13 the Clinical Development of Lurtotecan Experience with Water-Soluble and Liposomal Forms

Chapter 13 / Clinical Development of Lurtotecan 301 13 The Clinical Development of Lurtotecan Experience With Water-Soluble and Liposomal Forms Keith T. Flaherty, MD, James P. Stevenson, MD, Christopher J. Twelves, MD, and Peter J. O’Dwyer, MD CONTENTS INTRODUCTION WATER-SOLUBLE LURTOTECAN LIPOSOMAL LURTOTECAN SUMMARY REFERENCES 1. INTRODUCTION Camptothecin (CPT) derivatives have become integral to the manage- ment of lung and colon cancer. They continue to be the subject of intense investigation. The parent compound, CPT, was extracted from the leaves of Camptotheca acuminata by Wall and Wani in 1957. The hydrophilic car- boxylate salt entered clinical trials in the late 1960s. The lack of efficacy and unpredictable bone marrow and bladder toxicity halted its clinical development (1). When topoisomerase I (TOP-I) was discovered as the target of CPT class of compounds 1985 (2), there was a resurgence of interest in the compound. Camptothecins in Cancer Therapy Edited by: V. R. Adams and T. G. Burke © Humana Press Inc., Totowa, NJ 301 302 Flaherty et al. TOP-I is a non-energy–dependent enzyme that causes single-stranded breaks in DNA and allows relaxation of positively and negatively supercoiled DNA before transcription or replication (3). The CPTs form covalently bound complexes with TOP-I and DNA. S-phase–specific cytotoxicity results from replication fork collision of DNA polymerase and the CPT/DNA adduct (4). CPT-stabilized DNA cleavage complexes are not sufficient for cytotoxicity. The requirement for DNA replication has been shown by the protection against CPT-induced cytotoxicity by the DNA synthesis inhibitors hydrox- yurea and aphidicolin (5,6). Repair of TOP-I–mediated DNA damage is accomplished through ubiquitin/26S proteasome-mediated degradation of TOP-I (7). Whereas normal tissues such as peripheral blood mononuclear cells downregulate TOP-I in response to incubation with CPT (8), breast, colon, and leukemia cell lines do not (9). Subsequent to initial clinical trials, it was found that the structure of CPT derivatives is altered in plasma (10). An equilibrium exists between the five- ring structure and the open E-ring (Fig. 1). The latter form of the drug has less than 10% of the activity of the closed-ring compound against topoisomerase in vitro and binds with high affinity to human serum albumin (11). Although the active and inactive form of the drug exist in a 1:1 ratio in the plasma of mice, in humans the ratio shifts to 1:9 (12). These findings led to the generation of CPT derivatives with a lower affinity for albumin. Substitutions at the 10 and 11 positions on the A-ring have been shown to increase in vitro activity, provided that there is no steric encroachment on the 12 position (13). Alteration at the 20 position on the E-ring generally decreases activity (14), with the exception of substitutions with CH2, Br, and Cl (15,16). 10,11-ethylenedioxy-camptothecin is more water-soluble and more potently inhibits TOP-I compared with CPT by creating more stable TOP-I–DNA cleavage complexes (17,18). Two CPT derivatives have already shown remarkable antitumor activity in humans. Topotecan was generated by modifying the ninth and tenth position of the A-ring (Fig. 2). It was approved by the Food and Drug Administration for use in women with previously treated ovarian cancer based on the results of a Phase III trial comparing it with paclitaxel (19). Irinotecan is a CPT analogue with modifications at the seventh and tenth position on the A-ring (see Fig. 2). It is approved for use in patients with colon cancer that have recurred or progressed after 5-Fluorouracil (5-FU)– based chemotherapy (20,21). 2. WATER-SOLUBLE LURTOTECAN 2.1. Preclinical Studies Lurtotecan (GI147211, GlaxoSmithKline) was created by the addition of an ethylenedioxy group bridging the tenth and eleventh position of the A-ring, Chapter 13 / Clinical Development of Lurtotecan 303 Fig. 1. Picture of camptothecin with rings lettered and positions numbered and picture of lurtotecan from GSK investigator brochure. (Adapted from Kohn & Pommier, Annal NY Acad Sci, 2001.) as well as a 4- methylpiperazinomethylene moiety at the seventh position of the B ring yielding [7-(4-methylpiperazinomethylene)-10,11-ethylenedioxy-20(S)-camptothecin] (22) (Fig. 3). It is more water-soluble than topotecan or CPT. Topoisomerase-mediated DNA strand breaks, a measure of topoisomerase activity, are inhibited with more than twofold greater potency by lurtotecan compared with topotecan. The IC50 for lurtotecan was significantly lower than topotecan in five human tumor cell lines. The efficacy was not reduced in the multidrug-resistant (MDR)–positive cell line, SKVLB. In two mouse xenograft models with implanted human colon cancer cell lines, lurtotecan showed dose-dependent reduction in tumor vol- ume, whereas topotecan had only modest tumoristatic effect. Remarkable activity was also seen in a MX-1 breast cancer xenograft model. Toxicity in animal models resembled that of topotecan. 