Alwin D. R. Huitema

Introduction: Early-phase oncology clinical trials are often underrepresented in studies regarding publication of trial results. This study investigated the publication status of early-phase clinical trials, focusing on trials of compounds discontinued in clinical development. Methods: Two retrospective cohorts were formed: one included early-phase trials supporting European Medicines Agency marketing authorization applications (2017-2020), while the second cohort included early-phase trials of discontinued compounds. Trials were matched with database registry and their corresponding publications. Results: The first cohort consisted of 73 trials. Nine ongoing trials were excluded. No full publication or full report was found for 11% (n = 7/64) of trials. Median time from registered closure date to publication of trial results as full publication or full report was 109 days (IQR −733 to 597). Trials sponsored by large-size firms (HR 2.25 [95% CI, 1.23-4.1]), with >100 patients (HR 2.15 [95% CI, 1.19-3.88]) and duration >2 years (HR 6.83 [95% CI, 3.03-14.38]) were more likely to be published. The cohort with discontinued compounds consisted of 66 clinical trials. After exclusion of 9 ongoing trials, 39% (n = 22/57) lacked full publication or full report. Median time from registered closure date to publication of trial results as full publication or full report was 693 days (IQR 406–963). No covariates influencing publication status were found. Conclusions: Timely and complete publication of early-phase clinical trial results remains inadequate. Forty percent of trials with discontinued drugs are not publicly reported, and even among approved compounds, 11% of early-phase trial results cannot be found in the public domain.

Introduction: Currently, no established guidelines exist for dosing chemotherapy or immunotherapy in patients with achondroplasia. Case: A 69-year old female with congenital achondroplasia was diagnosed with stage IV non-small cell lung carcinoma type adenocarcinoma, with high Tumor Mutational Burden and 20% programmed death-ligand 1 expression. The patient received carboplatin dose based on renal function utilizing measured creatinine clearance, pemetrexed based on body surface area and pembrolizumab at a fixed dose of 100mg for body weight <65 kg. The doses of carboplatin and pemetrexed were adjusted after the first cycle based on therapeutic drug monitoring (TDM). The treatment was generally well tolerated, with the exception of grade 2 neutropenia, which resolved after a one-week delay of the third treatment cycle. A favorable clinical response was achieved after four treatment cycles. Conclusion: Given the uncertainty regarding the accuracy of dosing algorithms in patients with congenital achondroplasia, TDM may support dose optimization and attainment of adequate drug exposure.

Background and purpose: Unexpected high rates of grade ≥ 3 transaminase elevations were observed in patients receiving pazopanib and extremity radiotherapy. Although alanine transaminase (ALT) and aspartate transaminase (AST) primarily originate from the liver, both are also present in muscle tissue. In extremity soft tissue sarcomas (STS), where large muscle volumes are within the radiation field, radiation-induced muscle damage may contribute to these elevations. This study evaluated the impact of extremity radiotherapy, pazopanib, and their combination on the incidence and degree of ALT/AST elevations in STS patients.Patients and methods: A prospective cohort treated with extremity radiotherapy alone was combined with a retrospective cohort treated with pazopanib alone or in combination. Patient characteristics, treatment details, and laboratory values (liver enzymes and muscle injury biomarkers) were collected. Descriptive analyses and logistic regression were conducted to evaluate the association with grade ≥ 3 ALT/AST elevations. Results: Among 154 patients (10 radiotherapy, 108 pazopanib, 36 radiotherapy plus pazopanib), none of the radiotherapy-only patients experienced grade ≥ 3 elevations. Post-irradiation ALT/AST, creatine kinase and myoglobin elevations were minimal. Grade ≥ 3 elevations occurred in 6% of patients receiving pazopanib and 36% of those receiving both radiotherapy and pazopanib. All elevations typically resolved after pazopanib discontinuation. Grade ≥ 3 elevations were significantly associated with pazopanib, and modestly associated with pazopanib trough levels (odds ratio [OR]: 1.43 per 10 mg/L, 95% confidence interval [CI]: 1.12–1.90), but not with radiotherapy.Interpretation: Adding pazopanib to radiotherapy in localised extremity sarcoma significantly increases the rate of AST/ALT elevations. Extremity radiotherapy alone does not induce clinically relevant transaminase elevations. Grade ≥ 3 elevations were associated with pazopanib treatment. The mechanism underlying the substantially higher incidence of transaminase elevations with combined pazopanib and radiotherapy, compared with pazopanib alone, remains unknown.

Introduction: Pharmacodynamic analyses are increasingly important to early-phase oncology drug development, however these analyses use invasive methods to collect patient material. Yet, their role in guiding recommended phase II dose (RP2D) decisions remains unclear. Therefore, this review evaluates how pharmacodynamic analyses assisted the determination of the recommended phase II dose (RP2D) in first-in-human cancer trials of small-molecule agents. Method: First-in-human dose finding clinical trials of single-agent small-molecule anticancer therapies published between 2022 and 2025 that included pharmacodynamic assessments, were investigated. Clinical trials were evaluated for correlation of pharmacodynamic results at the analyzed doses and their influence in the RP2D decision-making process. Results: In total, 535 records were identified and 34 articles, reporting on 34 separate trials, were included. A correlation was found between the pharmacodynamic results and the analyzed dose levels in 92% ( n = 31/34). However, only half of the clinical trials ( n = 17/34) reported their pharmacodynamic results in the RP2D decision-making process, while 41% ( n = 14/34) did not. In most of the clinical trials that did not use their pharmacodynamic results in the RP2D decision-making process, only one pharmacodynamic analysis was performed ( n = 9/14, 64%) and they often determined their RP2D solely based on safety and/or tolerability ( n = 7/14, 50%). Invasive procedures were often performed without clear utilization of pharmacodynamic data, raising ethical considerations. Conclusion: These findings underscore the need for appropriate sample sizes planning and validated, fit-for-purpose pharmacodynamic assays to ensure meaningful use in dose selection, optimizing patient benefit and trial design.

