuppressed patients. In the Phase 2 and Phase 3 treatment trials of rezafungin compared with caspofungin (STRIVE [NCT02734862] and ReSTORE [NCT03667690], respectively), patients with severe hepatic impairment (HI) were not included due to lack of caspofungin data in this population. Rezafungin was previously evaluated in patients with moderate hepatic impairment. Here we report an open-label, single-dose study on rezafungin in patients with HI (Child-Pugh class C). Methods To investigate the safety, tolerability, and pharmacokinetics (PK) of RZF in subjects with HI and healthy subjects (HS), 8 subjects with HI and 8 HS matched for age, sex, and body mass index (BMI) were enrolled and received a single 400-mg intravenous 1-hour infusion of RZF. Plasma PK sampling was performed at various time points through 336 hours postdose. RZF PK parameters were derived using non-compartmental analysis. Safety was assessed throughout the study. Results The majority of the HI subjects were White (87.5%) and male (75%) while equal distribution between White and Black or African American was observed among HS (50%) and 75% were male. The mean age of HI subjects was 58 years (range, 41–68 years) and 56.6 years (range, 50–61 years) for the HS. Mean BMI was 29.7 kg/m2 (range, 24.5–34.3 kg/m2) for HI subjects and 29.7 kg/m2 (range, 25.4–34.2 kg/m2) for the HS. RZF exposure (Cmax and AUC) in subjects with HI was ~30% lower than that in HS (Table 1), while half-life was generally similar (HI: 121 h, HS:124 h; Figure 1). Three HI subjects had one adverse event (AE) each (bronchitis, worsening hepatic encephalopathy, hyponatremia), all moderate in severity; one HS had 1 AE of infusion site infiltration mild in severity. No AEs were considered related to RZF, and all were resolved or resolving by the end of the study. Table 1. Plasma Rezafungin PK Parameter Estimates in Subjects with Severe Hepatic Impairment or Normal Hepatic Function After a Single 400 mg IV Infusion of Rezafungin Figure 1. Mean (+SD) Plasma Rezafungin Concentration-Time Profiles in Subjects with Severe Hepatic Impairment or Normal Hepatic Function After a Single 400-mg IV Infusion of Rezafungin (Semi-Logarithmic Scale) Conclusion RZF was well tolerated in HI subjects and showed modestly reduced exposure that was within the range observed in matched HS. These findings support no RZF dose adjustment in subjects with severe hepatic impairment. Disclosures Voon Ong, PhD, Cidara Therapeutics (Employee, Shareholder) Taylor Sandison, MD, MPH, Cidara Therapeutics (Employee, Shareholder) Rebeca M. Melara, M.S., Altasciences (contract research organization) (Employee) Thomas C. Marbury, MD, Orlando Clinical Research Center (Employee, Other Financial or Material Support, Equity owner of Orlando Clinical Research Center) Alena Jandourek, MD, Cidara therapeutics (Consultant) Shawn Flanagan, PhD, Cidara Therapeutics (Employee, Shareholder)

Atezolizumab and Bevacizumab in Patients with Unresectable Hepatocellular Carcinoma: Pharmacokinetic and Safety Assessments Based on Hepatic Impairment Status and Geographic Region

