To determine the maximum-tolerated dose (MTD) and to assess the safety, pharmacokinetics, and evidence of antitumor activity of AMG 479, a fully human monoclonal antibody to insulin-like growth ...factor receptor 1 (IGF-1R).
Patients with advanced solid malignancies or non-Hodgkin's lymphoma received escalating doses of AMG 479 intravenously (IV) every 2 weeks (Q2W). Blood samples were assayed to determine pharmacokinetic parameters and IGF-1R occupancy on neutrophils; fluorodeoxyglucose-positron emission tomography scans were used to assess tumor metabolic effects.
Fifty-three patients received 312 infusions of AMG 479 Q2W. Overall, the most common grades 1 to 2 toxicities were fatigue, thrombocytopenia, fever, rash, chills, and anorexia. One dose-limiting toxicity (ie, grade 3 thrombocytopenia) occurred in a patient at 20 mg/kg during course 1; grade 3 thrombocytopenia (n = 8) and grade 3 transaminitis elevations (n = 1) also were reported but not in the escalation phase. The maximum-planned dose of 20 mg/kg was safely administered; thus, an MTD was not reached. High levels of neutrophil IGF-1R binding and increases from baseline in serum IGF-1 levels were observed in the 12- and 20-mg/kg cohorts. Tumor responses included one durable complete response (CR) and one unconfirmed partial response (PR) in two patients with Ewing/primitive neuroectodermal tumors and included one PR and one minor response in two patients with neuroendocrine tumors. The patients with Ewing/PNET who had a CR have remained disease free on therapy after 28 months.
AMG 479 can be administered safely at 20 mg/kg IV Q2W. The absence of severe toxicities, attainment of serum concentrations associated with high levels of IGF-1R binding on neutrophils, and provocative antitumor activity warrant additional studies of this agent.
Phosphoinositide 3-kinase δ (PI3Kδ) has a key role in lymphocytes, and inhibitors that target this PI3K have been approved for treatment of B cell malignancies
. Although studies in mouse models of ...solid tumours have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumour immunity
, its effect on solid tumours in humans remains unclear. Here we assessed the effects of the PI3Kδi AMG319 in human patients with head and neck cancer in a neoadjuvant, double-blind, placebo-controlled randomized phase II trial (EudraCT no. 2014-004388-20). PI3Kδ inhibition decreased the number of tumour-infiltrating regulatory T (T
) cells and enhanced the cytotoxic potential of tumour-infiltrating T cells. At the tested doses of AMG319, immune-related adverse events (irAEs) required treatment to be discontinued in 12 out of 21 of patients treated with AMG319, suggestive of systemic effects on T
cells. Accordingly, in mouse models, PI3Kδi decreased the number of T
cells systemically and caused colitis. Single-cell RNA-sequencing analysis revealed a PI3Kδi-driven loss of tissue-resident colonic ST2 T
cells, accompanied by expansion of pathogenic T helper 17 (T
17) and type 17 CD8
T (T
17) cells, which probably contributed to toxicity; this points towards a specific mode of action for the emergence of irAEs. A modified treatment regimen with intermittent dosing of PI3Kδi in mouse models led to a significant decrease in tumour growth without inducing pathogenic T cells in colonic tissue, indicating that alternative dosing regimens might limit toxicity.
To determine the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) of conatumumab, an investigational, fully human monoclonal agonist antibody against human death receptor 5, ...in patients with advanced solid tumors.
In the dose-escalation phase, patients received escalating intravenous doses of conatumumab (0.3, 1, 3, 10, or 20 mg/kg, 3-9 per cohort) every 2 weeks. In the dose-expansion phase, 10 patients with colorectal cancer (CRC) and 7 with non-small cell lung cancer (NSCLC) received 20 mg/kg of conatumumab every 2 weeks.
Thirty-seven patients received 1 or more doses of conatumumab. Conatumumab seemed to be well tolerated; there were no dose-limiting toxicities. Of adverse events possibly related to treatment, only 3 patients (8%) had a grade 3 event (fatigue and/or elevated lipase), and no anticonatumumab antibodies were detected. An MTD was not reached. Conatumumab exhibited dose linear kinetics from 3 to 20 mg/kg, with a mean terminal half-life of 13 to 19 days. One patient with NSCLC (0.3 mg/kg) had a confirmed partial response (PR) at week 32 (38% reduction in tumor size), with further reduction (48%) by week 96; this patient remains on conatumumab after 4.2 years with a sustained PR. Fourteen patients had a best response of stable disease, 2 for 32 weeks or more. One patient with CRC (0.3 mg/kg) and stable disease for 24 weeks had a 24% reduction in tumor size by RECIST (Response Evaluation Criteria in Solid Tumors) and a 35% reduction in the sum of standardized uptake values of all lesions measured by 18Ffluorodeoxyglucose positron emission tomographic scan. Changes in tumor levels of activated caspase-3 did not appear to be associated with tumor response.
