National Cancer Institute Organ Dysfunction Research Articles

Exploring the Impact of Hepatic Impairment on Pralsetinib Pharmacokinetics.

Pralsetinib is a kinase inhibitor indicated for the treatment of metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer. Pralsetinib is primarily eliminated by the liver and hence hepatic impairment (HI) is likely alter its pharmacokinetics (PK). Mild HI has been shown to have minimal impact on the PK of pralsetinib. This hepatic impairment study aimed to determine the pralsetinib PK, safety and tolerability in subjects with moderate and severe HI, as defined by the Child-Pugh and National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) classification systems, in comparison to subjects with normal hepatic function. Based on the Child-Pugh classification, subjects with moderate and severe HI had similar systemic exposure (area under the plasma concentration time curve from time 0 to infinity [AUC0-∞]) to pralsetinib, with AUC0-∞ geometric mean ratios (GMR) of 1.12 and 0.858, respectively, compared to subjects with normal hepatic function. Results based on the NCI-ODWG classification criteria were comparable; the AUC0-∞ GMR were 1.22 and 0.858, respectively, for subjects with moderate and severe HI per NCI-ODWG versus those with normal hepatic function. These results suggested that moderate and severe hepatic impairment did not have a meaningful impact on the exposure to pralsetinib, thus not warranting a dose adjustment in this population.

Effect of Mild and Moderate Hepatic Impairment (Defined by Child-Pugh Classification and National Cancer Institute Organ Dysfunction Working Group Criteria) on Pexidartinib Pharmacokinetics.

Pexidartinib is a novel oral small‐molecule tyrosine kinase inhibitor targeting the colony‐stimulating factor 1 receptor. Pexidartinib undergoes extensive hepatic metabolism via multiple cytochrome P450 and uridine 5'‐diphospho‐glucuronosyl transferase enzymes, with ZAAD‐1006a as the only major metabolite in human plasma. As pexidartinib is extensively metabolized, hepatic impairment (HI) could lead to increased exposure to pexidartinib. The objective of the two phase 1, open‐label studies was to determine the pharmacokinetics of pexidartinib after a single 200‐mg dose in subjects with mild and moderate HI, based on Child–Pugh classification (PL3397‐A‐U123: 8 mild HI and 8 moderate HI vs 16 matched healthy controls) and National Cancer Institute Organ Dysfunction Working Group (NCI‐ODWG) criteria (PL3397‐A‐U129: 8 moderate HI versus 8 matched healthy controls [NCT04223635]). Based on Child–Pugh classification, exposure to pexidartinib (maximum observed concentration [Cmax], area under the plasma concentration–time curve up to the last measurable concentration [AUClast], and extrapolated to infinity [AUCinf]) was similar in subjects with mild and moderate HI and in respective matched healthy controls, whereas ZAAD‐1006a exposure (AUC) was approximately 27% to 28% and 41% to 48% higher in mild and moderate HI, respectively. According to NCI‐ODWG criteria, total pexidartinib exposure was 42% to 46% higher in subjects with moderate HI, compared with healthy controls, and total ZAAD‐1006a exposure was 70% to 79% higher for subjects with moderate HI, compared with matched healthy controls with normal hepatic function. These findings were used to develop appropriate dose recommendations in patients with hepatic impairment.

Pharmacokinetics and safety of niraparib in patients with moderate hepatic impairment

PurposeThe purpose of this study is to characterize niraparib pharmacokinetics (PK) and safety in patients with normal hepatic function (NHF) versus moderate hepatic impairment (MHI).MethodsPatients with advanced solid tumors were stratified by NHF or MHI (National Cancer Institute-Organ Dysfunction Working Group criteria [bilirubin > 1.5–3 × upper limit of normal and any aspartate aminotransferase elevation]). In the PK phase, all patients received one 300 mg dose of niraparib. In the extension phase, patients with MHI received niraparib 200 mg daily; patients with NHF received 200 or 300 mg based on weight (< 77 kg, ≥ 77 kg)/platelets (< 150,000/µL, ≥ 150,000/µL). PK parameters included maximum concentration (Cmax), area under the curve to last measured concentration (AUClast) and extrapolated to infinity (AUCinf). Safety was assessed in both phases. Exposure–response (E–R) modeling was used to predict MHI effects on exposure and safety of niraparib doses ≤ 200 mg or 300/200 mg or 200/100 mg weight/platelet regimens.ResultsIn the PK phase (NHF, n = 9; MHI, n = 8), mean niraparib Cmax was 7% lower in patients with MHI versus NHF. Mean exposure (AUClast, AUCinf) was increased by 45% and 56%, respectively, in patients with MHI without impacting tolerability. In the extension phase (NHF, n = 8; MHI, n = 7), the overall safety profile was consistent with previous trials. In patients with MHI, E–R modeling predicted niraparib 200 mg reduced Grade ≥ 3 thrombocytopenia incidence, whereas a 200/100 mg regimen yielded exposures below efficacy-associated levels in 15% of patients.ConclusionThese findings support adjusting the 300 mg niraparib starting dose to 200 mg QD in patients with MHI.Trial registrationNCT03359850; registered December 2, 2017

Effect of Renal and/or Hepatic Impairment on the Pharmacokinetics and Safety of Inotuzumab Ozogamicin in Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia

