Radiopharmaceuticals are considered as regular medicinal products and therefore the same regulations as for non-radioactive medicinal products apply. However, specific aspects should be considered due to the radiochemical properties. Radiopharmaceutical dedicated monographs are developed in the European Pharmacopoeia to address this. Currently, different quality control methods for non-registered radiopharmaceuticals are utilized, often focusing on radio-TLC only, which has its limitations. When the radiochemical yield (RCY) is measured by radio-TLC analysis, degradation products caused by radiolysis are frequently not detected. In contrast, HPLC analysis defines the radiochemical purity (RCP), allowing for detection of peak formation related to radiolysis. During the introduction and optimization phase of therapeutic radiopharmaceuticals, significant percentages of impurities, like radiolysed construct formation, may have consequential impact on patient treatment. Since more hospitals and institutes are offering radiopharmaceutical therapies, such as [177Lu]Lu-PSMA with an in-house production, the demand for adequate quality control is increasing. Here we show the optimization and implementation of a therapeutic radiopharmaceutical, including the comparison of ITLC and HPLC quality control.Downscaled conditions (74 MBq/μg) were in concordance to clinical conditions (18 GBq/250 µg, 5 mL syringe/100 mL flacon); all results were consistent with an > 98% RCY (radio-TLC) and stability of > 95% RCP (HPLC). Radio-TLC did not identify radiolysis peaks, while clear identification was performed by HPLC analysis. Decreasing the RCP with 50%, reduced the cell-binding capacity with 27%.This research underlines the importance of the radiolabeling and optimization including clinical implementation and clarifies the need for cross-validation of the RCY and RCP for quality control measurements. Only HPLC analysis is suitable for identification of radiolysis. Here we have proven that radiolysed [177Lu]Lu-PSMA has less binding affinity and thus likely will influence treatment efficacy. HPLC analysis is therefore essential to include in at least the validation phase of radiopharmaceutical implementation to ensure clinical treatment quality.
Tamoxifen is a commonly prescribed drug in both early and metastatic breast cancer. Prospective studies in Asian populations demonstrated that tamoxifen-related liver steatosis occurred in more than 30% of the patients within 2 years after start of treatment. No well-designed prospective studies on potential tamoxifen-related liver steatosis have been conducted in Caucasian patients so far. Therefore, our prospective study aimed to assess the incidence of tamoxifen-related liver steatosis for a period of 2 years in a population of Caucasian breast cancer patients treated with tamoxifen. Patients with an indication for adjuvant treatment with tamoxifen were included in this study. Data were collected at 3 months (T1) and at 2 years (T2) after start of tamoxifen treatment (follow-up period of 21 months). For the quantification of liver steatosis, patients underwent liver stiffness measurement by transient elastography with simultaneous controlled attenuation parameter (CAP) determination using the FibroScan. A total of 95 Caucasian breast cancer patients were included in this evaluation. Liver steatosis was observed in 46 of 95 (48%) and 48 of 95 (51%) of the patients at T1 and T2, respectively. No clinically relevant increase in liver steatosis was observed during the treatment period of 2 years with tamoxifen (median CAP = 243 ± 49 dB/m (T1) and 253 ± 55 dB/m (T2), respectively; p = 0.038). Conclusion: In this prospective longitudinal study in Caucasian breast cancer patients, no clinically relevant alterations in liver steatosis in terms of CAP values and liver/lipid parameters were observed after 2 years of tamoxifen treatment. This study therefore demonstrates an absence of tamoxifen-related adverse events such as steatosis and (early) development of fibrosis or cirrhosis during a treatment period of at least 2 years.
