Heinz-Josef Klümpen

Moving towards dose individualization of tyrosine kinase inhibitors

Molecular targeted therapies with tyrosine kinase inhibitors (TKIs) have been a recent breakthrough in cancer treatment. These small molecules are mainly used at a fixed dose ignoring the possible need for dose individualization. Fixed dosing may indeed result in suboptimal treatment or excessive toxicity considering the high inter-individual variability in the pharmacokinetics (PK) of these therapies. The PK, toxicity and efficacy of ten commonly used molecular targeted anti-cancer therapies were reviewed in order to optimize their prescription. A wide interpatient variability in the pharmacokinetics of these small molecules is demonstrated. Moreover associations between certain toxicities and the treatment efficacy have also been demonstrated for some agents, such as erlotinib and skin rash, that may be used as a surrogate marker. Other biomarkers intended to substitute for a clinical endpoint have been described for some TKIs and may be useful for dose individualization. Promising alternatives to fixed dosing were explored such as therapeutic drug monitoring, genotype and phenotype adjusted dosing, and toxicity-adjusted dosing. Prospective studies are needed to validate these methods so that dosing algorithms may be developed in the near future in order to personalize therapeutics to the individual needs of each cancer patient.

Phase I study investigating everolimus combined with sorafenib in patients with advanced hepatocellular carcinoma

BACKGROUND & AIMS Sorafenib is the only therapy shown to improve overall survival in advanced hepatocellular carcinoma (HCC). Combination therapy targeting multiple signaling pathways may improve outcomes. This phase I study was designed to determine the maximum tolerated dose (MTD) of everolimus given with sorafenib 400mg twice daily in patients with advanced HCC of Child-Pugh class A liver function who were naive to systemic therapy. METHODS Everolimus was initiated at 2.5mg once daily and increased per a Bayesian sequential dose-escalation scheme based on the dose-limiting toxicities experienced within the first 28 days of treatment. Adverse events were assessed continuously. Efficacy was evaluated using the best overall response rate per RECIST. RESULTS Thirty patients were enrolled; 25 were evaluable for MTD determination. One out of 12 patients treated with everolimus 2.5mg once daily and 6 out of 13 patients treated with everolimus 5.0mg once daily experienced a dose-limiting toxicity, most commonly thrombocytopenia (n=5). All patients experienced 1 adverse event, most commonly diarrhea (66.7%), hand-foot skin reaction (66.7%), and thrombocytopenia (50.0%). Best overall response was stable disease (62.5% and 42.9% in the 2.5-mg and 5.0-mg cohorts, respectively). Median time to progression and overall survival in the 2.5-mg cohort were 4.5 months and 7.4 months, respectively, and 1.8 months and 11.7 months, respectively, in the 5.0-mg cohort. CONCLUSIONS In patients with advanced HCC, the everolimus MTD in combination with standard-dose sorafenib was 2.5mg once daily. The inability to achieve a biologically effective everolimus concentration at the MTD precluded phase II study of this combination.

Association Analysis of Genetic Polymorphisms in Genes Related to Sunitinib Pharmacokinetics, Specifically Clearance of Sunitinib and SU12662

Interpatient variability in the pharmacokinetics (PK) of sunitinib is high. Single nucleotide polymorphisms (SNPs) in PK candidate genes have been associated with the efficacy and toxicity of sunitinib, but whether these SNPs truly affect the PK of sunitinib remains to be elucidated. This multicenter study involving 114 patients investigated whether these SNPs and haplotypes in genes encoding metabolizing enzymes or efflux transporters are associated with the clearance of sunitinib and its active metabolite SU12662. SNPs were tested as covariates in a population PK model. From univariate analysis, we found that the SNPs in CYP3A4, CYP3A5, and ABCB1 were associated with the clearance of both sunitinib and SU12662. In multivariate analysis, CYP3A4*22 was found to be eliminated last with an effect size of −22.5% on clearance. Observed effect sizes are below the interindividual variability in clearance and are therefore too limited to directly guide individual dosing of sunitinib.

Inhibitors of mTOR

Inhibitors of mammalian target of rapamycin (mTOR) have been approved for the treatment of renal cell carcinoma and appear to have a role in the treatment of other malignancies. The primary objective of this drug review is to provide pharmacokinetic and dynamic properties of the commonly used drugs everolimus and temsirolimus. Additionally, information on clinical use, mechanism of action, bioanalysis, drug-drug interactions, alterations with disease or age, pharmacogenetics, and drug resistance is given. This overview should assist the treating medical oncologist in adjusting treatment with mTOR inhibitors to individual patient circumstances.