<b><i>Introduction:</i></b> Phase 1b GO30140 and phase 3 IMbrave150 studies evaluated first-line atezolizumab + bevacizumab for unresectable hepatocellular carcinoma (HCC). Here, we evaluated pharmacokinetics (PK) and safety by hepatic impairment status and geographic region. <b><i>Methods:</i></b> Patients received atezolizumab 1,200 mg + bevacizumab 15 mg/kg IV every 3 weeks. Drug concentrations were evaluated by descriptive statistics and population PK. PK and adverse event frequencies were evaluated by hepatic impairment status and region. <b><i>Results:</i></b> 323 IMbrave150 patients and 162 GO30140 patients were PK evaluable. Compared with IMbrave150 patients who had normal hepatic function per the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria (<i>n</i> = 123), patients with mild impairment (<i>n</i> = 171) had a geometric mean ratio (GMR) of 0.92 for cycle 1 atezolizumab area under the concentration-time curve (AUC); patients with moderate impairment (<i>n</i> = 27) had a GMR of 0.88. Patients in Asia ([<i>n</i> = 162] vs. outside [<i>n</i> = 161]) had a GMR of 1.25 for cycle 1 atezolizumab AUC. Compared with GO30140 patients who had normal hepatic function (NCI-ODWG [<i>n</i> = 61]), patients with mild impairment (<i>n</i> = 92) had a GMR of 0.97 for cycle 1 peak bevacizumab concentrations; those with moderate impairment (<i>n</i> = 9) had a GMR of 0.94. Patients in Asia (<i>n</i> = 111) versus outside Asia (<i>n</i> = 51) had a GMR of 0.94 for cycle 1 peak bevacizumab concentration. PK results were generally comparable when evaluated based on additional hepatic functional definitions (Child-Pugh or albumin/bilirubin criteria) or study enrollment in Japan. No associations between atezolizumab PK and HCC etiology were seen. Adverse event frequencies were similar across evaluated groups. <b><i>Conclusions:</i></b> IMbrave150 and GO30140 patients with unresectable HCC had varying baseline hepatic impairment and high enrollment from Asia. PK data demonstrated considerable exposure overlap across groups. Treatment was tolerable across groups. No need for dose adjustment based on mild or moderate hepatic impairment or region is recommended based on this analysis.

Pharmacokinetics and safety of rucaparib in patients with advanced solid tumors and hepatic impairment

Purpose The poly(ADP-ribose) polymerase inhibitor rucaparib is approved for the treatment of patients with recurrent ovarian and metastatic castration-resistant prostate cancer; however, limited data are available on its use in patients with hepatic dysfunction. This study investigated whether hepatic impairment affects the pharmacokinetics, safety, and tolerability of rucaparib in patients with advanced solid tumors. Methods Patients with normal hepatic function or moderate hepatic impairment according to the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria were enrolled and received a single oral dose of rucaparib 600 mg. Concentrations of rucaparib and its metabolite M324 in plasma and urine were measured. Pharmacokinetic parameters were compared between hepatic function groups, and safety and tolerability were assessed. Results Sixteen patients were enrolled (n = 8 per group). Rucaparib maximum concentration (Cmax) was similar, while the area under the concentration–time curve from time 0 to infinity (AUC0–inf) was mildly higher in the moderate hepatic impairment group than in the normal control group (geometric mean ratio, 1.446 [90% CI 0.668–3.131]); similar trends were observed for M324. Eight (50%) patients experienced ≥ 1 treatment-emergent adverse event (TEAE); 2 had normal hepatic function and 6 had moderate hepatic impairment. Conclusion Patients with moderate hepatic impairment showed mildly increased AUC0–inf for rucaparib compared to patients with normal hepatic function. Although more patients with moderate hepatic impairment experienced TEAEs, only 2 TEAEs were considered treatment related. These results suggest no starting dose adjustment is necessary for patients with moderate hepatic impairment; however, close safety monitoring is warranted.

Single-dose pharmacokinetics of BMS-986177/JNJ-70033093 in participants with mild or moderate hepatic impairment compared to healthy participants