▪Introduction: Inotuzumab ozogamicin (InO) is an antibody drug conjugate targeting CD22 antigen linked to N-acetyl-g-calicheamicin dimethyl hydrazide, a potent cytotoxic antibiotic that induces double strand DNA breaks. The pharmacokinetics of InO has been characterized in adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). The primary objective of this analysis was to assess the pharmacokinetics and safety of InO in patients with renal and/or hepatic impairment.Methods: The effects of renal and hepatic impairment on the pharmacokinetics of InO clearance (CL) were evaluated in adult patients with relapsed or refractory ALL (n=234) following administration of 1.2-1.8 mg/m2 fractionated over 2 or 3 doses given weekly. For assessment of renal function, patients were stratified into 5 subgroups using baseline creatinine clearance (BCrCL): normal (≥90 mL/min), mild (60-89 mL/min), moderate (30-59 mL/min), severe (15-29 mL/min), and end-stage renal disease (<15 mL/min).For assessment of hepatic impairment, patients were stratified into 5 subgoups per criteria from the National Cancer Institute (NCI) Organ Dysfunction Working Group (ODWG), which categorizes impairment based on baseline total bilirubin (TB) and aspartate aminotransferase (AST): normal (TB and AST ≤ upper limit of normal [ULN]), mild B1 (TB ≤ ULN and AST > ULN), mild B2 (TB >1-1.5 x ULN, any AST), moderate (TB >1.5-3 x ULN, any AST), and severe (TB >3 x ULN, any AST).Data from adult patients with relapsed or refractory ALL (n=161) who received InO at a starting fractionated dose of 1.8 mg/m2 were used to evaluate the safety of InO in patients with some degree of renal and/or hepatic dysfunction. For each of the renal function and NCI ODWG hepatic impairment subgroups, the percentage of patients exhibiting Grade ≥3 for any adverse events and Grade ≥3 hepatoxicity adverse event, respectively, was reported. Severity of hepatoxicity was determined through standardized search criteria with Standard Medical Dictionary for Regulatory Activities queries (cholestasis and jaundice of hepatic origin; hepatic failure, fibrosis and cirrhosis, and other liver damage-related conditions; hepatitis, noninfectious; and liver-related investigations, signs, and symptoms) and preferred terms (veno-occlusive liver disease or veno-occlusive disease; hepatic vein occlusion or thrombosis; portal vein thrombosis; Budd-Chiari syndrome; chronic graft versus host disease in liver; and acute graft versus host disease in liver).Results: For renal impairment, the median InO CL was 0.0394, 0.0403, 0.0308, and 0.0273 L/h, respectively, in individuals with normal (n=184), mild (n=32), moderate (n=17), and severe renal impairment (n=1). There were no patients with end-stage renal disease. Grade ≥3 adverse events were reported in 91.7% of patients with normal, 81.8% with mild, 100% with moderate, and 0% with severe or end-stage renal disease renal impairment.For hepatic impairment, the median InO clearance was 0.0363, 0.0520, 0.0382, and 0.0238 L/h, respectively, in individuals with normal (n=167), mild B1 (n=58), mild B2 (n=8), and moderate hepatic impairment (n=1). There were no patients with severe hepatic impairment. Hepatotoxicity Grade ≥3 adverse events were reported in 23.6% of patients with normal, 6.8% with mild B1, and 3.1% with mild B2 hepatic function; no such events occurred in patients with moderate or severe hepatic impairment.Conclusions: InO pharmacokinetics were not affected by renal or hepatic impairment status, and safety was similar regardless of renal and/or hepatic function. Therefore, no starting-dose adjustment is required for patients with relapsed or refractory ALL with pre-existing mild to severe renal dysfunction or mild hepatic impairment. DisclosuresGarrett:Pfizer: Employment. Kantarjian:Delta-Fly Pharma: Research Funding; Amgen: Research Funding; ARIAD: Research Funding; Bristol-Meyers Squibb: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. DeAngelo:Amgen: Consultancy, Research Funding; Celgene: Research Funding; BMS: Consultancy; Glycomimetics: Research Funding; Incyte: Consultancy, Honoraria; Blueprint Medicines: Honoraria, Research Funding; Takeda Pharmaceuticals U.S.A., Inc.: Honoraria; Shire: Honoraria; Pfizer Inc.: Consultancy, Honoraria, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding; Immunogen: Honoraria, Research Funding; ARIAD: Consultancy, Research Funding. Boni:ADC Therapeutics: Employment, Other: Potential equity interest.

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

PurposeThe 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.MethodsPatients 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.ResultsSixteen 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.ConclusionPatients 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.

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

Introduction: 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. Methods: 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. Results: 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 (n = 123), patients with mild impairment (n = 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 (n = 27) had a GMR of 0.88. Patients in Asia ([n = 162] vs. outside [n = 161]) had a GMR of 1.25 for cycle 1 atezolizumab AUC. Compared with GO30140 patients who had normal hepatic function (NCI-ODWG [n = 61]), patients with mild impairment (n = 92) had a GMR of 0.97 for cycle 1 peak bevacizumab concentrations; those with moderate impairment (n = 9) had a GMR of 0.94. Patients in Asia (n = 111) versus outside Asia (n = 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. Conclusions: 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.

