Els Witteveen

The Molecular Basis of Class Side Effects Due to Treatment with Inhibitors of the VEGF/VEGFR Pathway

UNLABELLED Vascular Endothelial Growth Factor (VEGF) is considered to be one of the most important regulators of angiogenesis and a new key target in anti-cancer treatment. Various clinical trials have validated the clinical importance of anti-VEGF or anti-VEGF receptor (VEGFR) therapy. Currently the humanized monoclonal antibody bevacizumab (blocks VEGF-A), and the tyrosine kinase inhibitors sunitinib and sorafenib (inhibit VEGFRs) are approved for patients with various malignancies and several others are expected in the coming years. Unfortunately, anti-VEGF/VEGFR treatment is not void of side effects. An array of unexpected side effects is now seen in clinical practice. Management of these side effects is extremely important in the development of the various anti-VEGF/VEGFR therapies and their optimal use. This review provides an overview of the toxicity profile of this class of agents, the molecular basis behind these side effects and indicates potential options for management. VEGF and its receptors play an important role in normal tissues and are widely expressed. It is likely that interference with this pathway induces an array of side effects due to the lack of normal function of VEGF. A consistent pattern of side effects is now emerging. Hypertension, gastro-intestinal toxicity, hypothyroidism, proteinuria, coagulation disorders and neurotoxicity are side effects observed with both anti-VEGF and anti-VEGFR inhibitors. For these side effects the role of VEGF/VEGFR pathway in normal tissue was reviewed in order to provide a molecular mechanism that linked side effect with physiological activity of VEGF/VEGFR. Insight into the molecular basis may aid specific supportive care measures to ensure optimal use of this class of agents. CONCLUSION Inhibiting the VEGF/VEGFR pathway is an effective approach to treat cancer. It has also provided new insight into the physiological role of this pathway in various organs. Integrating the knowledge in daily oncological practice will be a challenge for the future.

A Phase I, Randomized, Open-Label, Parallel-Cohort, Dose-Finding Study of Elacridar (GF120918) and Oral Topotecan in Cancer Patients

Purpose: Breast cancer resistance protein (ABCG2) substantially limits the oral bioavailability of topotecan. Coadministration with elacridar, an inhibitor of breast cancer resistance protein–mediated drug transport, increases the bioavailability of topotecan. The aim of this study was to establish the lowest effective dose of elacridar to obtain maximum oral bioavailability of topotecan and to determine the optimal schedule of coadministration of oral topotecan and elacridar. In the second part of this study, dose-limiting toxicities and maximum tolerated dose of oral topotecan coadministered with elacridar, at a daily times five regimen administered every 21 days, were established. Experimental Design: In part I, 20 patients were randomized to receive 100, 300, 500, 700, or 1,000 mg of elacridar on days 1 and 8 1 h before or simultaneously with 2.0 mg oral topotecan, which was also randomized. On day 15, all patients were treated with 1.5 mg/m2 i.v. topotecan. In part II of the study, patients were treated daily with oral topotecan and with the lowest effective dose of elacridar following from part I. The maximum tolerated dose and dose-limiting toxicity were determined in cohorts of three patients. Blood samples were taken on days 1, 8, and 15 of part I and on day 1 of cycles 1 and 2 of part II. Results: Complete apparent oral bioavailability of topotecan (102 ± 7%) for all treatment arms with elacridar in both schedules was seen in part I. In the topotecan dose escalation part, two dose-limiting toxicities were seen at the 2.5 mg topotecan dose level. Conclusion: The recommended schedule is 2.0 mg oral topotecan plus 100 mg elacridar administered concomitantly daily times five every 21 days.

Phase I Clinical Evaluation of Weekly Administration of the Novel Vascular-Targeting Agent, ZD6126, in Patients With Solid Tumors

