Ralf A. Hilger

Phase I Clinical and Pharmacokinetic Study of the Novel Raf Kinase and Vascular Endothelial Growth Factor Receptor Inhibitor BAY 43-9006 in Patients With Advanced Refractory Solid Tumors

PURPOSE BAY 43-9006 is a novel dual-action Raf kinase and vascular endothelial growth factor receptor inhibitor that inhibits tumor cell proliferation and angiogenesis. This study established the safety and pharmacokinetics of BAY 43-9006 in 69 patients with advanced refractory solid tumors. PATIENTS AND METHODS BAY 43-9006 (50 to 800 mg) was administered once or twice daily on a varying weekly schedule. Pharmacokinetic sampling was performed in all patients; preliminary tumor response was also assessed. The effect of BAY 43-9006 on phorbol myristate acetate-stimulated ERK phosphorylation in peripheral blood lymphocytes was studied using flow cytometry. RESULTS Mild to moderate diarrhea was the most common (55%) treatment-related adverse event. The maximum-tolerated dose was 400 mg bid continuous. Dose-limiting toxicities were grade 3 diarrhea and fatigue at 800 mg bid, and grade 3 skin toxicity at 600 mg bid. BAY 43-9006 pharmacokinetics were highly variable for single and multiple dosing, and toxicity did not appear to be dose dependent. Significant decreases of phorbol myristate acetate-stimulated ERK phosphorylation (P < .01) were identified at doses >/= 200 mg bid continuous. Forty-five patients were assessable for efficacy; one patient had a partial response (hepatocellular carcinoma at 400 mg bid continuous), 25 patients had stable disease, with eight lasting > 6 months and five for >12 months. Eighteen patients had progressive disease, and tumor response could not be evaluated in one patient. CONCLUSION Oral BAY 43-9006 was well tolerated and appeared to provide some clinical benefits. Based on the results of this study, BAY 43-9006 at 400 mg bid continuous is recommended for ongoing and future studies.

Pharmacokinetics of a novel anticancer ruthenium complex (KP1019, FFC14A) in a phase I dose-escalation study.

A phase I and pharmacokinetic study was carried out with the new ruthenium complex indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019, FFC14A). Seven patients with various types of solid tumours refractory to standard therapy were treated with escalating doses of KP1019 (25–600 mg) twice weekly for 3 weeks. No dose-limiting toxicity occurred. Ruthenium plasma concentration–time profiles after the first dose and under multiple-dose conditions were analysed using a compartmental approach. The pharmacokinetic disposition was characterised by a small volume of distribution, low clearance and long half-life. Only a small fraction of ruthenium was excreted renally. The area under the curve values increased proportionally with dose indicating linear pharmacokinetics.

Boron analysis and boron imaging in biological materials for Boron Neutron Capture Therapy (BNCT)

Boron Neutron Capture Therapy (BNCT) is based on the ability of the stable isotope 10B to capture neutrons, which leads to a nuclear reaction producing an alpha- and a 7Li-particle, both having a high biological effectiveness and a very short range in tissue, being limited to approximately one cell diameter. This opens the possibility for a highly selective cancer therapy. BNCT strongly depends on the selective uptake of 10B in tumor cells and on its distribution inside the cells. The chemical properties of boron and the need to discriminate different isotopes make the investigation of the concentration and distribution of 10B a challenging task. The most advanced techniques to measure and image boron are described, both invasive and non-invasive. The most promising approach for further investigation will be the complementary use of the different techniques to obtain the information that is mandatory for the future of this innovative treatment modality.

Clinical pharmacokinetics of intravenous treosulfan in patients with advanced solid tumors.

Abstract Treosulfan (l-threitol-1,4-bis-methanesulfonate, Ovastat) is a prodrug of a bifunctional alkylating agent with activity in ovarian carcinoma and other solid tumors. For a clinical and pharmacology study, patients with advanced, refractory, or resistant solid tumors were treated with a single-dose intravenous 30-min infusion of 8 or 10 g/m2 treosulfan. A sensitive method for the determination of treosulfan in plasma and urine by reverse-phase high-performance liquid chromatography was developed. A total of 14 plasma and urine treosulfan pharmacokinetics determinations were analyzed in the 8-g/m2 group and 7 were analyzed in the 10-g/m2 group, the maximum tolerated dose for this group of pretreated patients. The terminal half-life of treosulfan was in the range of 1.8 h. AUC and Cmax values were significantly (P < 0.01) higher in the 10-g/m2 group (AUC 708 ± 168 versus 977 ± 182 μg ml−1 h, Cmax 465 ± 98 versus 597 ± 94 μg/ml). The mean urinary excretion of the parent compound was about 25% of the total dose delivered over 48 h (range 5–49%), and about 20% was excreted during the first 6 h after administration. Currently, a clinical phase I pharmacokinetics and dose-escalation trial with autologous blood stem-cell support has been started at 20 g/m2 treosulfan using a 2-h infusion protocol.

