Background
A low skeletal muscle mass (SMM) has been associated with increased toxicity and shorter survival in cancer patients treated with capecitabine, an oral prodrug of 5‐fluorouracil (5‐FU). ...Capecitabine and its metabolites are highly water‐soluble and, therefore, more likely to distribute to lean tissues. The pharmacokinetics (PK) in patients with a low SMM could be changed, for example, by reaching higher maximum plasma concentrations. In this study, we aimed to examine whether the association between a low SMM and increased toxicity and shorter survival could be explained by altered PK of capecitabine and its metabolites.
Methods
Previously, a population PK model of capecitabine and metabolites in patients with solid tumors was developed. In our analysis, we included patients from this previous analysis for which evaluable abdominal computed tomography (CT)‐scans were available. SMM was measured on CT‐scans, by single slice evaluation at the third lumbar vertebra, using the Slice‐o‐Matic software. The previously developed population PK model was extended with SMM as a covariate, to assess the association between SMM and capecitabine and metabolite PK.
Results
PK and SMM data were available from 151 cancer patients with solid tumors. From the included patients, 55% had a low SMM. No relevant relationships were found between SMM and the PK parameters of capecitabine and, the active and toxic metabolite, 5‐FU. SMM only correlated with the PK of the, most hydrophilic, but inactive and non‐toxic, metabolite α‐fluoro‐β‐alanine (FBAL). Patients with a low SMM had a smaller apparent volume of distribution and lower apparent clearance of FBAL.
Conclusions
No alterations in PK of capecitabine and the active and toxic metabolite 5‐FU were observed in patients with a low SMM. Therefore, the previously identified increased toxicity and shorter survival in patients with a low SMM, could not be explained by changes in pharmacokinetic characteristics of capecitabine and metabolites.
A low skeletal muscle mass (SMM) has been associated with increased toxicity and shorter survival in cancer patients treated with capecitabine, an oral prodrug of 5‐fluorouracil (5‐FU). No alterations in PK of capecitabine and the active and toxic metabolite 5‐FU were observed in patients with a low SMM in our study. Therefore the previously identified increased toxicity and shorter survival in patients with a low SMM, could not be explained by changes in pharmacokinetic characteristics of capecitabine and metabolites.
Background
Personalized dosing based on measurement of individual drug levels and adjusting the dose accordingly can improve efficacy and decrease unnecessary toxicity of oncological treatment. For ...imatinib, sunitinib, and pazopanib, this therapeutic drug monitoring (TDM)‐guided dosing is, however, not routinely used, despite accumulating evidence favoring individualized dosing. Therefore, we aimed to identify and quantify (potential) barriers and facilitators in TDM‐guided dosing for imatinib, sunitinib, and pazopanib.
Methods
We performed a mixed methods study among all stakeholders involved: patients, healthcare professionals (HCPs), pharmaceutical companies, and health insurance companies. During the first qualitative part of this study, we performed semi‐structured individual interviews and one focus group interview to identify all (potential) barriers and facilitators, and during the second quantitative part of this study, we used a web‐based survey to quantify these findings. The interviews addressed the six domains of the implementation of change model of Grol and Wensing: (1) the innovation itself; (2) the HCP; (3) the patient; (4) social context; (5) organizational context; and (6) finances, law, and governance.
Results
In the qualitative study, we interviewed 20 patients, 18 HCPs and 10 representatives of pharmaceutical and health insurance companies and identified 72 barriers and 90 facilitators. In the quantitative study, the survey was responded by 66 HCPs and 58 patients. Important barriers were on the domain of the HCP, such as a lack of experience with TDM (36.4%), on the domain of the patient, such as lack of awareness of TDM (39.7%), and the processing time for measurement and interpretation of the TDM result (40.9%) (organizational domain). Important facilitators were education of HCPs (95.5%), education of patients (87.9%) and facilitating an overview of when and where TDM measurements are being performed (86.4%).
Conclusion
We identified and quantified important barriers and facilitators for the implementation of TDM‐guided dosing for imatinib, sunitinib, and pazopanib. Based on our results, the implementation strategy should mainly focus on educating both HCPs and patients and on the organizational aspect of TDM.
Alectinib is first-line therapy in patients with stage IV non-small cell lung carcinoma (NSCLC) and an anaplastic lymphoma kinase (ALK) fusion. A shorter median progression-free survival (mPFS) was ...observed when alectinib minimum plasma concentrations during steady state (C
) were below 435 ng/mL. This may suggest that patients should have an alectinib C
≥ 435 ng/mL for a more favorable outcome. This potential target could be attained by using therapeutic drug monitoring (TDM), i.e. adjusting the dose based on measured plasma trough concentrations. Hypothetically, this will increase mPFS, but this has not yet been evaluated in a randomized controlled trial (RCT). Therefore, the ADAPT ALEC trial is designed, with the primary objective to prolong mPFS in NSCLC patients treated with alectinib by using TDM.