Background According to the scientific evidence accumulated to date (ie, genetic, epidemiological, preclinical, clinical), the modulation of Factor XI (FXI) function may provide a novel mechanism for systemic anticoagulation without increasing the risk of clinically significant bleeding in a variety of conditions predisposing patients to a high risk of thrombotic or bleeding events. BMS-986177/JNJ-70033093 (BMS-177/JNJ-3093) is a small molecule that inhibits the active form of FXI (FXIa) with high affinity and selectivity. Depending on the indication, BMS-177/JNJ-3093 may provide benefit to patients as add-on or potentially replacement therapy to the current standard of care antithrombotic agents. Patients with hepatic impairment may have an increased risk of bleeding when using existing antithrombotic agents and therefore may benefit from drugs with an improved safety profile. Purpose To assess the effect of mild or moderate hepatic impairment on the pharmacokinetic (PK) properties of BMS-177/JNJ-3093. Methods This was a multicenter, open-label, non-randomized, single-dose study. A single 60-mg oral dose of BMS-177/JNJ-3093 was administered to 9 participants with mild hepatic impairment (Child-Pugh class A), 8 participants with moderate hepatic impairment (Child-Pugh class B), and 9 healthy participants with normal hepatic function. Healthy participants were matched to participants with hepatic impairment in each Child-Pugh class with regard to body weight. To assess the effects of hepatic impairment on BMS-177/JNJ-3093 PK, an analysis of variance was performed on the natural log-transformed Cmax, AUC(INF), and AUC(0-T) with hepatic function group as a fixed effect. Results BMS-177/JNJ-3093 was well tolerated when administered as an oral dose of 60 mg in participants with mild or moderate hepatic impairment and healthy participants with normal hepatic function. There were no deaths, serious adverse events (AEs), severe AEs, bleeding AEs, or discontinuations due to an AE reported during the study. The geometric mean ratios (GMRs) (90% CI) comparing mild hepatic impairment to normal hepatic function were 1.180 (0.735, 1.895) and 1.168 (0.725, 1.882) for total BMS-177/JNJ-3093 maximum concentration (Cmax) and area under the curve from time 0 to infinity (AUC(INF)), respectively. The GMRs (90% CI) comparing moderate hepatic impairment to normal hepatic function were 1.140 (0.699, 1.857) and 0.996 (0.609, 1.628) for total BMS-177/JNJ-3093 Cmax and AUC(INF), respectively. Overall, levels of activated partial thromboplastin time (aPTT) increased in an exposure-related manner following single oral doses of 60 mg BMS-177/JNJ-3093 in all groups. Conclusion BMS-177/JNJ-3093 was well tolerated in the normal healthy participants and those with mild or moderate hepatic impairment. The observed changes indicate that a dose adjustment in these populations may not be necessary. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): This work was sponsored by Bristol-Myers Squibb and Janssen Research & Development, LLC

Hemostasis and Liver Regeneration

The liver is unique in its remarkable regenerative capacity, which enables the use of liver resection as a treatment for specific liver diseases, including removal of neoplastic liver disease. After resection, the remaining liver tissue (i.e, liver remnant) regenerates to maintain normal hepatic function. In experimental settings as well as patients, removal of up to two-thirds of the liver mass stimulates a rapid and highly coordinated process resulting in the regeneration of the remaining liver. Mechanisms controlling the initiation and termination of regeneration continue to be discovered, and many of the fundamental signaling pathways controlling the proliferation of liver parenchymal cells (i.e., hepatocytes) have been uncovered. Interestingly, while hemostatic complications (i.e., bleeding and thrombosis) are primarily thought of as a complication of surgery itself, strong evidence suggests that components of the hemostatic system are, in fact, powerful drivers of liver regeneration. This review focuses on the clinical and translational evidence supporting a link between the hemostatic system and liver regeneration, and the mechanisms whereby the hemostatic system directs liver regeneration discovered using experimental settings.

Pharmacokinetics and safety following a single oral dose of niraparib in patients with moderate hepatic impairment.

6054 Background: Niraparib is approved for the maintenance treatment of adult patients (pts) with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy, or with similar cancers but advanced, associated with homologous recombination deficiency (HRD) and have been treated with ³3 prior chemotherapy regimens. Niraparib is extensively metabolized in the liver and eliminated via both hepatobiliary and renal routes. Objectives of this study included characterization of niraparib pharmacokinetics (PK) and safety in pts with normal hepatic function vs. pts with moderate hepatic impairment. Methods: This phase I, open-label, parallel-group, single-dose study enrolled pts with advanced solid tumors into 2 groups: normal hepatic function and moderately impaired hepatic function, defined as bilirubin >1.5 to 3 times the upper limit of normal and any aspartate aminotransferase elevation. Pts received a single 300-mg dose and underwent PK sampling for 7 days. Exposure parameters included maximum concentration (Cmax), area under the concentration-time curve calculated to last measured concentration (AUClast), and extrapolated to infinity (AUCinf). PK parameters were determined using a non-compartmental analysis in WinNonlin. Results: Seventeen pts were enrolled; 9 with normal hepatic function and 8 with hepatic impairment. Niraparib Cmax was 7% lower in pts with moderate hepatic impairment compared with pts with normal hepatic function (Table). Overall exposure was increased in pts with moderate hepatic impairment, with niraparib AUClast and AUCinf increased 45% and 60%, respectively. Safety data during the PK phase of the study is consistent with the known profile for niraparib. Conclusions: Pts with moderate hepatic impairment experienced increased niraparib exposure which did not noticeably alter the toxicity profile in this population. Clinical trial information: NCT03359850. [Table: see text]

