BackgroundLymphocyte-activation gene 3 (LAG-3) is an inhibitory immunoreceptor that negatively regulates T-cell activation. This paper presents preclinical characterization of the LAG-3 inhibitor, ...ieramilimab (LAG525), and phase I data for the treatment of patients with advanced/metastatic solid tumors with ieramilimab ±the anti-programmed cell death-1 antibody, spartalizumab.MethodsEligible patients had advanced/metastatic solid tumors and progressed after, or were unsuitable for, standard-of-care therapy, including checkpoint inhibitors in some cases. Patients received ieramilimab ±spartalizumab across various dose-escalation schedules. The primary objective was to assess the maximum tolerated dose (MTD) or recommended phase II dose (RP2D).ResultsIn total, 255 patients were allocated to single-agent ieramilimab (n=134) and combination (n=121) treatment arms. The majority (98%) had received prior antineoplastic therapy (median, 3). Four patients experienced dose-limiting toxicities in each treatment arm across various dosing cohorts. No MTD was reached. The RP2D on a 3-week schedule was declared as 400 mg ieramilimab plus 300 mg spartalizumab and, on a 4-week schedule (once every 4 weeks; Q4W), as 800 mg ieramilimab plus 400 mg spartalizumab; tumor target (LAG-3) suppression with 600 mg ieramilimab Q4W was predicted to be similar to the Q4W, RP2D schedule. Treatment-related adverse events (TRAEs) occurred in 75 (56%) and 84 (69%) patients in the single-agent and combination arms, respectively. Most common TRAEs were fatigue, gastrointestinal, and skin disorders, and were of mild severity; seven patients experienced at least one treatment-related serious adverse event in the single-agent (5%) and combination group (5.8%). Antitumor activity was observed in the combination arm, with 3 (2%) complete responses and 10 (8%) partial responses in a mixed population of tumor types. In the combination arm, eight patients (6.6%) experienced stable disease for 6 months or longer versus six patients (4.5%) in the single-agent arm. Responding patients trended towards having higher levels of immune gene expression, including CD8 and LAG3, in tumor tissue at baseline.ConclusionsIeramilimab was well tolerated as monotherapy and in combination with spartalizumab. The toxicity profile of ieramilimab in combination with spartalizumab was comparable to that of spartalizumab alone. Modest antitumor activity was seen with combination treatment.Trial registration numberNCT02460224.
•The NCCN recommends first-line re-challenge for relapsed SCLC with CTFI ≥ 180 days.•This recommendation is based on data from small trials from the 1980s.•Lurbinectedin has remarkable activity and ...acceptable safety in second-line SCLC.•ORR was 60.0 % in a preplanned subset of patients with CTFI ≥ 180 days.•Lurbinectedin can be a valuable alternative to re-treatment with first-line therapy.
The National Comprehensive Cancer Network guidelines recommend re-challenge with the first-line treatment for relapsed small cell lung cancer (SCLC) with chemotherapy-free interval (CTFI)≥180 days. A phase II study (NCT02454972) showed remarkable antitumor activity in SCLC patients treated with lurbinectedin 3.2 mg/m2 1 -h intravenous infusion every 3 weeks as second-line therapy. We report results for the pre-planned subset of patients with CTFI ≥ 180 days.
Twenty patients aged ≥18 years with pathologically proven SCLC diagnosis, pretreated with only one prior platinum-containing line, no CNS metastases, and with CTFI ≥ 180 days were evaluated. The primary efficacy endpoint was the overall response rate (ORR) assessed by the Investigators according to RECIST v1.1.
ORR was 60.0 % (95 %CI, 36.1−86.9), with a median duration of response of 5.5 months (95 %CI, 2.9−11.2) and disease control rate of 95.0 % (95 %CI, 75.1−99.9). Median progression-free survival was 4.6 months (95 %CI, 2.6−7.3). With a censoring of 55.0 %, the median overall survival was 16.2 months (95 %CI, 9.6-upper level not reached). Of note, 60.9 % and 27.1 % of patients were alive at 1 and 2 years, respectively. The most common grade 3/4 adverse events and laboratory abnormalities were hematological disorders (neutropenia, 55.0 %; anemia; 10.0 % thrombocytopenia, 10.0 %), fatigue (10.0 %) and increased liver function tests (GGT, 10 %; ALT and AP, 5.0 % each). No febrile neutropenia was reported.