304 Flaherty et al. Fig. 2. Chemical structure of camptothecin. Topotecan contains substitutions at the ninth and tenth position of the A ring . Irinotecan has substitutions at the seventh and tenth position of the A ring. Fig 3. Chemical structure of lurtotecan. 2.2. Phase I Clinical Trials A summary of the phase I clinical trials of water-soluble lurtotecan is presented in Table 1. In 1996, Gerrits et al. reported the results of a phase I trial of lurtotecan carried out at the Rotterdam Cancer Institute (23). The drug was administered intravenously daily for 5 consecutive days every 3 weeks. Nineteen patients with advanced cancer were enrolled in the study; six had received prior chemotherapy, and nine had colorectal cancer. The dose was escalated from 0.3 to 1.5 mg/m2/day. Neutropenia and thrombocytopenia were dose-limiting. The maximum tolerated dose (MTD) of 1.5 mg/ m2/day was determined by 11 instances of grade 4 neutropenia of 15 evaluable courses of treatment. Seven of 15 courses were complicated by grade 3 or 4 thrombocytopenia. There were no grade 3 or 4 nonhematologic toxicities, with mild nausea and vomiting being the most common adverse event. One patient with colon cancer had a short-lasting partial response and one patient with leiomyosarcoma had a minor response. Ten other patients had stable disease. Pharmacokinetic data were collected during the first 4 days of the first course on 18 patients. The area of the time-concentration curve (AUC) was linearly related to dose. The terminal half-life was 3.54 ± 0.99 hours. Chapter 13/ClinicalDevelopmentofLurtotecan 305 Table 1 Clincal Trials of Water-soluble Lurtotecan Phase I trials Investigator Schedule Phase II dose DLT Responses Gerrits et al. Days 1–5 q 3 weeks 1.5 mg/m2/d × 5 days Neutropenia 1 PR, 10 SD of 19 patients Gerrits et al. Day 1 PO, days 2–5 IV q 3 weeks 6.0 mg/m2 PO, 1.5 mg/ m2/day × 4 days Neutropenia 7 SD of 27 patients and thrombocytopenia Eckhardt et al. Days 1–5 q 3 weeks 1.5 mg/m2/day × 5 days Neutropenia None Paz-Ares et al. 72 hour CI q 4 weeks 1.2 mg/m2/day × 3 days, Neutropenia 3 PR, 2 MR of 44 patients heavily pretreated and thrombocytopenia 1.75 mg/m2/day × 3 days, minimally pretreated Stevenson et al. 7–21 day CI, 2 week break 0.4 mg/m2/day × 21 days Thrombocytopenia 2 PR, 2 SD of 38 patients Phase II trials Investigator Regimen Toxicity Responses Sessa et al. 1.2 mg/m2/day × 5 days q 3 weeks 25% grade 3 or 4 neutropenia 11 PR, 21 SD of 62 patients with SCLC 22% grade 3 or 4 thrombocytopenia Gamucci et al. 1.2 mg/m2/day × 5 days q 3 weeks 55% grade 3 or 4 neutropenia 3 PR, 9 SD of 20 patients with breast cancer 20% grade 3 or 4 thrombocytopenia 2 PR, 5 SD of 23 patients with NSCLC 7 SD of 19 patients with colorectal cancer CI, continuous infusion; SCLC, small cell lung cancer; PR, partial response; NSCLC, non-small cell lung cancer; MR, minor response; SD, stable disease. 306 Flaherty et al. The following year, Gerrits et al. published the results of a phase I study using a single dose of oral lurtotecan on day 1, followed by 4 days of intravenous infusion (24). The intravenous doses were fixed at 1.5 mg/m2/ day, based on the results of the all-intravenous phase I trial. Oral therapy was given on day 1 of the first two cycles only, because the goal of the study was to determine the bioavailability of the drug. The oral dose levels were 1.5, 3.0, and 6.0 mg/m2. Nineteen patients were entered into the study. To determine the interaction between bioavailability and food intake, eight addi- tional patients were added at the 6.0 mg/m2 level. Grade 3 or 4 neutropenia or thrombocytopenia was observed in 5 of 30 and 4 of 30 treatments courses, respectively. Treatment delay secondary to persistent leukopenia occurred in 5 of 13 patients at the highest dose level. The AUC after a 6.0 mg/m2 oral dose was 20.3 ng/mL/hour compared to 32.1 ng/mL/hour after an intravenous dose of 1.5 mg/m2/day. The absolute bioavailability was 11.8 ± 4.5%. The half-life of the oral drug was 6.8 ± 3.1 hours. Seven patients, five of whom had colon cancer, experienced stable disease. Another phase I study of intravenous lurtotecan was performed at the Institute for Drug Development in San Antonio and reported in 1998 (25).

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