3049 Background: Poor response to anti-PD1/PD-L1 remains a clinical challenge in a subgroup of patients with metastatic melanoma. Recent evidence strongly suggests that these poor responses are associated with TGF-β signaling and CD8+ T-cell excluded tumors characterized by a collagen-rich peritumoral stroma that blocks the interaction between T cells and tumor cells. In the pursuit of identifying non-invasive biomarkers associated with a T-cell excluded phenotype and predict resistance/response to immune checkpoint inhibitor therapy, we evaluated the association between blood-based biomarkers measuring type III collagen formation and cross-linking and survival outcomes in metastatic melanoma patients treated with anti-PD1 therapy. Methods: 107 patients with metastatic melanoma who started anti-PD1 monotherapy between May 2016 – March 2019 entered in a prospective real-life study (nivolumab n = 62, pembrolizumab n = 45). Type III collagen formation (PRO-C3) and type III collagen formation and cross-linking (PC3X) were measured with ELISAs in pre-treatment serum. Biomarker levels were associated to Disease Control Rate (according to RECIST v.1.1) by Mann-Whitney test and correlated to survival outcomes by Kaplan-Meier and Cox regression analyses. Results: PRO-C3 was significantly elevated in patients with progressive disease compared to the combined group of patients with complete response, partial response and stable disease (p = 0.046). High PRO-C3 and PC3X ( > 75 th percentile) prior to treatment were significantly associated with poor overall survival (PRO-C3: HR = 2.4, p = 0.008; PC3X: HR = 2.2, p = 0.019) and progression free survival (PRO-C3: HR = 1.91, p = 0.016; PC3X: HR = 1.94, p = 0.013). The median overall survival was 417 and 511 days in biomarker high patients compared to 1269 and 1269 days in biomarker low patients, for PRO-C3 and PC3X, respectively. Conclusions: Biomarkers quantified in a pre-treatment liquid biopsy reflecting excessive collagen formation and cross-linking were associated with poor response and survival outcomes in metastatic melanoma patients treated with anti-PD1 therapy. This supports an association between collagen formation and resistance to anti-PD1 therapy. Furthermore, if validated, these non-invasive collagen biomarkers may have potential for guiding patient stratification for immune checkpoint inhibitor therapy and combination therapies. Clinical trial information: NTR7015 .
Background: Osimertinib is the cornerstone in the treatment of epidermal growth factor receptor-mutated non-small cell lung cancer (NSCLC). Nonetheless, ±25% of patients experience severe treatment-related toxicities. Currently, it is impossible to identify patients at risk of severe toxicity beforehand. Therefore, we aimed to study the relationship between osimertinib exposure and severe toxicity and to identify a safe toxic limit for a preventive dose reduction. Methods: In this real-life prospective cohort study, patients with NSCLC treated with osimertinib were followed for severe toxicity (grade ⩾3 toxicity, dose reduction or discontinuation, hospital admission, or treatment termination). Blood for pharmacokinetic analyses was withdrawn during every out-patient visit. Primary endpoint was the correlation between osimertinib clearance (exposure) and severe toxicity. Secondary endpoint was the exposure–efficacy relationship, defined as progression-free survival (PFS) and overall survival (OS). Results: In total, 819 samples from 159 patients were included in the analysis. Multivariate competing risk analysis showed osimertinib clearance ( c.q. exposure) to be significantly correlated with severe toxicity (hazard ratio 0.93, 95% CI: 0.88–0.99). An relative operating characteristic curve showed the optimal toxic limit to be 259 ng/mL osimertinib. A 50% dose reduction in the high-exposure group, that is 25.8% of the total cohort, would reduce the risk of severe toxicity by 53%. Osimertinib exposure was not associated with PFS nor OS. Conclusion: Osimertinib exposure is highly correlated with the occurrence of severe toxicity. To optimize tolerability, patients above the toxic limit concentration of 259 ng/mL could benefit from a preventive dose reduction, without fear for diminished effectiveness.
To explore the dosimetric effect of substituting Lu-177 with Tb-161 in targeted radionuclide therapy (TRT) using the registered tracers DOTA-TATE and PSMA-617.Using established kinetic data for [177Lu]Lu-DOTA-TATE and [177Lu]Lu-PSMA-617, radiation absorbed doses to typical tumour lesion as well as non-target tissues ([177Lu]Lu-DOTA-TATE: kidneys, spleen and liver, [177Lu]Lu-PSMA-617: kidneys, liver and salivary glands) were calculated for Lu-177 and Tb-161.For both DOTA-TATE and PSMA-617, the substitution of Lu-177 with Tb-161 results in an increase in the delivered dose per unit of activity to tumour tissue by 40%. If an equivalent non-target delivered dose is strived for in order not to increase toxicity, based on kidney absorbed dose, 7400 MBq Lu-177 per cycle should be substituted with 5400 MBq Tb-161 for DOTA-TATE and 5300 MBq of Tb-161 for PSMA-617.When substituting Lu-177 with Tb-161, activity conversion is necessary in order not to exceed non-target dose limits.