131P - Cabozantinib in Asian patients with hepatocellular carcinoma and other solid tumours: Population pharmacokinetics analysis

BackgroundCabozantinib, an inhibitor of MET, AXL and VEGF receptors, was recently approved for the treatment of patients with advanced hepatocellular carcinoma (HCC) who had previously received sorafenib, based on findings of the CELESTIAL trial. We previously reported cabozantinib pharmacokinetics (PK) data based on 9 cabozantinib studies (N = 1534), Here, we report updated cabozantinib PK data in Asian and non-Asian ethnicities including patients with HCC. MethodsWe used data from ten cabozantinib studies that included healthy volunteers (HV) and patients with various cancer types (HCC, renal cell carcinoma, castration-resistant prostate cancer, medullary thyroid cancer [MTC], and glioblastoma multiforme). Studies pertinent to HCC were the CELESTIAL trial (NCT01908426) and the HCC cohort of a phase 2 trial (NCT00940225). The impact on PK parameters of selected covariates (age, weight, sex, race, cancer type, formulation, and liver dysfunction according to the National Cancer Institute Organ Dysfunction Working Group [NCI-ODWG]) was evaluated. Steady-state PK parameters were predicted for Asian and non-Asian patients. ResultsData from 2023 individuals were included (cancer patients, n = 1883; HV, n = 140), of whom 211 were of Asian ethnicity and 1812 of non-Asian ethnicity. MTC cancer type had the largest effect on cabozantinib PK parameters, with a 90% increase in apparent clearance (CL/F) relative to HV. Other cancer types, including HCC, and liver dysfunction per NCI-ODWG did not impact cabozantinib PK. However, because CELESTIAL excluded patients with Child-Pugh scores of B or C, results on patients with more compromised liver function are limited. A 24% decrease in CL/F was observed in females; Asian ethnicity, age, and weight had no clinically significant impact on cabozantinib clearance. ConclusionsMinimal cabozantinib PK and predicted exposure differences were observed across various cancer types except for MTC. The PK of cabozantinib was similar in individuals of Asian and non-Asian ethnicity. These findings are consistent with the major metabolic pathway of cabozantinib via cytochrome P450 3A4 which is not prone to genetic polymorphism. Editorial acknowledgementThe authors thank Isabelle Kaufmann, PhD of Oxford PharmaGenesis, Oxford, UK for providing medical writing support, which was sponsored by Ipsen, Abingdon, UK in accordance with Good Publication Practice guidelines. Legal entity responsible for the studyIpsen. FundingIpsen. DisclosureC-H. Hsu: Research grant/Funding (self): Ipsen; Honoraria (self): Ipsen. L. Nguyen: Full / Part-time employment: Exelixis. A-L. Cheng: Honoraria (self): Bayer; Honoraria (self): Eisai; Honoraria (self): Merck Sharp Dohme; Honoraria (self): Merck Serono; Honoraria (self): Novartis; Honoraria (self): Ono Pharmaceutical; Honoraria (self): Roche/Genentech; Honoraria (self): IQVIA. Advisory/Consultancy: Bayer Schering Pharma; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Eisai; Advisory/Consultancy: Merck Serono; Advisory/Consultancy: Novartis; Advisory/Consultancy: Ono Pharmaceutical; Advisory/Consultancy: Exelixis; Advisory/Consultancy: Nucleix Ltd.; Advisory/Consultancy: Roche/Genentech; Advisory/Consultancy: IQVIA. Speaker Bureau/Expert testimony: Bayer Yakuhin, Ltd.; Speaker Bureau/Expert testimony: Novartis; Speaker Bureau/Expert testimony: Eisai; Speaker Bureau/Expert testimony: Ono Pharmaceutical; Speaker Bureau/Expert testimony: Amgen Taiwan. Travel/Accommodation/Expenses: Bayer Yakuhin, Ltd.; Travel/Accommodation/Expenses: Novartis; Travel/Accommodation/Expenses: Eisai; Travel/Accommodation/Expenses: Ono Pharmaceutical; Travel/Accommodation/Expenses: Roche/Genentech; Travel/Accommodation/Expenses: IQVIA. T.X.Q. Nguyen: Full / Part-time employment: Ipsen. K. Brendel: Full / Part-time employment: Ipsen. V. Aslanis: Full / Part-time employment: Ipsen. F. Benzaghou: Full / Part-time employment: Ipsen.

Qualitative and quantitative variations in liver function thresholds among clinical trials in cancer: a need for harmonization.

The liver is critically involved in drug metabolism pathways and the potential for hepatic toxicity is significant with specific cancer therapeutics. Variations in the definition of liver function thresholds that may generate heterogeneity of toxicity and efficacy outcomes across therapeutics trials in cancer require assessment. A random sample of therapeutic trials in cancer (n = 500, general category), trials using hepatotoxic drugs (abiraterone, pazopanib: n = 181), trials using drugs metabolized by the liver (doxorubicin, vincristine: n = 606), and therapeutic trials in hepatic dysfunction (n = 49) were each identified on clinicaltrials.gov. Definitions of liver function thresholds and their distribution were collated and categorized in each group. A third of all trials listed on clinicaltrials.gov across the four categories failed to provide an explicit definition of liver function. Among trials with an explicit definition, a combination of bilirubin and transaminase levels was used in 33-64%, whereas a miscellaneous combination of definitions (in the general category consisting of 11 unique liver function parameters creating 17 unique combinations) was used 29-58% of the time across the four categories of studies. The Child-Pugh or National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria were rarely employed (0-12% studies). Allowance for Gilbert's disease in bilirubin thresholds was identified in only 6-23% studies and for liver metastases in 2-15% of studies. There is a marked heterogeneity in the liver function definitions used across cancer clinical trials even when the potential for drug toxicity and altered drug metabolism is significant. Harmonization of criteria will streamline eligibility and mitigate variations in key outcomes across trials.