Purpose: Lactation could offer benefit to the mother and child. Information on the safety of lactation during anti-cancer treatment, however, is scarce. Therefore, clinical data about drug exposure through breast milk is needed. To contribute to this, we present a case of a 34-year old woman who was treated with intravenous trastuzumab 600 mg and pertuzumab 1200 mg in the first cycle. Over the first 17 days of treatment, she collected breast milk samples. Methods: Trastuzumab and pertuzumab concentrations in breast milk were determined by validated ELISAs. Subsequently, infant exposure parameters such as infant daily dose (IDD), relative infant dose (RID), and cumulative RID were calculated. Results: The cumulative RID was 16.8% for trastuzumab and 24.3% for pertuzumab. Based on our results, we can conclude that intravenously administered trastuzumab and pertuzumab transfer into breast milk exceeding the safety threshold of an RID of 10%. Conclusion: Although the extent of systemic exposure in infants after ingestion of breast milk containing these monoclonal antibodies is unknown, systemic exposure cannot be excluded. Therefore, breastfeeding during treatment with trastuzumab and pertuzumab should be discouraged.

Purpose Prestin has been identified as a potential biomarker for cochlear damage and consequent ototoxicity. Although several preclinical and clinical studies have investigated prestin, a comprehensive overview of the evidence regarding its diagnostic value across different types of auditory damage and its use for cancer treatment-related ototoxicity is currently lacking. Methods A structured literature review, based on a systematic PubMed search, was conducted to summarize preclinical and clinical studies that evaluated serum and/or plasma prestin levels in association with cochlear damage. Studies were categorized by etiology, moment of biomarker assessment, and correlation with functional hearing outcomes. Results Twenty-one studies (six animal, 15 human) were included. In animal models, prestin levels increased within hours to days after cochlear injury. Clinical studies showed elevated prestin levels within 30 days after acute damage, due to cisplatin exposure, noise exposure, or surgery. Higher prestin levels correlated with elevated hearing thresholds in six studies, whereas findings were more variable in age-related or chronic hearing loss. So far, no pediatric populations have been studied, and reference values or diagnostic thresholds for prestin are lacking. Conclusion Prestin shows potential for use as a biomarker for acute cochlear damage, with time-dependent patterns observed in both animal and human studies. However, heterogeneity in study design, patient populations, and measurement methods limits current general conclusions and recommendations for its use in the clinical field. Further standardized and longitudinal studies, including pediatric and cancer-survivor cohorts, are needed to determine its clinical utility.

Whole genome sequencing (WGS) is increasingly accessible in clinical practice, enabling pharmacogenomics (PGx) integration, including in pediatric oncology. However, the lack of validated software to accurately annotate clinically actionable PGx variants from WGS limits routine implementation. We therefore aimed to identify and validate a PGx annotation tool suitable for clinical use in pediatric oncology. We evaluated several tools for technical performance and clinical integration. The Pharmacogenomics Clinical Annotation Tool (PharmCAT) was selected for its alignment with expert‐reviewed PGx guidelines, inclusion of relevant gene‐drug pairs and prescribing recommendations. PharmCAT was validated using an in silico dataset by introducing known diplotypes into the Genome in a Bottle (GIAB) reference sample, complemented by four clinically confirmed diplotypes from three patients. Diplotype and phenotype outputs from WGS were compared against the GIAB and patient reference data. We tested 71 diplotypes across seven genes ( TPMT , NUDT15 , CYP3A5 , CYP2C9 , CYP2C19 , DPYD , UGT1A1 ), using ≥ 95% sensitivity and specificity as validation criteria. CYP2D6 was excluded from this validation due to genotyping limitations from the input data used by PharmCAT. The tool was integrated into our WGS analysis pipeline using containerization for consistent, reproducible execution. Diplotype and phenotype results from PharmCAT fully matched the in silico GIAB set and patient samples, achieving 100% sensitivity and specificity. These findings confirm PharmCAT as a reliable tool for preemptive PGx annotation, supporting implementation in pediatric oncology. Its clinical integration supports individualized dosing, reducing adverse effects and improving efficacy. Further validation of additional gene‐drug pairs will broaden its clinical utility.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common enzymatic disorder that is often asymptomatic until exposure to oxidative stress, such as certain medications. Rasburicase, used for tumor lysis syndrome (TLS) prophylaxis, can trigger hemolysis in G6PD-deficient patients. We report a nine-year-old Asian boy with acute myeloid leukemia (AML) and hyperleukocytosis who developed severe hemolytic anemia and methemoglobinemia shortly after receiving rasburicase for TLS. Enzymatic testing suggested G6PD deficiency but was unreliable due to hyperleukocytosis. Rasburicase was discontinued, and supportive care with ascorbic acid led to rapid clinical improvement. Subsequent gene-panel analysis using whole exome sequencing (WES) confirmed a pathogenic class B G6PD variant (Viangchan). This case highlights the need for caution when administering rasburicase to patients with unknown G6PD status, particularly in individuals from regions or ethnic groups with a high prevalence of G6PD deficiency. Enzymatic testing may become unreliable due to hyperleukocytosis or recent transfusions. Therefore, close monitoring of hemolysis parameters with a low transfusion threshold in acute hemolytic anemia is essential. Genotyping using WES or whole genome sequencing (WGS) provides definitive G6PD variant classification. This enables careful dose adjustments and proactive monitoring for G6PD-related hemolysis caused by high-risk drugs in pediatric oncology.