PURPOSE ZD6126 is a novel vascular-targeting agent that induces selective effects on the morphology of endothelial cells by disrupting the tubulin cytoskeleton. This leads to cell detachment and tumor vessel congestion, resulting in extensive central necrosis in a range of tumor xenograft models. Results from a phase I dose-escalation study of ZD6126 are reported. PATIENTS AND METHODS Thirty-two patients with advanced cancer received weekly ZD6126 infusion (5 to 28 mg/m2). Assessments for safety and pharmacokinetics were performed. Circulating endothelial cells (CECs) were quantified as a pharmacodynamic marker of vascular damage. RESULTS Maximum concentrations of the active species were observed 5 to 25 minutes from the start of infusion, and decayed in a biexponential manner with a half-life of 1 to 3 hours. Maximum serum concentration and area under the time-concentration curve increased with dose in a linear fashion across the dose range of 5 to 28 mg/m2. One patient treated at 10 mg/m2 with a history of ischemic heart disease experienced acute myocardial infarction 2 weeks after drug discontinuation. Four others had asymptomatic creatine phosphokinase-muscle-brain elevation. Maximum-tolerated dose (MTD) was reached at 20 mg/m2/wk. Dose-limiting toxicities at 28 mg/m2 were hypoxia caused by pulmonary embolism and an asymptomatic decrease in left ventricular ejection fraction. No objective antitumor responses were observed. CEC levels increased in the hours after infusion, indicating potential effect of the compound on the vasculature. CONCLUSION ZD6126 administered as a weekly infusion was clinically well tolerated. The MTD was reached at 20 mg/m2.

Pharmacogenetic Screening of CYP3A and ABCB1 in Relation to Population Pharmacokinetics of Docetaxel

Purpose: Despite the extensive clinical experience with docetaxel, unpredictable interindividual variability in efficacy and toxicity remain important limitations associated with the use of this anticancer drug. Large interindividual pharmacokinetic variability has been associated with variation in toxicity profiles. Genetic polymorphisms in drug-metabolizing enzymes and drug transporters could possibly explain the observed pharmacokinetic variability. The aim of this study was therefore to investigate the influence of polymorphisms in the CYP3A and ABCB1 genes on the population pharmacokinetics of docetaxel. Experimental Design: Whole blood samples were obtained from patients with solid tumors and treated with docetaxel to quantify the exposure to docetaxel. DNA was collected to determine polymorphisms in the CYP3A and ABCB1 genes with DNA sequencing. A population pharmacokinetic analysis of docetaxel was done using nonlinear mixed-effect modeling. Results: In total, 92 patients were assessable for pharmacokinetic analysis of docetaxel. A three-compartmental model adequately described the pharmacokinetics of docetaxel. Several polymorphisms in the CYP3A and ABCB1 genes were found, with allele frequencies of 0.54% to 48.4%. The homozygous C1236T polymorphism in the ABCB1 gene (ABCB1*8) was significantly correlated with a decreased docetaxel clearance (−25%; P = 0.0039). No other relationships between polymorphisms and pharmacokinetic variables reached statistical significance. Furthermore, no relationship between haplotypes of CYP3A and ABCB1 and the pharmacokinetics could be identified. Conclusions: The polymorphism C1236T in the ABCB1 gene was significantly related to docetaxel clearance. Our current finding may provide a meaningful tool to explain interindividual differences in docetaxel treatment in daily practice.

Pharmacokinetics of chemotherapeutic agents in pregnancy: a preclinical and clinical study

Objective. To determine the impact of physiologic changes of pregnancy on pharmacokinetics of chemotherapeutic agents. Design. A preclinical and a clinical case–control trial. Setting. Institute of Primate Research Nairobi and collaborating hospitals in Belgium, the Netherlands and Czech Republic. Population. Pregnant and nonpregnant women and baboons receiving chemotherapy. Methods. Chemotherapy pharmacokinetics was compared between the pregnant and nonpregnant state. Standard‐dosed chemotherapy regimens were administered in pregnant and nonpregnant baboons/women, followed by serial blood samplings. Drug plasma levels were determined using high performance liquid chromatography and atomic absorption spectrometry. Main outcome measures. Area under the curve (AUC), maximal plasma concentration, terminal elimination half‐life, clearance and distribution volume of each drug in pregnant and nonpregnant state. Results. Intraindividual comparative pharmacokinetic data were obtained for doxorubicin and paclitaxel/platinum in three and two baboons, respectively. In the clinical trial, two patients were exposed to doxorubicin and one patient was exposed to paclitaxel/platinum during and after pregnancy. Furthermore, a pooled analysis was performed based on 16 cycles of pregnant and 11 cycles of nonpregnant women. Numbers of pregnant/nonpregnant patients were 5/2, 7/5, 4/4 and 2/2 for paclitaxel, doxorubicin, epirubicin and platinum, respectively. For all drugs tested in the preclinical and clinical study, a decreased AUC and maximal plasma concentration and an increased distribution volume and clearance were observed in pregnancy. Conclusions. Although numbers were too small for statistical significance, pregnancy‐associated physiologic alterations appear to lead to a decrease in plasma exposure of chemotherapeutic drugs. The importance of long‐term follow‐up of women treated with chemotherapy during pregnancy is underscored.

Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral Protein Kinase C β-Inhibitor Enzastaurin in Combination with Gemcitabine and Cisplatin in Patients with Advanced Cancer

Purpose: Enzastaurin targets the protein kinase C and phosphatidylinositol 3-kinase/AKT pathways to reduce tumor angiogenesis and cell proliferation and to induce cell death. A phase I trial was conducted to evaluate the feasibility of combining enzastaurin with gemcitabine and cisplatin. Experimental Design: Patients with advanced cancer received a 14-day lead-in treatment with oral enzastaurin followed by subsequent 21-day cycles of daily enzastaurin, gemcitabine on days 1 and 8, and cisplatin on day 1. Enzastaurin doses were escalated between 350 mg once daily to 500 mg twice daily, whereas gemcitabine doses were either 1,000 or 1,250 mg/m2 and cisplatin doses were either 60 or 75 mg/m2. Circulating endothelial cell numbers and CD146 and CD133 mRNA expression were evaluated as pharmacodynamic markers. Results: Thirty-three patients (median age, 58 years) were enrolled in seven dose levels. The maximum tolerated dose was not identified. Two dose-limiting toxicities (grade 2 QT interval corrected for heart rate prolongation and grade 3 fatigue) were reported. Other toxicities included grade 3/4 neutropenia (3 of 6 patients), thrombocytopenia (1 of 6 patients), grade 3 leukopenia (2 patients), and fatigue (5 patients). Enzastaurin twice daily (≥250 mg) resulted in more discontinuations and low-grade toxicities. In the combination, enzastaurin exposures decreased slightly but remained above the target of 1,400 nmol/L, whereas gemcitabine/cisplatin exposures were unaltered. Three patients (9.1%) had partial responses and 13 (39.4%) had stable disease. Measurement of circulating endothelial cell numbers and CD146 and CD133 mRNA expression did not contribute to decision-making on dose escalation. Conclusions: Recommended phase II dose is 500 mg enzastaurin once daily, 1,250 mg/m2 gemcitabine, and 75 mg/m2 cisplatin. This regimen is well tolerated with no significant alterations in the pharmacokinetic variables of any drug.

Gynecologic Cancer InterGroup (GCIG) consensus review for mullerian adenosarcoma of the female genital tract.

Mullerian adenosarcomas of the female genital tract are rare malignancies, originally described in the uterus, the most common site of origin, but they may also arise in extrauterine locations. Uterine adenosarcomas make up 5% of uterine sarcomas and tend to occur in postmenopausal women. They are usually low-grade tumors and are characterized by a benign epithelial component with a malignant mesenchymal component, which is typically a low-grade endometrial stromal sarcoma but can also be a high-grade sarcoma. Tumors that exhibit a high-grade sarcomatous overgrowth have a worse outcome. Adenosarcomas have been described as being midway along the spectrum between benign adenofibromas and carcinosarcomas. They generally have a good prognosis with the exception of deeply invasive tumors or those with high-grade sarcomatous overgrowth. Extrauterine adenosarcomas also have a higher risk for recurrence. In view of their rarity, there have not been any clinical trials in mullerian adenosarcomas and relatively little research. This article reviews the current knowledge and provides recommendation for the management of mullerian adenosarcomas.