Conatumumab can be administered safely up to the target dose of 20 mg/kg every 2 weeks.
Varying the rate of continuous intravenous infusions of 5-fluorouracil (5FU) chemotherapy over a 24-hour period has been reported to improve patient outcomes. It has been hypothesized that circadian ...variation in drug disposition is a contributing factor. We analyzed 5-FU concentrations during a 24-hour continuous 5-FU infusion.
Sixty-four subjects with advanced malignancies including pancreatic, hepatocellular, colorectal as well as other epithelial malignancies and either abnormal hepatic or renal function were treated on a phase I and pharmacokinetic study of weekly 24-hour intravenous infusions of 5-FU and leucovorin. No other concomitant anticancer therapy was administered. Blood samples were collected every three hours from 61 subjects for measurement of plasma 5-FU during the first two weekly infusions.
After adjusting for differences in dose, elapsed time from start of infusion and infusion number (2 versus 1), mean 5-FU concentration was highest at 6 am and lowest at 3 pm, with an overall change in the mean from 3 pm to 6 am of +20 percent (95% CI = 12-28%). However, this variation in mean concentration associated with time of day was comparable in magnitude to the between-patient differences, within-patient differences between infusions, and the residual variation within infusion (coefficient of variation = 21%).
Our data show systematic variation by time of day in plasma concentrations of 5-FU administered at a constant rate over 24 hours, but it is small compared to the total variation in plasma concentration contributed by other sources. Circadian variation in men was more pronounced than in women.
Background: Aurora kinases form a family of highly conserved serine/threonine protein kinases that regulate key steps in mitosis. Aurora kinases A and B are amplified and/or overexpressed in many ...malignancies, including various types of leukemia, and are associated with high proliferation rates, poor prognosis, and therapeutic resistance. AMG 900 is an investigational, orally administered, highly potent, selective, small-molecule pan-aurora kinase inhibitor that has shown single-agent activity in heavily pretreated pts with chemotherapy-resistant/refractory solid tumors. This open-label, multicenter, sequential dose escalation study (NCT01380756) assessed AMG 900 in adult pts with AML.
Methods: The primary objectives of this study were to evaluate the safety and tolerability of AMG 900, to evaluate pharmacokinetics after multiple oral administrations, to determine the optimal dose schedule, and to determine the maximum tolerated dose (MTD). A secondary objective was to evaluate antitumor activity in pts with AML. Key inclusion criteria included definitively diagnosed AML that had failed standard treatments or for which no standard therapy was available, Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2, and life expectancy > 3 months. Dose escalation included parallel evaluation of 2 schedules in separate groups. In group 1, AMG 900 was administered daily 4 days on/10 days off at doses of 15, 25, 40, 60, 80, 100, 125, and 150 mg. In group 2, AMG 900 was administered daily 7 days on/7 days off at doses of 30, 40, 50, 60, and 75 mg. Dose escalation was conducted using a 3+3+3 design; intrapatient dose escalation was not allowed. The relationship between gene expression at baseline and clinical response was an exploratory objective. RNA levels for preselected genes were measured by microarray in mononuclear cells obtained from bone marrow (BM) aspirates.