ADAPT ALEC is a multicenter, phase IV RCT, in which patients aged ≥ 18 years with advanced ALK positive (+) NSCLC eligible for alectinib in daily care are enrolled. Participants will be randomized (1:1 ratio) into intervention arm A (TDM) or B (control), stratified by brain metastases and prior ALK treatments. Starting dose in both arms is the approved flat fixed dose of alectinib 600 mg taken twice daily with food. In case of alectinib C
< 435 ng/mL, arm A will receive increased doses of alectinib till C
≥ 435 ng/mL when considered tolerable. The primary outcome is mPFS, where progressive disease is defined according to RECIST v1.1 or all-cause death and assessed by CT-scans and MRI brain. Secondary endpoints are feasibility and tolerability of TDM, patient and physician adherence, overall response rate, median overall survival, intracranial PFS, quality of life, toxicity, alectinib-M4 concentrations and cost-effectiveness of TDM. Exploratory endpoints are circulating tumor DNA and body composition.
The ADAPT ALEC will show whether treatment outcomes of patients with advanced ALK+ NSCLC improve when using TDM-guided dosing of alectinib instead of fixed dosing. The results will provide high quality evidence for deciding whether TDM should be implemented as standard of care and this will have important consequences for the prescribing of alectinib.
ClinicalTrials.gov, identifier NCT05525338.
Mutations in the estrogen receptor gene (ESR1), its transcriptional regulators, and the mitogen-activated protein kinase (MAPK) pathway are enriched in patients with endocrine-resistant metastatic ...breast cancer (MBC). Here, we integrated whole genome sequencing with RNA sequencing data from the same samples of 101 ER-positive/HER2-negative MBC patients who underwent a tumor biopsy prior to the start of a new line of treatment for MBC (CPCT-02 study, NCT01855477) to analyze the downstream effects of DNA alterations previously linked to endocrine resistance, thereby gaining a better understanding of the associated mechanisms. Hierarchical clustering was performed using expression of ESR1 target genes. Genomic alterations at the DNA level, gene expression levels, and last administered therapy were compared between the identified clusters. Hierarchical clustering revealed two distinct clusters, one of which was characterized by increased expression of ESR1 and its target genes. Samples in this cluster were significantly enriched for mutations in ESR1 and amplifications in FGFR1 and TSPYL. Patients in the other cluster showed relatively lower expression levels of ESR1 and its target genes, comparable to ER-negative samples, and more often received endocrine therapy as their last treatment before biopsy. Genes in the MAPK-pathway, including NF1, and ESR1 transcriptional regulators were evenly distributed. In conclusion, RNA sequencing identified a subgroup of patients with clear expression of ESR1 and its downstream targets, probably still benefiting from ER-targeting agents. The lower ER expression in the other subgroup might be partially explained by ER activity still being blocked by recently administered endocrine treatment, indicating that biopsy timing relative to endocrine treatment needs to be considered when interpreting transcriptomic data.
Gastrointestinal stromal tumour (GIST) is a disease of older adults and is dominated by
/
mutations. In children, GIST is rare, predominantly occurs in girls, has a stomach location and generally ...lacks
/
mutations. For young adults (YA), aged 18 to 40 years, the typical phenotypic and genotypic patterns are unknown. We therefore aimed to describe the clinical, pathological and molecular characteristics of GIST in in YA. YA GIST patients registered in the Dutch GIST Registry (DGR) were included, and data were compared to those of older adults (OA). From 1010 patients in the DGR, 52 patients were YA (54% male). Main tumour locations were stomach (46%) and small intestine (46%). GIST genetic profiles were mutations in
(69%),
(6%), SDH deficient (8%), NF1 associated (4%),
gene fusion (2%) or wildtype (10%). Statistically significant differences were found between the OA and YA patients (localisation, syndromic and mutational status). YA presented more often than OA in an emergency setting (18% vs. 9%). The overall five-year survival rate was 85%. In conclusion, YA GISTs are not similar to typical adult GISTs and also differ from paediatric GISTs, as described in the literature. In this series, we found a relatively high percentage of small intestine GIST, emergency presentation, 25% non-
mutations and a relatively good survival.