Lurbinectedin is an effective treatment for platinum-sensitive relapsed SCLC, especially in patients with CTFI ≥ 180 days, with acceptable safety and tolerability. These encouraging results suggest that lurbinectedin can be another valuable therapeutic option rather than platinum re-challenge.
Purpose
To evaluate the effect of renal impairment on eribulin mesylate pharmacokinetics following a single dose in adults with advanced solid tumors.
Methods
Patients were grouped by renal function: ...moderate impairment (creatinine clearance CrCl 30–50 mL/min), severe impairment (CrCl 15–29 mL/min), or normal (CrCl ≥80 mL/min). During each 21-day cycle, eribulin mesylate doses (days 1 and 8) were administered intravenously: moderate, 1.1 mg/m
2
(except cycle 1 day 1, 1.4 mg/m
2
); severe, 0.7 mg/m
2
; normal, 1.4 mg/m
2
.
Results
Nineteen patients were enrolled (normal,
n
= 6; moderate,
n
= 7; severe,
n
= 6). Renal impairment was associated with an increased mean dose-normalized area under the concentration–time curve (ratios for moderate/normal and severe/normal: 1.49; 90 % confidence interval CI 0.9, 2.45). CrCl and renal function correlated positively, with a numerically small slope (0.0184; 90 % CI −0.00254, 0.0394). A simulated dose reduction to eribulin 1.1 mg/m
2
in patients with moderate or severe renal impairment achieved the same exposure as 1.4 mg/m
2
in those with normal renal function. All groups had similar toxicity profiles, with no unexpected adverse events.
Conclusions
Renal impairment decreased eribulin clearance and increased exposure. Pharmacokinetic evaluation supports an eribulin dose reduction to 1.1 mg/m
2
in patients with moderate or severe renal impairment.
ClinicalTrials.gov Identifier
NCT01418677.
Summary
Aim
Two studies investigated the effect of gastric acid reducing agents and strong inducers/inhibitors of CYP3A4 on the pharmacokinetics of alisertib, an investigational Aurora A kinase ...inhibitor, in patients with advanced malignancies.
Methods
In Study 1, patients received single doses of alisertib (50 mg) in the presence and absence of either esomeprazole (40 mg once daily QD) or rifampin (600 mg QD). In Study 2, patients received single doses of alisertib (30 mg) in the presence and absence of itraconazole (200 mg QD). Blood samples for alisertib and 2 major metabolites were collected up to 72 h (Study 1) and 96 h (Study 2) postdose. Area under the curve from time zero extrapolated to infinity (AUC
0-inf
) and maximum concentrations (C
max
) were calculated and compared using analysis of variance to estimate least squares (LS) mean ratios and 90% confidence intervals (CIs).
Results
The LS mean ratios (90% CIs) for alisertib AUC
0-inf
and C
max
in the presence compared to the absence of esomeprazole were 1.28 (1.07, 1.53) and 1.14 (0.97, 1.35), respectively. The LS mean ratios (90% CIs) for alisertib AUC
0-inf
and C
max
in the presence compared to the absence of rifampin were 0.53 (0.41, 0.70) and 1.03 (0.84, 1.26), respectively. The LS mean ratios (90% CIs) for alisertib AUC
0-inf
and C
max
in the presence compared to the absence of itraconazole were 1.39 (0.99, 1.95) and 0.98 (0.82, 1.19), respectively.
Conclusions
The use of gastric acid reducing agents, strong CYP3A inhibitors or strong metabolic enzyme inducers should be avoided in patients receiving alisertib.
Introduction: The PK profile of carfilzomib is well characterized in patients with multiple myeloma. However, during clinical development of carfilzomib, patients with moderate to severe hepatic ...impairment (HI) were excluded from initial clinical studies. To support carfilzomib dose recommendations for patients with baseline HI, this study evaluated PK and safety of carfilzomib in patients with varying degrees of HI and relapsed or progressive advanced malignancies.