Results: A total of 35 pts were enrolled: 22 in group 1 and 13 in group 2. Twenty-three pts (65.7%) were male, 27 (77.1%) were white, and mean (SD) age was 66.1 (12.2) years. ECOG status was 0 in 7 pts (20.0%), 1 in 22 pts (62.9%), and 2 in 6 pts (17.1%). Pts received a median (min, max) of 14 (4, 49) doses of AMG 900. Mean maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) increased with increasing dose. Thirty pts (85.7%) had treatment-related adverse events (AEs). The most common AEs (in ≥ 10% of pts overall) were nausea (31.4%), diarrhea (28.6%), febrile neutropenia (28.6%), fatigue (22.9%), vomiting (17.1%), alopecia (14.3%), dyspnea (11.4%), epistaxis (11.4%), mucosal inflammation (11.4%), and rash (11.4%). Nine pts (25.7%) died during the study from lung infection and respiratory failure (2 pts each) and acute respiratory failure, cardiorespiratory arrest, respiratory distress, sepsis, and septic shock (1 pt each). Only respiratory failure and septic shock (1 pt each) were considered potentially related to AMG 900 by the investigators. All 35 pts discontinued treatment. Reasons for discontinuation were disease progression (65.7%), AEs (11.4%), death (8.6%), withdrawal of consent (5.7%), other reasons (5.7%), and requirement for alternative therapy (2.9%). Two pts (5.7%) experienced dose-limiting toxicities: 1 pt from group 1 (40 mg) had grade 3 pancytopenia, and 1 pt from group 2 (50 mg) had febrile neutropenia and grade 3 abdominal pain. The MTD of AMG 900 was not formally reached in either dose schedule. Three pts (8.6%) from group 1 (40 mg 2 pts and 60 mg 1 pt) had a best response of complete response with incomplete count recovery (CRi). Overall, the objective response rate for CRi was 8.6% (80% confidence interval: 3%, 18%). Higher gene expression of BIRC5, AURKB, AURKA, TTK, and CCNB1 was associated with objective response in univariate logistic regression models (P < .02), and was still significant after adjusting for average dose and percentage of blasts in the BM in a multivariate model (P < .01). Expression profiles of responders were clustered together in a principal component analysis.
Conclusions: AMG 900 had an acceptable safety profile in this grievously ill population of adult pts with recurrent/refractory AML. Prolonged cytopenias hampered further dose escalation in this single-agent treatment setting. Combination of low doses of AMG 900 with other anticancer agents should be evaluated in future studies.
Schuster:Amgen Inc.: Equity Ownership, Honoraria, Speakers Bureau. Sekeres:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Gamelin:Amgen Inc.: Employment, Equity Ownership. Rasmussen:Amgen Inc.: Employment, Equity Ownership. Juan:Amgen Inc.: Employment, Equity Ownership. Anderson:Amgen Inc.: Employment, Equity Ownership. Chow:Amgen Inc.: Employment, Equity Ownership. Friberg:Amgen Inc.: Employment, Equity Ownership. Vogl:Amgen Inc.: Employment, Equity Ownership.
To examine the angiopoietin pathway inhibitor trebananib IV plus the anti-VEGF agents bevacizumab or motesanib in advanced solid tumours.
In this open-label phase 1b study, patients received IV ...trebananib 3 mg kg-1 QW plus bevacizumab 15 mg kg-1 Q3W (cohort 1) or motesanib orally 75 mg (cohort 2); or trebananib 10 mg kg-1 plus bevacizumab 15 mg kg-1 (cohort 3) or motesanib 125 mg (cohort 4). If <33% of patients had dose-limiting toxicities (DLTs), dose escalation occurred. Endpoints were treatment-related adverse events (AEs) incidence and pharmacokinetics (primary); anti-trebananib antibodies, biomarkers, and tumour response (secondary).
Thirty-six patients received ≥ 1 dose of trebananib (cohorts 1, 2, 3, 4; n = 6, 8, 19, 3). DLT of G3 intestinal perforation and G3 tumor haemorrhage occurred in cohorts 2 and 3, respectively (both n = 1). Across both trebananib plus bevacizumab cohorts, the most common AEs included fatigue (n = 8), diarrhoea (n =4), constipation (n = 3), nausea (n = 3), and epistaxis (n = 3). Three patients across those cohorts had grade ≥ 3 AEs. Across the trebananib plus motesanib cohorts, the most common AEs included hypertension (n = 4), diarrhoea (n = 4), nausea (n = 3), fatigue (n = 3), vomiting (n = 2), and decreased appetite (n = 2). Two patients had grade ≥ 3 AEs. Trebananib did not markedly affect motesanib pharmacokinetics. Across the trebananib plus bevacizumab cohorts, two patients had a partial response; 11 patients had stable disease lasting >6 months. Across the trebananib plus motesanib cohorts, one patient had a partial response; five patients had stable disease lasting >6 months.
Trebananib IV 3 mg kg-1 or 10 mg kg-1 plus bevacizumab or motesanib in advanced solid tumours may be associated with less severe toxicities relative to those emerging when combining two anti-VEGF agents.