Cisplatin is a chemotherapeutic agent widely used for multiple indications. Unfortunately, in a substantial set of patients treated with cisplatin, dose-limiting acute kidney injury (AKI) occurs. Here, we assessed the association of 3 catechol-O-methyltransferase (COMT) single nucleotide polymorphisms (SNPs) with increased cisplatin-induced nephrotoxicity. In total, 551 patients were genotyped for the 1947 G>A (Val158Met, rs4680), c.615 + 310 C>T (rs4646316), and c.616–367 C>T (rs9332377) polymorphisms. Associations between these variants and AKI grade ≥3 were studied. The presence of a homozygous variant of c.616-367C>T was associated with a decreased occurrence of AKI grade 3 toxicity (p = 0.014, odds ratio (OR) 0.201, 95% confidence interval (CI) (0.047–0.861)). However, we could not exclude the role of dehydration as a potential cause of AKI in 25 of the 27 patients with AKI grade 3, which potentially affected the results substantially. As a result of the low incidence of AKI grade 3 in this dataset, the lack of patients with a COMT variant, and the high number of patients with dehydration, the association between COMT variants and AKI does not seem clinically relevant.
The transdermal fentanyl patch is widely used to treat cancer-related pain despite its wide inter- and intrapatient variability in pharmacokinetics. The aim of this study was to investigate whether smoking and body size (i.e. body mass index) influence fentanyl exposure in patients with cancer. These are factors that typically change during treatment and disease trajectories. We performed an explorative cohort study in patients with cancer using transdermal fentanyl patches (Durogesic®), by taking a blood sample for pharmacokinetic analysis one day after applying a patch in patients with a stable fentanyl dose. A total of 88 patients were evaluable. Although no statistically significant difference was found, the plasma concentrations of non-smokers was 28% (95% CI [-14%; +89-%]) higher than those of smokers normalizing for a dose of 25μg/min. Patients with a low BMI (< 20 kg/m2) had almost similar (10% (95% CI [-39%; +97%]) higher) plasma concentrations compared to patients with a high BMI (> 25 kg/m2). A wider variation in fentanyl plasma concentrations was found in this study than anticipated. Due to this variation, studies in larger patient cohorts are needed to further investigate the effect of smoking on plasma concentration of fentanyl and thereby clarify the clinical significance of our findings.
Abstract INTRODUCTION Little progress has been made in the development of effective new therapies for glioblastoma (GBM) the past decades. Fresh patient-derived GBM cell culture models have become the gold standard for GBM drug discovery and development. One of the major obstacles in identifying novel candidate drugs against GBM remains the blood-brain barrier (BBB). Therefore, it is crucial to select drugs with favourable physicochemical properties to cross BBB and reach the tumour tissue in therapeutically effective concentrations. In current drug repurposing approach, we evaluated available anti-cancer agents in our patient-derived drug screening platform against GBM. METHODS The FDA-approved Oncology Drug Set II library was tested on 45 primary GBM cell cultures. We developed a drug shortlisting pipeline combining efficacy data with pharmacodynamic and pharmacokinetic characteristics of each compound. The therapeutic efficacy of the selected agent was assessed in an orthotopic mouse PDX model, while penetration into the CNS by LC/MS/MS. RESULTS Omacetaxine mepesuccinate (OMA) was ranked as one of the most promising candidates applying our drug selection approach. In vitro, OMA revealed anti-tumour activity at IC50 values well-below reported Cmax plasma values in approximately 80% of GBM cultures. NanoString nCounter analysis, revealed DNA damage repair as the main pathway involved in OMA’s anti-tumour effect. Activation of caspase 3/7 activity and decrease of glioma cell invasiveness were also linked to its anti-tumour effect. In vivo, 1mg/kg dose of OMA was found to reach the brain tumour tissue in concentrations similar to the reported IC50 values in vitro. No adverse reactions were noted and a survival benefit was observed in a proportion of the treated mice. CONCLUSIONS At 1 mg/kg, OMA reaches the tumour brain tissue in therapeutically effective concentrations in mice while a moderate therapeutic benefit was observed. Additional in vivo experiments are ongoing investigating higher dosages of OMA and longer exposure.