Integrated population pharmacokinetic (PopPK) modeling of cabozantinib (C) in patients (pts) with various cancer types including hepatocellular carcinoma (HCC).

305 Background: C significantly improved overall survival vs placebo in pts with previously treated advanced HCC in the phase 3 CELESTIAL trial (NCT01908426). In a previous single dose PK study, increased C exposure was observed in healthy volunteers (HV) with mild or moderate hepatic impairment (Nguyen, J Clin Pharmacol, 2016). An integrated PopPK model was recently developed to characterize C concentration data from HV and pts with various cancers, including renal cell carcinoma, castration-resistant prostate cancer, and medullary thyroid cancer (MTC) (Lacy, Cancer Chemother Pharmacol, 2018). Here, we update the model to include data for pts with advanced HCC from CELESTIAL and a prior phase 2 trial. Methods: The updated PopPK model was developed using nonlinear mixed effects modeling methodology (NONMEM v7.3) and incorporated data from 10 clinical studies with 9510 measurable C concentrations from 2023 subjects, including 489 pts with advanced HCC. Eligible pts with HCC were Child-Pugh class A. Evaluated covariates included age, gender, race, body weight, cancer type, and liver dysfunction as defined by the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG). Results: Overall, 70% of pts had normal hepatic function by NCI-ODWG criteria; 28% had mild, 1% had moderate, and &lt;1% had severe hepatic dysfunction. A 2-compartment model with first-order elimination and dual first- and zero-order absorption processes adequately described the data. As in the previous model, the MTC population was the only cancer type to have a notable difference in C PK, with ~90% increase in apparent clearance (CL/F) versus HV and pts with other cancers including HCC. For a White male, CL/F was estimated as 2.48 L/hr and apparent volume of the central compartment (Vc/F) as 212 L. Inter-individual variability was ~46% for CL/F and ~67% for Vc/F. Other demographic covariates were predicted to have a small to moderate impact on C CL/F. Liver dysfunction, per NCI-ODWG criteria, had no discernable effect on C CL/F. Conclusions: C exposure at an equivalent daily dose is predicted to be similar in pts with several cancer types including advanced HCC with mild liver dysfunction.

Severe hepatic dysfunction is associated with venous thromboembolic events in phase 1 clinical trials

IntroductionVenous thromboembolic events (VTEs) are a significant cause of death in patients with cancer. The incidence of VTE is not well characterized in early phase clinical trials of novel antineoplastic agents, or in hepatic dysfunction studies designed for patients with varying degrees of liver test abnormalities. We compared the incidences of VTE in phase 1 clinical trials (P1CTs) and hepatic dysfunction trials (HDCTs) sponsored by the Cancer Therapy Evaluation Program of the National Cancer Institute (NCI) of the United States. Materials & methodsWe reviewed individual patient records of 1841 subjects for symptomatic VTE diagnosed while on study: 1328 subjects on 42 P1CTs, and 513 subjects on 9 HDCTs. The NCI's Organ Dysfunction Working Group definitions were used to categorize patients. The incidences of VTEs between patients were compared by the Chi square test. Confounders were evaluated with the Cochran–Mantel–Haenszel method. Results & conclusionsThere were 43 VTEs identified among all subjects (2.3%). There were significantly more VTE observed in the subjects on P1CTs (n=38, 2.9%) than in the subjects on HDCTs (n=5, 1.0%; RR 0.341, 95% 0.13–0.86, p=0.015). For patients on HDCTs, those with severe dysfunction had a high incidence of VTE (RR 10.5 (1.12–93.6), p=0.021) that remained significant in a multivariate model.VTEs were observed less frequently in patients who were enrolled in HDCT than those who were enrolled in P1CT; however, patients with severe hepatic dysfunction were more likely to experience VTE. Severe liver test abnormalities may not be protective against VTE in patients with malignancies receiving chemotherapy.

Clinical Safety and Efficacy Of Nilotinib Or Dasatinib In Patients (Pts) With Newly Diagnosed Chronic-Phase Chronic Myelogenous Leukemia (CML-CP) With Pre-Existing Liver and/Or Renal Dysfunction