There is a lack of understanding whether plasma levels of anticancer drugs (such as pazopanib) correlate with intra-tumoral levels and whether the plasma compartment is the best surrogate for ...pharmacokinetic and pharmacodynamic evaluation. Therefore, we aimed to quantify pazopanib concentrations in tumor tissue, to assess the correlation between tumor concentrations and plasma concentrations and between tumor concentrations and efficacy. In this clinical trial, non-metastatic STS patients were treated with neo-adjuvant concurrent radiotherapy and pazopanib. Plasma samples and tumor biopsies were collected, and pazopanib concentrations were measured using liquid chromatography-tandem mass spectrometry. Twenty-four evaluable patients were included. The median pazopanib tumor concentration was 19.2 µg/g (range 0.149–200 µg/g). A modest correlation was found between tumor concentrations and plasma levels of pazopanib (ρ = 0.41, p = 0.049). No correlation was found between tumor concentrations and percentage of viable tumor cells (p > 0.05); however, a trend towards less viable tumor cells in patients with high pazopanib concentrations in tumor tissue was observed in a categorical analysis. Possible explanations for the lack of correlation might be heterogeneity of the tumors and timing of the biopsy procedure.
•Imatinib is described as a well-tolerated drug, one of the rare and lesser-known side effects is pneumonitis, which occurred in 0.8 % of the imatinib-treated Dutch GIST patients.•There is no ...commonality in presentation and treatment of imatinib-induced pneumonitis.•Before making final treatment decisions, it is important to take into account the indication for imatinib, the availability of alternatives (i.e., possibility of resection, second-line sunitinib), the grade of the pneumonitis, the risks and consequences of a possible relapse or progression of GIST and pneumonitis.
Imatinib has led to a phenomenal progress in the treatment of GIST. A rare and lesser-known side effect of imatinib is pneumonitis, an uncommon multicausal interstitial lung disease.
Patients registered within the Dutch GIST Registry (DGR) were reviewed. For the patients identified with an imatinib-induced pneumonitis we reported the time on imatinib to develop pneumonitis, how the pneumonitis was diagnosed, graded and managed, and how the GIST treatment was managed.
Of the 1934 patients registered in the DGR, 1161 patients received imatinib at some point, of which nine patients (0.8 %) were identified with an imatinib-induced pneumonitis. At time of the pneumonitis, patients received a daily imatinib dose of 200–400 mg for a mean duration of 486 days. One patient was able to continue imatinib in a lower dose, in the other eight patients imatinib was interrupted, and six of these patients started prednisolone treatment. After management of the imatinib-induced pneumonitis, four patients stopped imatinib permanently, two patients were rechallenged with imatinib, and two patients started treatment with second-line sunitinib.
Imatinib-induced pneumonitis is a rare side effect, which may affect GIST management considerably. After the management of imatinib-induced pneumonitis, clinicians are left with difficult treatment dilemmas.
BackgroundDose-limiting toxicity (DLT) due to systemic CD40 activation and peripheral target-mediated drug disposition are major challenges in clinical development of CD40 agonists. MP0317, a ...CD40-agonistic DARPin (designed ankyrin repeat protein), is exclusively active in the presence of fibroblast activation protein (FAP) expressed by cancer-associated fibroblasts in the tumor microenvironment (TME). This mode of action enables tumor-localized CD40 activation, while reducing systemic toxicity.MethodsThis ongoing Phase 1, multicenter, open-label, dose-escalation study aims to establish safety/tolerability, pharmacokinetics/pharmacodynamics, and preliminary antitumor activity of MP0317 monotherapy (NCT05098405). The dose-escalation scheme uses an adaptive Bayesian logistic regression model guided by the escalation with overdose control principle to determine the recommended dose. Eligible adult patients with selected advanced solid tumors (based on anticipated FAP expression) are enrolled into 9 sequentially-escalating dose cohorts of MP0317 (0.03–10 mg/kg), administered IV 3-weekly (Q3W) or 1-weekly (Q1W) until disease progression or unacceptable toxicity. The study was approved by the Dutch and French Ethics Boards.ResultsAs of data cut-off (02 May 2023), 36 patients received ≥1 MP0317 dose across 8 cohorts, including 19 women (53%) and 17 men (47%). The median age at enrollment was 63 years (range 35–79) and patients received a median number of 3.5 prior treatments (range 1–13). Colorectal cancer was the most frequent tumor type (11 patients, 31%). One patient experienced a DLT (asymptomatic Grade 3 elevation of alanine and aspartate aminotransferases), at the highest planned dose of MP0317 (10 mg/kg Q3W). Grade 2 infusion-related reaction was the most frequently observed adverse reaction (7 patients, 19%), followed by Grade ≤2 fatigue, nausea and vomiting in 9, 6, and 4 patients, respectively. One patient achieved unconfirmed partial response, and stable disease was observed in 5 patients. Paired tumor biopsies confirmed colocalization of MP0317 with FAP and CD40. MP0317 detection in tumor biopsies was associated with an increase in abundance of antigen-presenting cells (dendritic cells, B cells and plasma cells) and IFNγ signature in the TME. Increases in CXCL10 serum levels post-MP0317 treatment support these findings.ConclusionsThese data of 36 patients, dosed across 8 dose levels (0.03–10 mg/kg, Q3W and Q1W schedules), confirmed a favorable safety profile of MP0317 monotherapy with limited systemic inflammation compared to other CD40 agonists. Analysis of paired tumor biopsies and peripheral biomarkers provided evidence of target occupancy and pharmacodynamic modulation in the TME, consistent with tumor-localized CD40 activation. These data support continued clinical evaluation of MP0317, including combination studies.Trial RegistrationThis study is registered at ClinicalTrials.gov: NCT05098405Ethics ApprovalThe study was approved by the Dutch and French Ethics Boards.