The epidermal growth factor receptor tyrosine kinase inhibitor gefitinib sensitizes colon cancer cells to irinotecan

Epidermal growth factor receptor (EGFR) overactivity plays a significant role in colon cancer biology and has been associated with poor clinical prognosis. Early clinical trials reported efficacy of receptor-targeted compounds, including modulation of clinical irinotecan resistance. We investigated the effects of the EGFR tyrosine kinase inhibitor gefitinib on cellular determinants of irinotecan resistance in human colon cancer cells. At non-cytotoxic concentrations, gefitinib sensitized colon cancer cells to SN-38, the active metabolite of irinotecan. Gefitinib increased the SN-38-mediated induction of protein-linked DNA single-strand breaks in a dose-dependent manner, with no alteration of topoisomerase (Topo) I protein expression or enzymatic activity. Whereas Topo II&bgr; protein expression was not affected by gefitinib, significant time- and concentration-dependent downregulation of Topo II&agr; protein and inhibition of its enzymatic function were observed, corresponding to a G1 phase cell cycle arrest. Gefitinib significantly inhibited EGFR-associated signaling molecules, including phospho-mitogen-activated protein kinase or protein kinase C, which may account for decreases in proliferation or topoisomerase activity, respectively. Although a dose-dependent decrease of the BCRP/MXR/ABCP half-transporter was observed under gefitinib, cellular pharmacokinetics revealed no significant differences in accumulation or retention of the active SN-38 lactone using reverse-phase HPLC analysis. This study delineates mechanisms that may contribute to the synergism observed between irinotecan and EGFR inhibitors.

Investigation of bioavailability and pharmacokinetics of treosulfan capsules in patients with relapsed ovarian cancer.

Purpose: Treosulfan (l-threitol-1,4-bis-methanesulfonate, Ovastat) is a prodrug of a bifunctional alkylating agent with activity in ovarian carcinoma and other solid tumors. In a pharmacologic study of the bioavailability of treosulfan in a capsule formulation, patients with relapsed ovarian carcinoma were treated with alternating doses of oral and intravenous (i.v.) treosulfan of 1.5 or 2.0 g daily for 5 to 8 days. Methods: A sensitive method for the determination of treosulfan in plasma and urine by reversed-phase high-performance liquid chromatography had previously been developed. Pharmacokinetic analyses of treosulfan were carried on plasma and urine samples from 20 i.v. courses and 20 courses of oral administration. Results: The bioavailability ratio (f) of oral to i.v. administration was calculated as 0.97 ± 0.18 (mean ± SD) using the values AUCoral=82.1 ± 39.4 μg/ml h and AUCi.v.=85.4 ± 30.3 μg/ml h. The peak plasma concentration cmax (29 ± 14 μg/ml vs 65 ± 23 μg/ml) was significantly (P < 0.01) higher after i.v. administration and the tmax after oral administration was 1.5 ± 0.34 h. The terminal half-life of treosulfan was about 1.8 h. The mean urinary excretion of the parent compound was about 15% of the administered total dose over 24 h (range 6–26%). Conclusions: The high and relatively constant bioavailability of treosulfan indicates that capsules provide a satisfactory noninvasive treatment alternative. A feasible and reliable oral treosulfan formulation could provide the basis for the development of long-term low-dose outpatient treatment of patients with malignant diseases.

Results of a phase I trial of BAY 43-9006 in combination with oxaliplatin in patients with refractory solid tumors

3056 Background:BAY 43-9006 (BAY) is a novel signal transduction inhibitor that prevents tumor cell proliferation and angiogenesis through blockade of the Raf/MEK/ERK pathway at the level of Raf kinase and the receptor tyrosine kinases VEGFR-2 and PDGFR-β. Previous single-agent phase I trials show BAY is well tolerated with manageable and reversible side effects, most commonly hand-foot skin (HFS) reaction, rash, fatigue, and diarrhea. This study was initiated to determine safety and pharmacokinetics (PK) of BAY in combination with oxaliplatin (OXAL). METHODS Patients (pts) received continuous BAY at 200 mg bid (cohort 1) followed by escalation to 400 mg bid (cohort 2) given with a fixed dose of OXAL at 130 mg/m2 q3wks. RESULTS 24 pts (M:F ratio =16:8; median age 60.5 yrs range 32-73) entered the study. Common tumor types were CRC (21%), Mel (21%) and RCC (13%). Drug-related dose-limiting toxicities to either drug were gr 3 thrombocytopenia and gr 3 diarrhea in cohort 1 (thrombocytopenia 1/8 pts; diarrhea 1/8 pts) and in cohort 2 (thrombocytopenia 2/16 pts; diarrhea 1/8 pts). Other toxicities consisted of non-hematologic: gastrointestinal-92% (diarrhea-58%, nausea-50%), constitutional-71% (fatigue-38%), neurological-67% (sensory neuropathy-46%), pain-50%, dermatological-46%. Hematologic AEs were uncommon. Single infusions of 130 mg/m2 OXAL did not significantly alter the steady state PK profile of BAY following multiple oral doses of 200 and 400 mg bid BAY. Similarly, PK profiles of total and unbound platinum were not significantly influenced by concomitant multiple doses of BAY. Prolonged stabilization of previously progressive disease was obtained in 2/8 pts in cohort 1 and 5/16 pts in cohort 2. Two additional pts with gastric cancer (1 in each cohort) had partial responses according to modified WHO criteria. CONCLUSIONS Continuous 400 mg bid BAY in combination with 130 mg/m2 OXAL (q3week) appears to be well tolerated with no clinically relevant PK interaction. Clinical activity has been observed and an extension in CRC pts is ongoing. The recommended dose of BAY for phase II studies in combination with OXAL is 400 mg bid BAY. [Table: see text].