The Aurora family of serine-threonine kinases are essential regulators of cell division in mammalian cells. Aurora-A and -B expression and kinase activity is elevated in a variety of human cancers ...and is associated with high proliferation rates and poor prognosis. AMG 900 is a highly potent and selective pan-aurora kinase inhibitor that has entered clinical evaluation in adult patients with advanced cancers. In mice, oral administration of AMG 900 blocks the phosphorylation of histone H3 on serine-10 (p-Histone H3), a proximal substrate of aurora-B and inhibits the growth of multiple human tumor xenografts, including multidrug-resistant models.
In order to establish a preclinical pharmacokinetic-pharmacodynamic (PK-PD) relationship for AMG 900 that could be translated to the clinic, we used flow cytometry and laser scanning cytometry detection platforms to assess the effects on p-Histone H3 inhibition in terms of sensitivity, precision, and specificity, in human tumor xenografts in conjunction with mouse skin and bone marrow tissues. Mice with established COLO 205 tumors were administered AMG 900 at 3.75, 7.5, and 15 mg/kg and assessed after 3 hours.
Significant suppression of p-Histone H3 in mouse skin was only observed at 15 mg/kg (p <0.0001), whereas in mouse bone marrow and in tumor a dose-dependent inhibition was achieved at all three doses (p ≤ 0.00015). These studies demonstrate that AMG 900 inhibits p-Histone H3 in tumors and surrogate tissues (although tissues such as skin may be less sensitive for assessing PD effects). To further extend our work, we evaluated the feasibility of measuring p-Histone H3 using fine-needle aspirate (FNA) tumor xenograft biopsies. Treatment with AMG 900 significantly inhibited p-Histone H3 (>99% inhibition, p <0.0001) in COLO 205 tumors. Lastly, we illustrate this LSC-based approach can detect p-Histone H3 positive cells using mock FNAs from primary human breast tumor tissues.
Phosphorylation of histone H3 is a useful biomarker to determine the pharmacodynamics (PD) activity of AMG 900. FNA biopsies may be a viable approach for assessing AMG 900 PD effects in the clinic.
Summary
Background
Trebananib is an anti-angiogenic peptibody under investigation in patients with advanced cancer. This study evaluated the pharmacokinetic (PK) drug-drug interaction of paclitaxel ...and trebananib.
Patients and methods
Patients with advanced solid tumors received weekly 80 mg/m
2
intravenous (IV) paclitaxel (3 weeks on/1 week off) with weekly 15 mg/kg IV trebananib starting at Week 2. Blood samples for PK analysis were collected at Week 1 (paclitaxel alone), Week 6 (paclitaxel and trebananib), and Week 8 (trebananib alone). An absence of interaction was to be concluded if the 90 % confidence intervals (CI) for the differences in paclitaxel exposure fell within the 0.80–1.25 interval.
Results
The primary study was conducted between 7/2012 and 10/2013. Thirty-five patients were enrolled and 34 received both treatments. Most patients were white (91 %) and female (59 %); mean age was 61 years. The most common tumor types were ovarian (32 %) and bladder (27 %), 71 % of patients had stage IV disease, and all had Eastern Cooperative Oncology Group (ECOG) scores of 0 or 1. PK parameter analysis was done on patients with evaluable PK data at both assessments (with and without concomitant therapy;
n
= 28). The geometric least squares mean (GLSM) ratio (90 % CI) of paclitaxel AUC
inf
with and without trebananib was 1.17 (1.10, 1.25). The GLSM ratio (90 % CI) of trebananib AUC
tau,ss
with and without paclitaxel was 0.92 (0.87, 0.97). The most common adverse events were fatigue, local edema, peripheral edema, and nausea.
Conclusions
This study showed no evidence of clinically meaningful PK interaction between paclitaxel and trebananib.