Aims
Previously published pharmacokinetic (PK) models for sunitinib and its active metabolite SU12662 were based on a limited dataset or lacked important elements such as correlations between ...sunitinib and its metabolite. The current study aimed to develop an improved PK model that circumvented these limitations and to prove the utility of the PK model in treatment optimization in clinical practice.
Methods
One thousand two hundred and five plasma samples from 70 cancer patients were collected from three PK studies with sunitinib and SU12662. A semi‐physiological PK model for sunitinib and SU12662 was developed incorporating pre‐systemic metabolism using non‐linear mixed effects modelling (nonmem). Allometric scaling based on body weight was applied. The final model was used for simulation of the PK of different treatment regimens.
Results
Sunitinib and SU12662 PK were best described by a one and two compartment model, respectively. Introduction of pre‐systemic formation of SU12662 strongly improved model fit, compared with solely systemic metabolism. The clearance of sunitinib and SU12662 was estimated at 35.7 (relative standard error (RSE) 5.7%) l h−1 and 17.1 (RSE 7.4%) l h−1, respectively for 70 kg patients. Correlation coefficients were estimated between inter‐individual variability of both clearances, both volumes of distribution and between clearance and volume of distribution of SU12662 as 0.53, 0.48 and 0.45, respectively. Simulation of the PK model predicted correctly the ratio of patients who did not reach proposed PK targets for efficacy.
Conclusions
A semi‐physiological PK model for sunitinib and SU12662 in cancer patients was presented including pre‐systemic metabolism. The model was superior to previous PK models in many aspects.
Background
BI 853520 is a potent inhibitor of focal adhesion kinase and is currently under clinical development for the treatment of non-hematological malignancies.
Objective
The objective of this ...study was to evaluate the effect of food and liquid dispersion on the pharmacokinetics of BI 853520 in two open-label, crossover substudies.
Patients and Methods
Sixteen patients with advanced solid tumors were enrolled in each substudy. The order of administration was randomized, and pharmacokinetic samples were collected for 48 h after administration of a 200 mg dose of BI 853520. Lack of effect would be demonstrated if the 90% confidence interval (CI) of the ratio of the adjusted geometric mean (GMR) of the area under the plasma curve (area under the plasma concentration–time curve from time zero to the last quantifiable concentration at
t
z
AUC
0
-
t
z
and observed area under the plasma concentration–time curve extrapolated from time zero to infinity AUC
0–∞,obs
) and maximum plasma concentration (
C
max
) did not cross the 80–125% (bioequivalence) boundaries.
Results
Adjusted GMRs (90% CIs) for the fed versus fasted state were 92.46% (74.24–115.16), 98.17% (78.53–122.74), and 87.34% (71.04–107.38) for
AUC
0
-
t
z
, AUC
0–∞,obs
, and
C
max
, respectively. Although the 90% CIs were not within bioequivalence limits for the food-effect study, the limited reductions in these pharmacokinetic parameters after administration with a high-fat meal are unlikely to be clinically relevant. Compared with a tablet, administration of BI 853520 as a liquid dispersion did not strongly affect
AUC
0
-
t
z
, AUC
0–∞,obs
, or
C
max
, resulting in adjusted GMRs (90% CIs) of 1.00 (0.92–1.09), 0.98 (0.90–1.07), and 0.93 (0.86–1.01), respectively.
Conclusions
These studies demonstrate that BI 853520 can be given with no food restrictions, and as a liquid dispersion, without strongly impacting pharmacokinetics. These pharmacokinetic properties may help make BI 853520 dosing more convenient and flexible, improving treatment compliance.
Clinical trials registration
ClinicalTrials.gov identifier: NCT01335269.
PDF