Dose calculation of anticancer drugs

Background: Anticancer drugs are characterized by a narrow therapeutic window and significant inter-patient variability in therapeutic and toxic effects. Current body surface area (BSA)-based dosing fails to standardize systemic anticancer drug exposure and other alternative dosing strategies also have their limitations. Just as important as the initial dose selection is the subsequent dose revision to ensure the dose is correct. Objective: To provide an insight into the different dose individualization and dose adjustment methods, their feasibility and applicability in daily oncology practice and to suggest a practical framework for dose calculation and a basis for future research. Methods: Review of relevant literature related to dose calculation of anticancer drugs. Results: Strategies using clinical parameters, genotype and phenotype markers, and therapeutic drug monitoring all have potential and each has a role for specific drugs. However, no one method is a practical dose calculation strategy for many or all drugs. Conclusion: Given that BSA-dosing leads to significant underdosing it is not reasonable to use this as the sole method of dose calculation. Because of wide disparity in individual patient characteristics and elimination mechanisms, we are unlikely to find the ‘Holy Grail’ of a single individualized dosing strategy for every patient and anticancer drug in the near future. We propose a pragmatic, although invalidated system for initial dose calculation using dose clusters and structured subsequent dose revision based on treatment-related toxicities and therapeutic drug monitoring. These models need to be tested in clinical trials.

Diagnostic accuracy of 18F‐methylcholine positron emission tomography/computed tomography for intra‐ and extrahepatic hepatocellular carcinoma

Diagnosis of hepatocellular carcinoma (HCC) primarily involves imaging. The aim of this study was to assess the accuracy of 18F‐fluorocholine (18F‐FCH) positron emission tomography (PET) for detection of HCC and evaluation of extent of disease. Patients with HCC >1 cm were included between 2009 and July 2011, and follow‐up closed in February 2013. Diagnosis was based on American Association for the Study of Liver Diseases criteria, and all patients underwent 18F‐FCH PET/computed tomography (CT) at baseline before treatment, 6 underwent a second PET/CT posttreatment, and 1 a third during follow‐up. Whole‐body PET and low‐dose CT imaging were performed 15 minutes after 18F‐FCH injection. Evaluation of imaging was done with standardized uptake value (SUV) ratios: SUV maximum of the lesion divided by the SUV mean of surrounding tissue. Statistical analyses included descriptive analyses, receiver operating characteristic curve, McNemars test, and Kaplan‐Meiers test at 5% level of significance. Twenty‐nine patients revealed 53 intrahepatic lesions. In 48 of 53 lesions, 18F‐FCH PET was positive (SUVratio, 1.95 ± 0.66; sensitivity, 88%; specificity, 100%). PET/CT showed uptake in 18 extrahepatic lesions and no uptake in 3 lesions affirmed non‐HCC lesions; all lesions were confirmed with additional investigation (accuracy, 100%). In 17 of 29 patients, additional lesions were found on PET/CT imaging, with implications for treatment in 15 patients. Posttreatment PET/CT showed identical results, compared with standard treatment evaluation. Conclusion: This study shows additional value of 18F‐FCH PET/CT for patients with HCC. 18F‐FCH PET/CT has implications for staging, management, and treatment evaluation because of accurate assessment of extrahepatic disease. (Hepatology 2014;59:996–1006)

Hepatocellular carcinoma in cirrhotic versus noncirrhotic livers : results from a large cohort in the Netherlands

Objectives Hepatocellular carcinoma (HCC) usually occurs in patients with cirrhosis, but can also develop in noncirrhotic livers. In the present study we explored associated risk factors for HCC without cirrhosis and compared patient and tumor characteristics and outcomes in HCC patients with and without underlying cirrhosis. Methods Patients with HCC diagnosed in the period 2005–2012 in five Dutch academic centers were evaluated. Patients were categorized according to the presence of cirrhosis on the basis of histology or combined radiological and laboratory features. Results In total, 19% of the 1221 HCC patients had no underlying cirrhosis. Noncirrhotic HCC patients were more likely to be female and to have nonalcoholic fatty liver disease or no risk factors for underlying liver disease, and less likely to have hepatitis C virus or alcohol-related liver disease than did cirrhotic HCC patients. HCCs in noncirrhotic livers were more often unifocal (67 vs. 48%), but tumor size was significantly larger (8 vs. 4 cm). Despite the larger tumors, more patients underwent resection (50 vs. 10%) and overall survival was significantly better than in cirrhotics. In multivariate analyses, absence of cirrhosis [hazard ratio (HR) 0.49, 95% confidence interval (CI) 0.38–0.63] and presence of hepatitis B (HR 0.68, 95% CI 0.51–0.91) were independent predictors for lower mortality, whereas hepatitis C virus was associated with higher mortality (HR 1.32, 95% CI 1.01–1.65). Conclusion HCC without cirrhosis was strongly associated with female sex and presence of nonalcoholic fatty liver disease or no risk factors for underlying liver disease. In absence of cirrhosis, resections were more often performed, with better survival despite larger tumor size.