Conatumumab is a fully human monoclonal antibody that binds to and activates human death receptor 5 (DR5; also known as TRAIL receptor 2). The purpose of this study was to characterize ^sup ...64^Cu-labeled conatumumab as a PET tracer for imaging DR5 in tumors. Methods: DOTA-conatumumab was synthesized by incubating conatumumab with 2,2',2''-(10-(2-(2,5-dioxopyrrolidin-1-yloxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (DOTA-NHS). The absolute numbers of DOTA molecules per conatumumab molecules were determined by matrix-assisted laser desorption ionization mass spectrometry and electrospray ionization quadrupole time-of-flight mass spectrometry. ^sup 64^Cu-DOTA-conatumumab was prepared by incubating ^sup 64^CuCl^sub 2^ (33-222 MBq) with DOTA-conatumumab at 37°C for 1 h. Binding of conatumumab and DOTA-conatumumab to Fc-coupled human DR5 (huTR2-Fc) was tested in a kinetic analysis assay, and the biologic activity of copper-DOTA-conatumumab was measured using a caspase-3/7 luminescent assay. In vivo evaluation of DOTA-conatumumab and copper-DOTA-conatumumab was done in severe combined immunodeficiency mice bearing Colo205 xenografts: tissue uptake was determined with biodistribution studies, and small-animal PET and autoradiography were used to determine the uptake of ^sup 64^Cu-DOTA conatumumab into tumors and other tissues. Results: DOTA-conatumumab was prepared with an average of 5 DOTA molecules per conatumumab molecule. The in vitro median effective concentration required to induce a 50% effect of DOTA-conatumumab and conatumumab from the assay were 389 and 320 pM, respectively. The median effective dose (±SD) of DOTA-conatumumab and conatumumab via the caspase assay was 135 ± 31 and 128 ± 30 pM, respectively. In female CB17 severe combined immunodeficiency mice bearing Colo205 xenografts, DOTA-conatumumab and conatumumab inhibited tumor growth to the same extent. Small-animal PET studies showed tumor uptake at 24 h after injection of the tracer, with a mean standardized uptake value of 3.16 (n = 2). Tumor uptake was decreased by the coadministration of 400 µg of unlabeled conatumumab (mean standardized uptake value, 1.55; n = 2), suggesting saturable uptake. Tissue uptake determined by biodistribution studies was in agreement with the small-animal PET findings. Conclusion: These results suggest that ^sup 64^Cu-DOTA-conatumumab is a potential PET tracer for imaging DR5 in tumors and may be useful for measuring on-target occupancy by conatumumab. PUBLICATION ABSTRACT
Conatumumab is a fully human monoclonal antibody that binds to and activates human death receptor 5 (DR5; also known as TRAIL receptor 2). The purpose of this study was to characterize (64)Cu-labeled ...conatumumab as a PET tracer for imaging DR5 in tumors.
DOTA-conatumumab was synthesized by incubating conatumumab with 2,2',2″-(10-(2-(2,5-dioxopyrrolidin-1-yloxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (DOTA-NHS). The absolute numbers of DOTA molecules per conatumumab molecules were determined by matrix-assisted laser desorption ionization mass spectrometry and electrospray ionization quadrupole time-of-flight mass spectrometry. (64)Cu-DOTA-conatumumab was prepared by incubating (64)CuCl(2) (33-222 MBq) with DOTA-conatumumab at 37°C for 1 h. Binding of conatumumab and DOTA-conatumumab to Fc-coupled human DR5 (huTR2-Fc) was tested in a kinetic analysis assay, and the biologic activity of copper-DOTA-conatumumab was measured using a caspase-3/7 luminescent assay. In vivo evaluation of DOTA-conatumumab and copper-DOTA-conatumumab was done in severe combined immunodeficiency mice bearing Colo205 xenografts: tissue uptake was determined with biodistribution studies, and small-animal PET and autoradiography were used to determine the uptake of (64)Cu-DOTA conatumumab into tumors and other tissues.
DOTA-conatumumab was prepared with an average of 5 DOTA molecules per conatumumab molecule. The in vitro median effective concentration required to induce a 50% effect of DOTA-conatumumab and conatumumab from the assay were 389 and 320 pM, respectively. The median effective dose (±SD) of DOTA-conatumumab and conatumumab via the caspase assay was 135 ± 31 and 128 ± 30 pM, respectively. In female CB17 severe combined immunodeficiency mice bearing Colo205 xenografts, DOTA-conatumumab and conatumumab inhibited tumor growth to the same extent. Small-animal PET studies showed tumor uptake at 24 h after injection of the tracer, with a mean standardized uptake value of 3.16 (n = 2). Tumor uptake was decreased by the coadministration of 400 μg of unlabeled conatumumab (mean standardized uptake value, 1.55; n = 2), suggesting saturable uptake. Tissue uptake determined by biodistribution studies was in agreement with the small-animal PET findings.
These results suggest that (64)Cu-DOTA-conatumumab is a potential PET tracer for imaging DR5 in tumors and may be useful for measuring on-target occupancy by conatumumab.
PDF