IntroductionDasatinib and nilotinib have become standard frontline therapy for pts with CML-CP. Their clinical safety and efficacy in the setting of pre-existing liver and/or renal dysfunction has not been described. Methods215 CP-CML pts treated with nilotinib or dasatinib as a frontline therapy in clinical trials at our institution between 5/05 and 10/12 were analyzed. Renal and liver functions were classified according to the National Cancer Institute Organ Dysfunction Working Group. Normal renal function was defined as creatinine clearance (CrCl) ≥ 60 ml/min; mild as CrCl 40-59 ml/min; moderate as CrCl 20-39 ml/min; and severe as CrCl ≤ 20 ml/min. Normal liver function was defined as total bilirubin (TB) levels ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) ≤ ULN; mild as TB ≤ 1.5 x ULN and AST > ULN; moderate as TB 1.5 to 3.0 x ULN and AST of any value; and severe as TB > 3.0 x ULN and AST of any value. Starting doses were nilotinib 400 mg twice daily and dasatinib 100 mg daily. Survival was dated from the start of nilotinib or dasatinib until death from any cause. Event free survival (EFS) was calculated from the start of nilotinib or dasatinib to loss of complete hematologic response, loss of major cytogenetic response, transformation to accelerated or blast phase, or death from any cause. ResultsThe results of patient characteristics, EFS and OS are summarized in Table 1 and Figure 1. The median age for all pts was 48.8 yrs (range, 16.2 to 86.4) and the median follow-up was 48 months (2 to 93). Of the 107 pts treated with dasatinib, 6 pts (6%) had mild renal dysfunction and 13 pts (12%) mild liver dysfunction. Of 108 pts treated with nilotinib, 8 pts had mild renal dysfunction, 1 pt moderate renal dysfunction and 9 pts mild liver dysfunction. Of 89 pts with normal organ function treated with dasatinib, the Sokal risk score was low in 73% for those with normal organ function, intermediate in 22%, and high in 4%. For the 18 pts with liver or renal dysfunction treated with dasatinib, low in 77%, intermediate in 17% and high in 6%. Of 91 pts with normal organ function treated with nilotinib, low in 71%, intermediate in 20%, and high in 9%. Of 17 pts with liver or renal dysfunction, low in 76%, intermediate in 24% and high in 0%. A complete cytogenetic response (CCyR) was achieved in 167 pts (93%) with normal organ function compared to 32 pts (91%) in pts with renal or liver organ dysfunction. Corresponding rates for major molecular response (MMR) were 160 pts (89%) and 31 pts (89%), respectively, and for complete molecular response (CMR) 89 pts (49%) and 12 pts (34%), respectively. The rate of CCyR at 12 months was 143 pts (79%) for those with normal organ function and 28 pts (80%) for those with organ dysfunction. There were no significant differences by treatment arm or between renal and liver dysfunction. Treatment was overall well tolerated in all patients with no significant difference in adverse events, except for a trend for more grade 3/4 pleural effusion in pts with renal dysfunction treated with dasatinib (2/6), and grade 3/4 bleeding in pts with renal dysfunction treated with nilotinib (2/9). Overall, 38 pts (21%) in the normal organ function group and 10 pts(29%) in the organ dysfunction group have discontinued therapy, including 16 pts (9%) and 5 pts (14%) respectively for intolerance. Overall survival in renal dysfunction was significantly worse compared to normal organ function (p= 0.034).Table 1Dasatinib (n=107)Nilotinib (n=108)Overall Response, (%)NormalRenal or LiverNormalRenal or LiverCMR51444824MMR85949282CCyR9210093823-yr EFS, (%)9410093943-yr OS, (%)10010099100 [Display omitted] [Display omitted] ConclusionPts with mild to moderate renal or liver dysfunction can be safely treated with dasatinib or nilotinib as initial therapy for CML-CP and can achieve similar rates of response as their counterparts with normal organ function at the start of therapy. Disclosures:Jabbour:BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Ariad: Consultancy.

Phase I Study of Pazopanib in Patients with Advanced Solid Tumors and Hepatic Dysfunction: A National Cancer Institute Organ Dysfunction Working Group Study

Pazopanib is a potent, multitargeted receptor tyrosine kinase inhibitor; however, there is limited information regarding the effects of liver function on pazopanib metabolism and pharmacokinetics. The objective of this study was to establish the maximum-tolerated dose (MTD) and pharmacokinetic profile of pazopanib in patients with varying degrees of hepatic dysfunction. Patients with any solid tumors or lymphoma were stratified into four groups based on the degree of hepatic dysfunction according to the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria. Pazopanib was given orally once a day on a 21-day cycle. A modified 3+3 design was used. Ninety-eight patients were enrolled. Patients in the mild group tolerated 800 mg per day. The moderate and severe groups tolerated 200 mg per day. Pharmacokinetic data in the mild group were similar to the data in the normal group. Comparison of the median Cmax and area under the curve [AUC(0-24)] in the moderate or severe groups at 200 mg per day to the values in the normal and mild groups at 800 mg per day indicated less than dose-proportional systemic exposures in patients with moderate and severe hepatic impairment. This suggests that the lower maximum-tolerated dose in the moderate and severe group is not due to a decrease in drug clearance or alteration in the proportion of metabolites. In patients with mild liver dysfunction, pazopanib is well tolerated at the Food and Drug Administration (FDA)-approved dose of 800 mg per day. Patients with moderate and severe liver dysfunction tolerated 200 mg per day.