Study protocol of a phase IB/II clinical trial of metformin and chloroquine in patients with IDH1-mutated or IDH2-mutated solid tumours

Introduction High-grade chondrosarcoma, high-grade glioma and intrahepatic cholangiocarcinoma are aggressive types of cancer with a dismal outcome. This is due to the lack of effective treatment options, emphasising the need for novel therapies. Mutations in the genes IDH1 and IDH2 (isocitrate dehydrogenase 1 and 2) occur in 60% of chondrosarcoma, 80% of WHO grade II–IV glioma and 20% of intrahepatic cholangiocarcinoma. IDH1/2-mutated cancer cells produce the oncometabolite D-2-hydroxyglutarate (D-2HG) and are metabolically vulnerable to treatment with the oral antidiabetic metformin and the oral antimalarial drug chloroquine. Methods and analysis We describe a dose-finding phase Ib/II clinical trial, in which patients with IDH1/2-mutated chondrosarcoma, glioma and intrahepatic cholangiocarcinoma are treated with a combination of metformin and chloroquine. Dose escalation is performed according to a 3+3 dose-escalation scheme. The primary objective is to determine the maximum tolerated dose to establish the recommended dose for a phase II clinical trial. Secondary objectives of the study include (1) determination of pharmacokinetics and toxic effects of the study therapy, for which metformin and chloroquine serum levels will be determined over time; (2) investigation of tumour responses to metformin plus chloroquine in IDH1/2-mutated cancers using CT/MRI scans; and (3) whether tumour responses can be measured by non-invasive D-2HG measurements (mass spectrometry and magnetic resonance spectroscopy) of tumour tissue, serum, urine, and/or bile or next-generation sequencing of circulating tumour DNA (liquid biopsies). This study may open a novel treatment avenue for IDH1/2-mutated high-grade chondrosarcoma, glioma and intrahepatic cholangiocarcinoma by repurposing the combination of two inexpensive drugs that are already approved for other indications. Ethics and dissemination This study has been approved by the medical-ethical review committee of the Academic Medical Center, Amsterdam, The Netherlands. The report will be submitted to a peer-reviewed journal. Trial registration number This article was registered at ClinicalTrials.gov identifier (NCT02496741): Pre-results.

Short-Term Fasting Alters Cytochrome P450–Mediated Drug Metabolism in Humans

Experimental studies indicate that short-term fasting alters drug metabolism. However, the effects of short-term fasting on drug metabolism in humans need further investigation. Therefore, the aim of this study was to evaluate the effects of short-term fasting (36 h) on P450-mediated drug metabolism. In a randomized crossover study design, nine healthy subjects ingested a cocktail consisting of five P450-specific probe drugs [caffeine (CYP1A2), S-warfarin (CYP2C9), omeprazole (CYP2C19), metoprolol (CYP2D6), and midazolam (CYP3A4)] on two occasions (control study after an overnight fast and after 36 h of fasting). Blood samples were drawn for pharmacokinetic analysis using nonlinear mixed effects modeling. In addition, we studied in Wistar rats the effects of short-term fasting on hepatic mRNA expression of P450 isoforms corresponding with the five studied P450 enzymes in humans. In the healthy subjects, short-term fasting increased oral caffeine clearance by 20% (P = 0.03) and decreased oral S-warfarin clearance by 25% (P < 0.001). In rats, short-term fasting increased mRNA expression of the orthologs of human CYP1A2, CYP2C19, CYP2D6, and CYP3A4 (P < 0.05), and decreased the mRNA expression of the ortholog of CYP2C9 (P < 0.001) compared with the postabsorptive state. These results demonstrate that short-term fasting alters cytochrome P450–mediated drug metabolism in a nonuniform pattern. Therefore, short-term fasting is another factor affecting cytochrome P450-mediated drug metabolism in humans.

Diagnostic dilemma in a man with seminoma.

2230 www.thelancet.com Vol 364 December 18/25, 2004 In January, 2003, a 30-year-old student was referred to our centre with a stage 1 seminoma with good prognostic indicators. He had a left orchidectomy and radiotherapy of para-aortic nodes. Because of an elevated -fetoprotein (AFP) both before and after treatment, a microscopically undetected non-seminoma part of the tumour was suspected, and he was entered into our follow up surveillance programme for stage I non-seminoma testicular tumours. AFP is a well established tumour marker for diagnosis, staging, monitoring treatment, follow up, and prognosis in nonseminomatous germ-cell tumours. AFP is normal (under 10 μg/L) in patients with seminoma and an elevated AFP is considered almost diagnostic of nonseminoma tumours. During a year of follow-up, his AFP fluctuated (figure), never rising above 51 μg/L nor decreasing to under 20 μg/L. He had no complaints and physical examination continued to be normal. Liver function tests, hepatitis serology, and imaging studies of the liver were normal. Routine CT scan showed enlarged mediastinal lymph nodes in October, 2003, which showed 2-fluoro-D-2-desoxyglucose uptake on PET scan. To exclude a recurrence of seminoma, a thoracotomy was done and the nodes were removed. The histological diagnosis was a granulomatous inflammation consistent with sarcoidosis. Because he had no symptoms, it was decided not to start any treatment. Diagnostic dilemma in a man with seminoma