Methods: This open-label, single-arm, phase 1 study evaluated adult patients with normal (Norm) hepatic function or, mild, moderate (Mod), severe HI receiving carfilzomib infusion on days (D) 1-2, 8-9, 15 and 16 in 28-D cycles (C). Dose was escalated from 20 mg/m2 on C1 D1-D2 to 27 mg/m2 on D8 of C1 and if tolerated, further to 56 mg/m2 on D1 of C2. Norm hepatic function defined as bilirubin and aspartate aminotransferase (AST) levels </=upper limit of normal (ULN). HI defined as mild: bilirubin >1-1.5 x ULN, or AST >ULN but with bilirubin </=ULN; Mod: bilirubin >1.5-3 x ULN with any AST; or severe: bilirubin >3 x ULN and any AST. The primary objective was to assess the effect of HI on area under the curve (AUC) from time 0 to the last concentration measured (AUC0-last) and from time 0 extrapolated to infinity (AUC0-inf) of carfilzomib. Secondary objectives included evaluation of carfilzomib maximum plasma concentration (Cmax), time to maximum concentration (Tmax), clearance (CL), terminal half-life (T1/2), volume of distribution at steady state (Vss), mean residence time (MRT), and safety and tolerability, as well as PK parameters for carfilzomib’s major metabolites. Plasma for analysis of PK parameters were collected on C1D16 for carfilzomib 27 mg/m2 and on C2D1 for the 56 mg/m2 dose. PK parameters were evaluated using a non-compartmental approach. The carfilzomib PK in HI patients was compared with Norm patients using summary statistics and analysis of variance. Due to enrollment challenges and lack of demonstrable efficacy with carfilzomib monotherapy, enrollment of severe HI patient (mostly advanced solid tumors) was discontinued.
Results: 11 Norm, 17 Mild, 14 Mod, and 4 severe patients were enrolled; 61% male, mean age 62 years. Of these patients, 10 Norm, 14 Mild, 9 Mod, and 0 severe HI patients were PK evaluable. Following carfilzomib 27 and 56 mg/m2, considerable PK variability was seen within each of the treatment groups, with an overlapping exposure observed between groups (Table 1). Median Tmax ranged from 0.29 to 0.48 hour with peak concentrations of carfilzomib most often observed at 15 minutes after start or immediately before the end of infusion. Thereafter, concentrations of carfilzomib declined rapidly with a mean T1/2 of approximately 0.5 to 0.7 hour in all patient groups. A dose-dependent increase in mean AUC and Cmax of carfilzomib was observed between 27 mg/m2 and 56 mg/m2 in all 3 patient groups (Table 1); however, there was no consistent trend of increasing exposure (AUC0-last, AUC0-inf, and Cmax) with increasing severity of HI (Table 1 and 2). The mean AUC of the most abundant metabolite, PR-389/M14 was similar across all groups. A mean increase of approximately 60%-80% was observed for M15 and M16 AUC0-last, AUC0-inf and Cmax in patients with Mod HI vs Norm patients. These metabolites have no known biological activity. Median duration of exposure was 6 (Norm), 4.3 (Mild), 2.3 (Mod), and 0.8 (severe) wks. Thirty-five (76%) patients had grade >/=3 adverse events (AEs) including 15 patients with treatment-related grade >/=3 AEs. Grade >/=3 increased blood bilirubin (22%; Mod HI patients only), anemia (15%), fatigue (15%), and increased alanine aminotransferase (9%; Mod HI patients only) occurred in >3 patients.
Conclusions: No marked differences in exposures (AUC and Cmax) were observed between Norm patients and mild/Mod HI patients following carfilzomib doses of 27 and 56 mg/m2.No consistent trend in carfilzomib exposure related to HI severity was seen. With the exception of the increased frequency of AEs consistent with hepatic function abnormalities, the observed AE profile in this study was consistent with the known safety profile of carfilzomib. HI did not appear to substantially increase severity of AEs; however, the number of patients was limited. Based on the results in this study, no carfilzomib dose adjustment appears to be warranted in patients with relapsed or progressive advanced malignancies and mild or Mod HI.
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Anthony:Spectrum Pharmaceuticals: Speakers Bureau; Paradigm Diagnostics: Consultancy. De Vos:European Organization for Research and Treatment of Cancer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Dutch Working Group Neuro-Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; University Medical Center Utrecht: Employment. White:Amgen: Employment. Schupp:Amgen Inc.: Employment, Equity Ownership. Ou:Amgen: Employment, Equity Ownership.
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).
BNC105P inhibits tubulin polymerization, and preclinical studies suggest possible synergy with everolimus. In this phase I/II study, efficacy and safety of the combination were explored in patients ...with metastatic renal cell carcinoma (mRCC).
A phase I study in patients with clear cell mRCC and any prior number of therapies was conducted using a classical 3 + 3 design to evaluate standard doses of everolimus with increasing doses of BNC105P. At the recommended phase II dose (RP2D), patients with clear cell mRCC and one to two prior therapies (including ≥ 1 VEGF-TKI) were randomized to BNC105P with everolimus (arm A) or everolimus alone (arm B). The primary endpoint of the study was 6-month progression-free survival (6MPFS). Secondary endpoints included response rate, PFS, overall survival, and exploratory biomarker analyses.