Open-label, randomized study of individualized, pharmacokinetically (PK)-guided dosing of paclitaxel combined with carboplatin or cisplatin in patients with advanced non-small-cell lung cancer (NSCLC).

BACKGROUND Variable chemotherapy exposure may cause toxicity or lack of efficacy. This study was initiated to validate pharmacokinetically (PK)-guided paclitaxel dosing in patients with advanced non-small-cell lung cancer (NSCLC) to avoid supra- or subtherapeutic exposure. PATIENTS AND METHODS Patients with newly diagnosed, advanced NSCLC were randomly assigned to receive up to 6 cycles of 3-weekly carboplatin AUC 6 or cisplatin 80 mg/m(2) either with standard paclitaxel at 200 mg/m(2) (arm A) or PK-guided dosing of paclitaxel (arm B). In arm B, initial paclitaxel dose was adjusted to body surface area, age, sex, and subsequent doses were guided by neutropenia and previous-cycle paclitaxel exposure [time above a plasma concentration of 0.05 µM (Tc>0.05)] determined from a single blood sample on day 2. The primary end point was grade 4 neutropenia; secondary end points included neuropathy, radiological response, progression-free survival (PFS) and overall survival (OS). RESULTS Among 365 patients randomly assigned, grade 4 neutropenia was similar in both arms (19% versus 16%; P = 0.10). Neuropathy grade ≥2 (38% versus 23%, P < 0.001) and grade ≥3 (9% versus 2%, P < 0.001) was significantly lower in arm B, independent of the platinum drug used. The median final paclitaxel dose was significantly lower in arm B (199 versus 150 mg/m(2), P < 0.001). Response rate was similar in arms A and B (31% versus 27%, P = 0.405), as was adjusted median PFS [5.5 versus 4.9 months, hazard ratio (HR) 1.16, 95% confidence interval (CI) 0.91-1.49, P = 0.228] and OS (10.1 versus 9.5 months, HR 1.05, 95% CI 0.81-1.37, P = 0.682). CONCLUSION PK-guided dosing of paclitaxel does not improve severe neutropenia, but reduces paclitaxel-associated neuropathy and thereby improves the benefit-risk profile in patients with advanced NSCLC. CLINICAL TRIAL INFORMATION NCT01326767 (https://clinicaltrials.gov/ct2/show/NCT01326767).

Sodium mercaptoundecahydro-closo-dodecaborate (BSH), a boron carrier that merits more attention

Boron neutron capture therapy relies on the preferential delivery of a (10)B-compound to tumor cells. The BSH-biodistribution was investigated in nu/nu mice and human patients. The boron concentration was measured with prompt gamma ray spectroscopy. BSH accumulates to a very low extent not only in brain, but also in fat tissue, bone and muscle, which makes BSH an interesting drug not only for brain lesions but also for tumors located at the extremities. The differential uptake in different organs indicates a complex mechanism.

High-dose chemotherapy with peripheral blood stem cell transplantation for patients with advanced ovarian cancer

Purpose: We report the results of high-dose chemotherapy (HDC) with peripheral blood stem cell transplantation in twenty-one patients with primarily advanced or relapsed ovarian cancer. Methods: Twenty-five women underwent stem cell collection, and 21 were finally treated with different regimens of HDC containing cyclophosphamide, etoposide, carboplatin, and treosulfan. The patients received cyclophosphamide ± cisplatin and cisplatin + paclitaxel, respectively, followed by G-CSF (n=24) or GM-CSF (n=1) for stem cell mobilization. Results: A mean of 7.2 ± 6.1 × 106 CD34+ cells per kg bw were collected. Thirteen patients received double transplants and one patient received a triple transplant. The median age was 47 years (range 24–61 years) and the mean number of prior regimens was three (range 1–8). Engraftment occurred on time in all patients and there was one treatment-related death resulting in an overall mortality rate of 4.8% among the 21 patients treated with HDC. The response rate was 72% (48% CR, 24% PR) and the mean time to progression and overall survival after HDC were 7 and 32 months, respectively. Conclusion: HDC could be performed safely in patients with advanced ovarian cancer. However, even with a high response rate, the duration of response is short, warranting new treatment approaches to further improve the outcome of this population of patients with unfavorable prognosis.