Jeany M. Rademaker-Lakhai

A Phase I and Pharmacological Study with Imidazolium-trans-DMSO-imidazole-tetrachlororuthenate, a Novel Ruthenium Anticancer Agent

Purpose: NAMI-A {H2Im[trans-RuCl4(DMSO)HIm] or imidazolium-trans-DMSO-imidazole-tetrachlororuthenate} is a novel ruthenium-containing compound that has demonstrated antimetastatic activity in preclinical studies. This Phase I study was designed to determine the maximum-tolerated dose (MTD), profile of adverse events, and dose-limiting toxicity of NAMI-A in patients with solid tumors. Furthermore, the ruthenium pharmacokinetics (PK) after NAMI-A administration and preliminary antitumor activity were evaluated. Patients and Methods: Adult patients with solid tumors received NAMI-A as an i.v. infusion over 3 h daily for 5 days every 3 weeks. PK of total and unbound ruthenium was determined during the first and second treatment using noncompartmental pharmacokinetic analysis. The total accumulation of ruthenium in WBCs was also quantified. Results: Twenty-four patients were treated at 12 dose levels (2.4–500 mg/m2/day). At 400 mg/m2/day, blisters developed on the hands, fingers, and toes. At 500 mg/m2/day, blisters persisted from weeks to months and slowly regressed. Although no formal common toxicity criteria (CTC) grade 3 developed, painful blister formation was considered dose limiting. Because the first signs developed at 400 mg/m2/day, the advised dose for further testing of NAMI-A was determined to be 300 mg/m2/day on this schedule. PK analysis revealed a linear relationship between dose and area under the concentration-time curve (AUC) of total and unbound ruthenium (R2 = 0.75 and 0.96, respectively) over the whole dose range. Plasma clearance of total ruthenium was 0.17 ± 0.09 liter/h, and terminal half-life was 50 ± 19 h. The volume of distribution at steady state of total ruthenium was 10.1 ± 2.8 liters. The accumulation of ruthenium in WBC was not directly proportional to the increasing total exposure to ruthenium. One patient with pretreated and progressive nonsmall cell lung cancer had stable disease for 21 weeks. Conclusion: NAMI-A can be administered safely as a 3-h i.v. infusion at a dose of 300 mg/m2/day for 5 days, every 3 weeks.

A Phase I and Pharmacological Study of the Platinum Polymer AP5280 Given as an Intravenous Infusion Once Every 3 Weeks in Patients with Solid Tumors

Purpose: This Phase I study was designed to determine the maximum tolerated dose, profile of adverse events, and dose-limiting toxicity of AP5280 in patients with solid tumors. Furthermore, the platinum (Pt) pharmacokinetics after AP5280 administration and preliminary antitumor activity were evaluated. AP5280 is a Pt agent linked to the water-soluble, biocompatible copolymer N-(2-hydroxypropyl)methacrylamide, which potentially increases Pt accumulation in tumors via the enhanced permeability and retention effect. In this way, it is anticipated that a higher activity of therapeutic Pt can be reached. The pharmaceutical product contains approximately 8.5% of Pt by weight and has a molecular weight of approximately 25,000. Experimental Design: Adult patients with solid tumors received AP5280 as a 1-h i.v. infusion every 21 days. Pharmacokinetics of total and unbound Pt were determined during the first treatment course and before the start of each new cycle using noncompartmental pharmacokinetic analysis. Pt-DNA adduct concentrations in WBCs and, if available, in tumor tissue were quantified using a sensitive 32P postlabeling assay. Results: Twenty-nine patients were treated at eight dose levels (90–4500 mg Pt/m2). The dose-limiting toxicity was Common Toxicity Criteria grade 3 vomiting and was experienced at 4500 mg Pt/m2 in two of six patients. The maximum tolerated dose on this schedule was therefore 4500 mg Pt/m2, and the recommended dose for a Phase II study is 3300 mg Pt/m2. Renal toxicity and myelosuppression, toxicities typically observed with cisplatin and carboplatin, were minimal for AP5280. The area under the curve of total Pt increased with increasing AP5280 dose. Plasma clearance of total Pt was 644 ± 266 ml/h, and the terminal half-life was 116 ± 46.2 h. After AP5280 administration, Pt-guanine-guanine DNA adduct concentrations in WBCs ranged from 70 to 1848 amol/μg DNA, concentrations that were substantially lower than concentrations measured after administration of therapeutic doses of cisplatin. Conclusions: AP5280 can be administered safely as a 1-h i.v. infusion at a dose of 3300 mg Pt/m2 once every 3 weeks and produces prolonged plasma exposure compared with any of the free Pt-containing drugs. However, it remains to be determined whether AP5280 can actually increase Pt delivery to the DNA of tumor cells in man as has been shown in experimental models.