A correlative analysis of biochemical and radiologic hepatic disease in metastatic pancreatic adenocarcinoma (PA).

e15163 Background: The liver is the most common site of distant metastases (mets) in patients with PA. We aimed to study radiomorphology of PA-related liver mets and its correlation with the degree of biochemical hepatic dysfunction. The impact of liver failure on patient mortality was also assessed. Methods: Using National Cancer Institute-Organ Dysfunction Working Group guidelines, patients were stratified into 4 groups A (Normal), B (Mild), C (Moderate), D (severe) based on serum bilirubin and aspartate transaminase levels. Two sets of results were recorded for each patient - at diagnosis (baseline) and the the last available prior to death. CT scan at diagnosis were used to measure both the number and diameter of two largest lesions for each patients’ liver mets. Results: 58 patients with metastatic PA were identified. 5 of these patients were excluded from this study as their imaging was not available. 34 (59%) had hepatic mets. Of 34 patients, 47.1% (n=16) had diffuse mets. 23.5% (n=8) had 6-10 liver mets. 20.6% (n=7) had 2-5 liver mets. 8.8% (n=3) had a solitary metastasis. Four of these patients were excluded as they were still alive at the time of the biochemical analysis. Of 31 patients at baseline: 25.8% (n=8), 35.5% (n=7), 22.6% (n=7), 16.1% (n=5) of patients had group A, B, C and D hepatic dysfunction respectively. The median time between last liver function testing and death was 10 days (range 0-114 days). Prior to death, 16.1% (n=5), 35.5% (n=11), 6.5% (n=2), 41.9% (n=13) of patients had group A, B, C and D dysfunction respectively. Of the 13 patients with severe hepatic dysfunction prior to death, 7 had no radiographic evidence of extrinsic obstruction. No difference in number of liver mets were seen between groups A and B when compared to C and D. However, groups C+D had higher mean size, 2.8 x 2.3 vs. 2.4 x 1.8 cm (p=0.047). No survival difference was noted (4.6 vs 2.5 months, p=0.425). Conclusions: The majority of patients had diffuse liver mets at diagnosis. There was no significant correlation between the radiological burden of hepatic disease and the degree of hepatic impairment at diagnosis. PA-related liver mets was the likeliest cause of death in up to 22.6% of patients.

Phase I Study of Pazopanib in Patients with Advanced Solid Tumors and Hepatic Dysfunction: A National Cancer Institute Organ Dysfunction Working Group Study

Phase I Study of Pazopanib in Patients with Advanced Solid Tumors and Hepatic Dysfunction: A National Cancer Institute Organ Dysfunction Working Group Study

Pharmacokinetics and Safety of Bortezomib in Patients with Advanced Malignancies and Varying Degrees of Liver Dysfunction: Phase I NCI Organ Dysfunction Working Group Study NCI-6432

The proteasome inhibitor bortezomib undergoes oxidative hepatic metabolism. This study (NCI-6432; NCT00091117) was conducted to evaluate bortezomib pharmacokinetics and safety in patients with varying degrees of hepatic impairment, to inform dosing recommendations in these special populations. Patients received bortezomib on days 1, 4, 8, and 11 of 21-day cycles. Patients were assigned to four hepatic function groups based on the National Cancer Institute Organ Dysfunction Working Group classification. Those with normal function received bortezomib at the 1.3 mg/m(2) standard dose. Patients with severe, moderate, and mild impairment received escalating doses from 0.5, 0.7, and 1.0 mg/m(2), respectively, up to a 1.3 mg/m(2) maximum. Serial blood samples were collected for 24 hours postdose on days 1 and 8, cycle 1, for bortezomib plasma concentration measurements. Sixty-one patients were treated, including 14 with normal hepatic function and 17, 12, and 18 with mild, moderate, and severe impairment, respectively. Mild hepatic impairment did not alter dose-normalized bortezomib exposure (AUC(0-tlast)) or C(max) compared with patients with normal function. Mean dose-normalized AUC(0-tlast) was increased by approximately 60% on day 8 in patients with moderate or severe impairment. Patients with mild hepatic impairment do not require a starting dose adjustment of bortezomib. Patients with moderate or severe hepatic impairment should be started at a reduced dose of 0.7 mg/m(2).

Dose-escalating and pharmacological study of bortezomib in adult cancer patients with impaired renal function: a National Cancer Institute Organ Dysfunction Working Group Study

To determine the toxicities, pharmacokinetics, pharmacodynamics, and maximum tolerated dose of bortezomib in patients with renal impairment and to develop dosing guidelines for such a patient population. Sixty-two adult cancer patients received intravenous bortezomib at 0.7-1.5 mg/m(2) on days 1, 4, 8, and 11 every 3 weeks. Patients were stratified by 24-h creatinine clearance (CrCl) normalized to body surface area (BSA) 1.73 m(2) into five cohorts: normal renal function (≥ 60 ml/min/1.73 m(2)); mild dysfunction (40-59 ml/min/1.73 m(2)); moderate dysfunction (20-39 ml/min/1.73 m(2)); severe dysfunction (<20 ml/min/1.73 m(2)); and dialysis. Dose escalation was planned for the four cohorts with renal dysfunction. Plasma bortezomib concentrations and blood 20S proteasome inhibition were assayed. Bortezomib escalation to the standard 1.3 mg/m(2) dose was well tolerated in all patients with CrCl ≥ 20 ml/min/1.73 m(2); 0.7 mg/m(2) was tolerated in three patients with severe renal dysfunction (<20 ml/min/1.73 m(2)). Bortezomib dose escalation was well tolerated in nine dialysis patients, including to 1.3 mg/m(2) in four patients. Decreased CrCl did not affect bortezomib pharmacokinetics or pharmacodynamics. Bortezomib-related side-effects were neither more common nor severe in patients with renal dysfunction versus those with normal renal function. Bortezomib 1.3 mg/m(2) is well tolerated, and dose reductions are not necessary in patients with renal dysfunction. Extrapolation from clinical and pharmacologic data suggests patients with severe renal dysfunction, including dialysis patients, can receive bortezomib at the full dose established to be clinically effective in the general patient population.