In the phase I study (N = 15), a dose of BNC105P at 16 mg/m(2) with everolimus at 10 mg daily was identified as the RP2D. In the phase II study, 139 patients were randomized, with 69 and 67 evaluable patients in arms A and B, respectively. 6MPFS was similar in the treatment arms (arm A: 33.82% vs. arm B: 30.30%, P = 0.66) and no difference in median PFS was observed (arm A: 4.7 mos vs. arm B: 4.1 mos; P = 0.49). Changes in matrix metalloproteinase-9, stem cell factor, sex hormone-binding globulin, and serum amyloid A protein were associated with clinical outcome with BNC105P.
Although the primary endpoint was not met in an unselected population, correlative studies suggest several biomarkers that warrant further prospective evaluation.
Aims
We evaluated the potential effect of sonidegib at an oral dose of 800 mg once daily (QD) on the pharmacokinetics (PK) of the probe drugs warfarin (CYP2C9) and bupropion (CYP2B6).
Methods
This ...was a multicentre, open‐label study to evaluate the effect of sonidegib on the PK of the probe drugs warfarin and bupropion in patients with advanced solid tumours. Cohort 1 patients received a single warfarin 15‐mg dose on Day 1 of the run‐in period and on Cycle 2 Day 22 (C2D22) of sonidegib administration. Cohort 2 patients received a single bupropion 75‐mg dose on Day 1 of run‐in period and on C2D22 of sonidegib administration. Sonidegib 800 mg QD oral dosing began on Cycle 1 Day 1 of a 28‐day cycle after the run‐in period in both cohorts.
Results
The geometric means ratios 90% confidence interval for (S)‐warfarin with and without sonidegib were: area under the concentration–time curve from time 0 to infinity (AUCinf) 1.15 1.07, 1.24 and maximum plasma concentration (Cmax) 0.88 0.81, 0.97; and for (R)‐warfarin were: AUCinf 1.10 0.98, 1.24 and Cmax 0.93 0.87, 1.0. The geometric means ratios 90% confidence interval of bupropion with and without sonidegib were: AUCinf 1.10 0.99, 1.23 and Cmax 1.16 0.95, 1.42. Sonidegib 800 mg had a safety profile that was similar to that of lower dose sonidegib 200 mg and was unaffected by single doses of the probe drugs.
Conclusions
Sonidegib dosed orally at 800 mg QD (higher than the Food and Drug Administration‐approved dose) did not impact the PK or pharmacodynamics of warfarin (CYP2C9 probe substrate) or the PK of bupropion (CYP2B6 probe substrate).
Purpose
Melanomas are vascular tumors with a high incidence of BRAF mutations driving tumor proliferation. Complete inhibition of vascular endothelial growth factor (VEGF) signaling has potential for ...enhanced antitumor efficacy.
Methods
Patients with advanced melanoma and adequate organ function were eligible. Sorafenib was given orally at 200 mg BiD for 5 days every week; bevacizumab was administered 5 mg/kg intravenously every 14 days. The primary objective was to determine clinical biological activity. The secondary objectives were safety, tolerability, and time to progression (TTP). Pharmacodynamic analysis included serum VEGF and soluble VEGF receptor-1 and VEGF receptor-2 performed at baseline, C1D15 and C2D1. The study was terminated during the first stage of a Simon two-stage design, after 14 of planned 21 subjects were enrolled.
Results
Of the 14 patients who received treatment, no objective tumor responses were observed. Stable disease (SD) ≥16 weeks was observed in 57 % patients, including three patients with SD lasting ≥1 year. Median TTP was 32 weeks. The most frequently reported drug-related adverse events (AEs) were hand–foot syndrome (57.1 %), fatigue (57.1 %), hypertension (64.3 %), and proteinuria (35.7). Grade 3/4 drug-related AEs were hypertension (14.2 %), hand–foot syndrome, proteinuria, and thrombocytopenia (7 % each). Patients with low VEGF (<300 pg/ml) experienced longer TTP than those with high VEGF median 50 vs. 15 weeks,
p
= 0.02). A similar pattern was seen for VEGFR1 and VEGFR2, although it did not reach statistical significance.
Conclusions
Combined VEGF/VEGFR blockade using bevacizumab with sorafenib shows clinical activity. The linkage between VEGF levels and time to tumor progression needs further exploration.
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