Relationship Between Cisplatin Administration and the Development of Ototoxicity

PURPOSE To determine the auditory toxicity associated with dose- and schedule- intensive cisplatin/gemcitabine chemotherapy in non-small-cell lung carcinoma patients. PATIENTS AND METHODS Patients were treated with gemcitabine followed by cisplatin according to an interpatient dose-escalation scheme. Patients were randomly assigned to receive treatment once a week for 6 weeks or once every 2 weeks for 4 weeks. The following cohorts of patients were treated with a reversed schedule once every 2 weeks, in which cisplatin was followed by gemcitabine. The dose-intensity of cisplatin was equal in both schedules. Audiometric evaluations were obtained for each ear at several frequencies. Mean hearing loss after cisplatin treatment was computed for each dose level at each tested frequency in each ear at baseline and subsequent follow-up audiometry. Pure tone averages (PTAs) were also calculated. The pharmacokinetics of cisplatin was determined to study the correlation among the maximum drug concentration, the area under the curve of unbound platinum, and the development of ototoxicity. RESULTS A total of 328 audiograms were analyzed. At the higher frequencies, a more severe hearing impairment was recorded. Most patients showed a decrease in hearing thresholds at dosages above 60 mg/m2 cisplatin at the higher frequencies. PTAs at 1, 2, and 4 kHz show a mean hearing loss of 19 dB after cisplatin administration at dosages above 90 mg/m2. Threshold shifts at 8 and 12.5 kHz after cisplatin administration were experienced at dosages above 60 mg/m2. CONCLUSION Hearing loss after cisplatin therapy occurs mainly at high frequencies and at cisplatin dosages more than 60 mg/m2. It is more pronounced when cisplatin is given once every 2 weeks.

Phase I Clinical and Pharmacokinetic Study of Kahalalide F in Patients with Advanced Androgen Refractory Prostate Cancer

Purpose: The purpose is to determine the maximum tolerated dose, profile of adverse events, and dose-limiting toxicity of Kahalalide F (KF) in patients with androgen refractory prostate cancer. Furthermore, the pharmacokinetics after KF administration and preliminary antitumor activity were evaluated. KF is a dehydroaminobutyric acid–containing peptide isolated from the marine herbivorous mollusk, Elysia rufescens. Experimental Design: Adult patients with advanced or metastatic androgen refractory prostate cancer received KF as an i.v. infusion over 1 hour, during five consecutive days every 3 weeks. The starting dose was 20 μg per m2 per day. Clinical pharmacokinetics studies were done in all patients using noncompartmental analysis. Prostate-specific antigen levels were evaluated as a surrogate marker for activity against prostate cancer. Results: Thirty-two patients were treated at nine dose levels (20-930 μg per m2 per day). The maximum tolerated dose on this schedule was 930 μg per m2 per day. The dose-limiting toxicity was reversible and asymptomatic Common Toxicity Criteria grade 3 and 4 increases in transaminases. The recommended dose for phase II studies is 560 μg per m2 per day. Pharmacokinetics analysis revealed dose linearity up to the recommended dose. Thereafter, a more than proportional increase was observed. Elimination was rapid with a mean (SD) terminal half-life (t1/2) of 0.47 hour (0.11 hour). One patient at dose level 80 μg per m2 per day had a partial response with a prostate-specific antigen decline by at least 50% for ≥4 weeks. Five patients showed stable disease. Conclusions: KF can be given safely as a 1-hour i.v. infusion during five consecutive days at a dose of 560 μg per m2 per day once every 3 weeks.

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.

Trabectedin (YondelisTM, formerly ET-743), a mass balance study in patients with advanced cancer

Trabectedin (YondelisTM, formerly ET-743) is an anti-cancer drug currently undergoing phase II development. Despite extensive pharmacokinetic studies, the human disposition and excretory pathways of trabectedin remain largely unknown. Our objective was to determine the mass balance of trabectedin in humans. To this aim, we intravenously administered [14C]trabectedin to 8 cancer patients, followed by collection of whole blood, urine and faeces samples. A 24-h infusion was administered to 2 patients, whereas the other 6 patients received a 3-h infusion. Levels of total radioactivity and unchanged trabectedin were determined and used for calculation of pharmacokinetic parameters. No schedule dependency of pharmacokinetic parameters was observed apart from Cmax. Plasma and whole blood concentrations of [14C]trabectedin related radioactivity were comparable. Only 8% of the plasma exposure to [14C]trabectedin related compounds is accounted for by trabectedin, indicating the importance of metabolism in trabectedin elimination. Trabectedin displays a large volume of distribution (±1700 L), relative to total radioactivity (±220 L). [14C]trabectedin related radioactivity is mainly excreted in the faeces (mean: 55.5% of the dose). Urinary excretion accounts for 5.9% of the dose on average resulting in a mean overall recovery of 61.4% (3-h administration schedule). The excretion of unchanged trabectedin is very low both in faeces and in urine (< 1% of dose). In conclusion, trabectedin is extensively metabolised and principally excreted in the faeces.

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].