Pharmacokinetics and Safety of Bortezomib In Patients with Advanced Malignancies and Varying Degrees of Liver Dysfunction: Results of the Phase 1 National Cancer Institute Organ Dysfunction Working Group Study NCI 6432

AbstractAbstract 3975Background: Bortezomib (btz, VELCADE®) is approved in the US for the treatment of patients (pts) with multiple myeloma, and for the treatment of pts with mantle cell lymphoma who have received at least one prior therapy. Btz is oxidatively metabolized by hepatic cytochrome P450 enzymes to pharmacologically inactive deboronated metabolites. Thus, btz pharmacokinetics (PK) may be altered in pts with hepatic impairment (HI). This phase 1 study was undertaken to evaluate the PK and safety of btz in pts with varying grades of HI and to inform dosing recommendations in these subpopulations. Here we present the available interim results. Methods: Pts with advanced malignancies were assigned to four groups based on hepatic function (bilirubin and aspartate aminotransferase [AST] levels relative to the upper limit of normal [ULN]) using the classification developed for organ dysfunction studies by the National Cancer Institute's Cancer Therapy Evaluation Program. Normal function was defined as bilirubin and AST ≤ULN. Pts with mild HI had bilirubin ≤ULN and AST >ULN, or bilirubin >1.0–1.5 × ULN (with any AST). Moderate and severe HI were defined as bilirubin >1.5–3 × ULN and >3 × ULN, respectively, with any AST. Pts received btz on days 1, 4, 8, and 11 of 21-day cycles. Pts with normal hepatic function received btz at the standard dose of 1.3 mg/m2. Pts with severe, moderate, and mild HI received escalating doses of btz from starting doses of 0.5, 0.7, and 1.0 mg/m2, respectively, via a standard 3+3 design to 1.3 mg/m2. Serial blood samples were collected for 24 hours post-dose on days 1 and 8 of cycle 1 for measurement of btz plasma concentrations. Individual values of dose-normalized (DN) area under the concentration–time curve from time zero to the point of last quantifiable concentration (AUC) and maximum concentration (Cmax) were calculated by noncompartmental analysis. PK parameters were summarized by hepatic function and subject to an analysis of variance to estimate the ratio of geometric means and 90% confidence intervals (CIs) for each HI group relative to the control group. Results: A total of 53 pts were treated, 14 with normal hepatic function, and 16, 9, and 14 with mild, moderate, and severe HI, respectively. Median age was 62 years (range 30–85), 53% were female, 94% were white, and 11/58/30% had ECOG performance status 0/1/2. Dose escalation proceeded to 1.3 mg/m2 in pts with mild HI; data collection is ongoing at 1.0 mg/m2 in pts with moderate and severe HI. The most common adverse events (AEs) were fatigue (53%), nausea (42%), and dyspnea (32%). For most AEs, no association was apparent between increased incidence and poorer hepatic function; the incidence of elevated AST was 7, 25, 33, and 36% in the normal group and mild, moderate, and severe HI groups, respectively. PK data were available for 51 pts. Geometric mean DN AUC was 30.2, 23.0, 50.3, and 47.7 (ng.hr/mL)/(mg/m2) on day 1 and 52.2, 51.9, 83.4, and 80.3 (ng.hr/mL)/(mg/m2) on day 8 in pts with normal hepatic function and mild, moderate, and severe HI, respectively. Respective values for geometric mean DN Cmax were 56.7, 38.2, 66.0, and 84.2 (ng/mL)/(mg/m2) on day 1, and 88.9, 79.6, 59.2, and 96.1 (ng/mL)/(mg/m2) on day 8. Geometric least square mean ratios for DN AUC and DN Cmax between groups are shown in the table. Compared to pts with normal hepatic function, mild HI did not alter DN AUC and DN Cmax. However, mean DN AUC was increased by approximately 60% in pts with moderate or severe HI. Conclusions: Pts with mild HI do not require a starting dose adjustment and should be treated per the recommended dose of btz. Pts with moderate or severe HI should be started at a reduced dose of 0.7 mg/m2 during the first cycle, and a subsequent dose escalation to 1.0 mg/m2 or further dose reduction to 0.5 mg/m2 may be considered based on pt tolerance. These data have resulted in an update to the US Prescribing Information for VELCADE®.Comparison vs normalGeometric least square mean ratio (90% CI)Day 1Day 8DN AUCMild HI0.833 (0.603–1.151)0.954 (0.664–1.371)Moderate HI1.662 (1.136–2.430)1.538 (0.969–2.440)Severe HI1.578 (1.139–2.186)1.477 (1.046–2.085)Average of moderate/severe HI1.619 (1.199–2.186)1.507 (1.075–2.113)DN CmaxMild HI0.697 (0.446–1.090)0.879 (0.528–1.463)Moderate HI1.162 (0.688–1.962)0.612 (0.318–1.178)Severe HI1.483 (0.947–2.323)1.023 (0.633–1.653)Average of moderate/severe HI1.313 (0.868–1.986)0.791 (0.493–1.271) Disclosures:Venkatakrishnan:Millennium Pharmaceuticals: Employment. Off Label Use: Discussion of Velcade in patients with advanced non-hematologic malignancies is included. Takimoto:Johnson & Johnson: Employment, Equity Ownership. Neuwirth:Millennium Pharmaceuticals, Inc.: Employment. Parasuraman:Millennium Pharmaceuticals: Employment, Equity Ownership. LoRusso:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding.