Phase I and pharmacologic study of enzastaurin HCl, gemcitabine and cisplatin

3129 Background: Enzastaurin HCl (LY317615, e-HCl), an acyclic bisindolylmaleimide, is a potent inhibitor of Protein Kinase C-β isozyme. The β isoform lies in the signal cascade of VEGF and inhibition of this pathway may lead to a block in tumor angiogenesis. In preclinical studies gemcitabine (G) and cisplatin (C) exerted synergistic effects in combination with e-HCl. The objective of the study is to investigate the feasibility and toxicities of e-HCl in combination with G and C in patients (pts) with advanced malignancies, to evaluate the pharmacokinetics (PK) of all 3 agents and to recommend the Phase II doses when given in combination. METHODS Pts received a lead-in treatment period of single-agent oral e-HCl administered daily for 14 days, followed by repeated 21 day (d) combination cycles. In each combination cycle, e-HCl was taken orally on d1 - d21, G was administered as a 30 min. intravenous (iv) infusion on d1 and d8, followed by C as a 3 hr iv infusion on d1. The starting dose of e-HCl was 350 mg once daily and of G and C 1000 and 60 mg/m2, respectively. RESULTS Currently, 17 pts have been treated at 5 dose levels. No dose limiting toxicities have been reported. Drug related adverse events to date include max. CTC grade 2 gastro-intestinal toxicities, vitiligo, anorexia, tinnitus and deafness, and max. CTC grade 3 fatigue, neutropenia, thrombocytopenia, anemia and leukopenia. PK data indicate that the geometric mean (%CV) exposures of e-HCl in Cycle 1 were 20500 (196) nM*h at 350 mg, 32100 (94.8) nM*h at 500 mg; in Cycle 2, 18500(161) nM*h at 350 mg and 25500(83.2) nM*h at 500 mg. No apparent differences in e-HCl exposures were seen when given in combination with G and C. G exposures were not altered when given in combination with e-HCl as compared to historical data. C data is pending. Due to less than dose proportional increase in e-HCl exposures in a previous study, dosing of e-HCl was changed to a bid-dosing regimen. Bid dosing started at the most recent dose level 5; 250 mg bid e-HCl, 1250 mg/m2 G and 75 mg/m2 C. 3 Pts showed a PR (prostate, papilla and head/neck cancer). CONCLUSIONS Preliminary safety and PK data enable continued dose-escalation. [Table: see text].

European network of gynaecological oncological trial groups' requirements for trials between academic groups and industry partners - First update 2015

Abstract The first version of ENGOT’s Requirements for Trials Between Academic Groups and Industry Partners in Europe was published 2010. This first update integrates the experiences made by the ENGOT network and the cooperative group studies while performing, analyzing, and publishing -among others - three large phase III trials. Furthermore, progress in European legislation and its impact on clinical studies in Europe have been considered in this update process.

Phase I and pharmacological study of oral topotecan and the BCRP and P-gp inhibitor elacridar

2003 Background: Oral topotecan has a moderate (∼ 40%) and variable bioavailability (F). Complete apparent F can be obtained by combining topotecan with elacridar which inhibits BCRP and P-gp in the gut wall. The OBJECTIVES were 1] to determine the lowest effective dose (LED) of elacridar resulting in complete apparent F of topotecan and the optimal schedule of elacridar and topotecan and 2] to determine the maximal tolerated dose (MTD) and dose-limiting toxicity (DLT) of topotecan in combination with the LED of elacridar at a dailyx5 schedule every 21 days. Methods of part 1: Patients (pts) were randomized to receive 1000, 700, 500, 300 or 100 mg of elacridar (tablets) plus 2 mg topotecan (capsules) after a standard breakfast. Elacridar was administered 60 minutes prior to topotecan or simultaneously with topotecan on day 1 and 8, which was randomized within patients. I.V. topotecan was given on day 15. Pharmacokinetics (PK) of topotecan (total and lactone form) and elacridar were obtained by validated LC/MS/MS on days 1, 8 and 15. Part 2: The LED of elacridar was combined with increasing doses of topotecan in patient cohorts of 3 to determine MTD and DLT of the regimen. Results Part 1: 23 pts with advanced cancer (age range 27-75) were included in part 1. Three pts were not evaluable for PK and were replaced. There was no statistically significant effect of the elacridar dose or administration schedule on the apparent F of topotecan, which was 102 ± 7 % (range 94-111%). Part 2: 15 pts were included with age range 27-71 yrs. Dose levels of topotecan evaluated were 1.0, 1.5, 2.0, and 2.5 mg/day for 5 days. DLTs consisting of CTC Grade 4 leukocytopenia, neutropenia and thrombocytopenia were observed at 2.5 mg/d of topotecan. The MTD (6 pts) was 2.0 mg plus 100 mg elacridar. GI toxicity was minimal and the combination was well tolerated. CONCLUSIONS 100 mg elacridar given simultaneously was sufficient to provide maximal apparent F of topotecan. The recommended oral dose of topotecan in this combination and schedule is 2.0 mg. [Table: see text].