Analysis of hematologic adverse events (HeAEs) in trifluridine/tipiracil (FTD/TPI)-treated patients (pts) with or without renal/hepatic impairment (RI/HI): Pooled safety analyses from TAGS and RECOURSE.

145 Background: FTD/TPI has shown clinical benefit and consistent safety in pretreated pts with metastatic colorectal cancer (mCRC) and metastatic gastric or gastroesophageal junction cancer (mGC/GEJC) in the phase 3 RECOURSE and TAGS trials, respectively. HeAEs were the most frequent AEs with FTD/TPI treatment. Methods: Pts in this analysis received ≥1 FTD/TPI dose in the TAGS and RECOURSE trials. Subgroups included pts with normal renal function (nRF; CrCl ≥90 mL/min), mild RI (CrCl 60–89 mL/min), moderate (mod) RI (CrCl 30–59 mL/min), normal hepatic function (nHF) and mild HI (total bilirubin <1.5 X ULN, or AST >ULN). Results: FTD/TPI was administered to 868 pts in the overall pooled population (OPP; n=335, TAGS [mGC/GEJC]; n=533, RECOURSE [mCRC]); 52%, 36%, and 11% had nRF, mild and moderate RI, and 66% and 33% had nHF and mild HI, respectively. Frequencies of any-cause grade (gr) ≥3 HeAEs were similar across subgroups and the OPP, except for gr ≥3 anemia and gr ≥3 leukopenia, which were higher with mod RI (table). In the OPP, most gr 3/4 neutropenia events occurred within the first 2 cycles (median time to onset [mTTO], 49 d). Median time to resolution (mTTR) was 8 d. Gr 3/4 neutropenia TTO and TTR in most subgroups were consistent with the OPP, except with mod RI (mTTO, 29 d). HeAE management and correlative efficacy analyses will be presented. Conclusions: In this pooled analysis of pts with mCRC and mGC/GEJC, HeAEs with FTD/TPI in pts with mild to mod RI and mild HI were manageable and not largely different from those in the OPP. Clinical trial information: NCT02500043 and NCT01607957. [Table: see text]

Dotinurad: a clinical pharmacokinetic study of a novel, selective urate reabsorption inhibitor in subjects with hepatic impairment

Background Dotinurad is a novel, selective urate reabsorption inhibitor, which reduces serum uric acid levels by inhibiting the urate transporter 1 (URAT1). We compared the pharmacokinetics (PK), pharmacodynamics (PD), and safety of dotinurad in subjects with hepatic impairment and normal hepatic function. Methods This was a multicenter, open-label, single dose study. A total of 24 subjects were divided into four groups: the normal hepatic function group and the mild, moderate, and severe hepatic impairment groups. The primary endpoints were changes in plasma dotinurad levels and PK parameters. Results The geometric mean ratio of the maximum plasma concentration (Cmax) [two-sided 90% confidence interval (CI)] of dotinurad in in the mild, moderate, and severe hepatic impairment groups relative to that in the normal hepatic function group was 0.840 (0.674–1.047), 0.798 (0.653–0.976), and 0.747 (0.570–0.979), respectively, showing a lower Cmax in the moderate and severe hepatic impairment groups. Following adjustment for body weight, only the moderate hepatic impairment group had a lower Cmax than the normal hepatic function group. No meaningful differences in other PK parameters were observed between the groups. Regarding the PD of dotinurad, the changes in serum uric acid levels after dosing were similar in all groups. As for safety, no noteworthy concerns were raised in relation to any group. Conclusion The study revealed no clinically meaningful influence of hepatic impairment on the PK, PD, or safety of dotinurad. These findings indicate possibility that dotinurad can be used without dose adjustment in patients with hepatic impairment.