A phase I study of S-1 treatment with a 3 week schedule in advanced biliary cancer patients with or without hepatic dysfunction

A 3 week treatment schedule consisting of 2 weeks of S-1 therapy and 1 week of no therapy was introduced to reduce the toxicity and increase the convenience of combination chemotherapy. Hepatic dysfunction (HD) is common in patients with biliary tract cancer. A phase I study was conducted to assess the effects of a 3 week treatment schedule in Asian patients with or without HD. Forty-six patients were stratified into four groups, according to the HD criteria of the National Cancer Institute Organ Dysfunction Working Group. A three dose escalation schema was used. In the normal hepatic function group, two dose-limiting toxicity (DLT) events occurred among 12 patients at the prespecified maximal dose of 100 mg/m²/day. This dose was thereby established as the maximal tolerable dose (MTD). No DLT events were observed at the predefined maximal dose of 80 mg/m²/day in the mild HD group. In the moderate HD group, two DLT events occurred among five patients treated with 80 mg/m²/day, and the MTD was defined as 70 mg/m²/day. Two of six subjects in the severe HD group experienced DLT events at doses of 60 mg/m²/day and none developed DLT events at 50 mg/m²/day. The MTDs for a 3 week schedule of S-1 treatment were defined in patients with or without hepatic dysfunction. A 3 week treatment regimen of S-1 might be a platform for combination with newer cytotoxic agents or biologics.

Phase I and Pharmacokinetic Study of Imatinib Mesylate in Patients With Advanced Malignancies and Varying Degrees of Liver Dysfunction: A Study by the National Cancer Institute Organ Dysfunction Working Group

To develop dosing guidelines and to evaluate the pharmacokinetics of imatinib in patients with liver dysfunction (LD). Patients (N = 89) with varying solid tumors and liver function were stratified into four groups according to serum total bilirubin and AST and were treated with escalating doses of imatinib. Plasma and urine were assayed for concentrations of imatinib and its active metabolite, CGP74588. In the mild LD group, dose-limiting toxicity, specifically nausea/vomiting and fatigue, occurred in two patients at the 600 mg/d dose level. In the moderate and severe LD groups, the maximal dose evaluated was 300 mg/d. Grade 3 to 4 toxicities consisted primarily of liver function test elevations (24%), nausea/vomiting (10%), fatigue (6%), and edema (5%). After the first imatinib dose, the mean (+/- SD) dose-normalized areas under the plasma concentration-time curve from time 0 to infinity (AUC(0-infinity)) were 162 +/- 155, 171 +/- 72, 182 +/- 157, and 185 +/- 172 (mug/mL x h)/mg for normal, mild, moderate, and severe LD groups, respectively. Renal excretion of imatinib was less than 10% of the total dose in all groups. Imatinib exposure (as measured by the dose-normalized AUC) did not differ between patients with normal liver function and those with LD. The maximal recommended dose of imatinib for patients with mild LD is 500 mg/d. Dosing guidelines for patients with moderate and severe LD remain undetermined.

Phase I and Pharmacokinetic Study of Imatinib Mesylate in Patients With Advanced Malignancies and Varying Degrees of Renal Dysfunction: A Study by the National Cancer Institute Organ Dysfunction Working Group

This study was undertaken to determine the safety, dose-limiting toxicities (DLT), maximum-tolerated dose (MTD), and pharmacokinetics of imatinib in cancer patients with renal impairment and to develop dosing guidelines for imatinib in such patients. Sixty adult patients with advanced solid tumors and varying renal function (normal, creatinine clearance [CrCL] >or= 60 mL/min; mild dysfunction, CrCL 40 to 59 mL/min; moderate dysfunction, CrCL 20 to 39 mL/min; and severe dysfunction, CrCL < 20 mL/min) received daily imatinib doses of 100 to 800 mg. Treatment cycles were 28 days long. The MTD was not reached for any group. DLTs occurred in two mild group patients (600 and 800 mg) and two moderate group patients (200 and 600 mg). Serious adverse events (SAEs) were more common in the renal dysfunction groups than in the normal group (P = .0096). There was no correlation between dose and SAEs in any group. No responses were observed. Several patients had prolonged stable disease. Imatinib exposure, expressed as dose-normalized imatinib area under the curve, was significantly greater in the mild and moderate groups than in the normal group. There was a positive correlation between serum alpha-1 acid glycoprotein (AGP) concentration and plasma imatinib, and an inverse correlation between plasma AGP concentration and imatinib clearance. Urinary excretion accounted for 3% to 5% of the daily imatinib dose. Daily imatinib doses up to 800 or 600 mg were well tolerated by patients with mild and moderate renal dysfunction, respectively, despite their having increased imatinib exposure.