Exatecan Mesylate), a Hexacyclic Camptothecin, on a Daily-Times- Five Schedule in Patients with Advanced Leukemia1

2134 Vol. 8, 2134–2141, July 2002 Clinical Cancer Research Phase I and Pharmacokinetic Study of DX-8951f (Exatecan Mesylate), a Hexacyclic Camptothecin, on a Daily-Times- Five Schedule in Patients with Advanced Leukemia1 Francis J. Giles,2 Jorge E. Cortes, Conclusions: Phase II studies are warranted to further Deborah A. Thomas, Guillermo Garcia-Manero, define the activity of DX-8951f in patients with hematological malignancies. Stephan Faderl, Sima Jeha, Robert L. De Jager, and Hagop M. Kantarjian INTRODUCTION Department of Leukemia, The University of Texas M. D. Anderson Novel agents are required to improve the prognosis of Cancer Center, Houston, 77030 Texas [F. J. G.], and Daiichi patients with hematological malignancies. Camptothecin, an Pharmaceutical Corporation, Montvale, New Jersey 07645 alkaloid isolated from the Chinese tree Camptotheca acuminata, has a cytotoxic effect mediated through interference with the ABSTRACT catalytic cycle of DNA topo I3 enzyme and stabilization of the Purpose: DX-8951f is a novel hexacyclic camptothecin- covalent DNA-enzyme complex by inhibiting DNA religation analogue topoisomerase I inhibitor with both in vitro anti- (1–4). The reversible drug-enzyme-DNA ternary complex causes arrest of the replication fork and formation of single- leukemic activity and myelosuppression as a dose-limiting strand DNA breaks during DNA synthesis (5). Initial clinical toxicity in solid tumor Phase I studies. DX-8951f is active in studies of camptothecin were halted because of severe and a human acute myeloid leukemia (AML) severe combined unpredictable adverse effects (6, 7). Camptothecin derivatives, immunodeficient mouse model. In a leukemia Phase I study, including irinotecan (CPT-11) and topotecan, were developed to we investigated the toxicity profile and pharmacokinetics of improve the toxicity profile and poor aqueous solubility of the DX-8951f in patients with primary refractory or relapsed parent drug (8, 9). Topotecan administered as a single agent has AML or acute lymphocytic leukemia, myelodysplastic syn- significant antileukemic activity in patients with AML and MDS dromes, or chronic myelogenous leukemia in blastic phase (9–17). We have recently reported on its activity as a compo- (CML-BP). nent of combination regimes in these patients (18–20). Further Experimental Design: DX-8951f was given as an i.v. development of novel topo I inhibitors was spurred by the infusion over 30 min daily for 5 or 7 days. The starting dose spectrum of potencies of this class of drugs in terms of enzyme was 0.6 mg/m2/day for 5 days (3.0 mg/m2/course). Courses inhibition, antiproliferative activity, toxicities, and pharmaceu- were given every 3–4 weeks according to toxicity and anti- tical properties (21–24). One such novel agent is the hexacyclic leukemic efficacy. camptothecin derivative DX-8951f {(1S,9S)-1-amino-9-ethyl-5- Results: Twenty-five patients (AML, 21 patients; my- fluoro-1,2,3,9,12,15-hexahydro-9-hydroxy-4-methyl-10H,13H- elodysplastic syndrome, 1 patient; acute lymphocytic leuke- benzo-(de)-pyrano-[3Ј,4Ј:6,7]indolizino[1,2-b]quinoline-10,13- mia, 2 patients; CML-BP, 1 patient) were treated. Stomatitis dione monomethane sulfonate (salt), dihydrate, exatecan was the dose-limiting toxicity, occurring in two of two pa- mesylate; Daiichi Pharmaceutical Co, Ltd, Tokyo, Japan (Fig. 1; tients treated at 1.35 mg/m2/day for 5 days, two of three Refs. 25–28)}. treated at 1.2 mg/m2/day for 5 days, and one of six treated at Many camptothecins require enzymatic activation that may 0.9 mg/m2/day for 7 days. The recommended Phase II dose accentuate interindividual variability in their pharmacological was 0.9 mg/m2/day for 5 days. The pharmacokinetics of behavior, antiproliferative activity, and toxicities (21–23, 29, 30). DX-8951f is water-soluble and does not require enzymatic DX-8951 was linear and well fit by a two-compartment activation (25). DX-8951f is a more potent topo I inhibitor, and model. causes more DNA fragmentation, than do camptothecin, topotecan, or 10-hydroxy-7-ethylcamptothecin (SN-38), the active metabolite of irinotecan (25, 27, 31). DX-8951f is 3- and 10-fold Received 2/4/02; revised 3/25/02; accepted 3/27/02. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked 3 The abbreviations used are: topo I, topoisomerase I; MTD, maximum advertisement in accordance with 18 U.S.C. Section 1734 solely to tolerated dose; DLT, dose-limiting toxicity; SCID, severe combined indicate this fact. immunodeficient; MDS, myelodysplastic syndrome; AML, acute mye- 1 Presented in part at the Thirty-Sixth Annual Meeting of the American loid leukemia; ALL, acute lymphocytic leukemia; CML-BP, chronic Society of Clinical Oncology, New Orleans, LA, May 20–23, 2000. myelogenous leukemia in blastic phase; PGP, P-glycoprotein; CR, com- 2 To whom requests for reprints should be addressed, at Department of plete remission; PR, partial remission; HI, hematological improvement; Leukemia, Box 428, The University of Texas M. D. Anderson Cancer MLI, marrow leukemia infiltrate; PK, pharmacokinetic(s); IT2S, itera- Center, 1515 Holcombe Boulevard, Houston, TX 77030-4095. Email: tive two-stage methodology; CV, coefficient of variation; ara-C, cyto- [email protected]. sine arabinoside. Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2002 American Association for Cancer Research. Clinical Cancer Research 2135 can were not completely cross-resistant, with cell lines cross- resistant to CPT-11 and topotecan retaining sensitivity to DX- 8951f (28). Unlike topotecan, 9-aminocamptothecin, and SN- 38, DX-8951f is not a substrate for multidrug transporter PGP and has cytotoxic activity against tumor cell lines and xe- nografts with acquired multidrug resistance (MDR) conferred by PGP overexpression (27, 28, 31–35). We have previously reported on the activity of DX-8951f in a human AML SCID mouse model (36, 37). This activity was schedule-dependent, and DX-8951f had significant activity against central nervous system leukemia in this model (37, 38). On the basis of this SCID mouse data, we conducted a Phase I study of DX-8951f in adult and pediatric patients with primary refractory or relapsed AML or ALL, MDS, or CML-BP. The starting dose and schedule were chosen based on the overall toxicities and specifically on the pattern and degree of myelosuppression seen in solid tumor Phase 1 studies of DX-8951f (39–42). PATIENTS AND METHODS Patient Selection. Patients with refractory MDS (refractory anemia with excess blasts, refractory anemia with excess blasts in Transformation, or chronic myelomonocytic leukemia), AML, ALL, or CML-BP were eligible. Eligibility criteria were: Eastern Cooperative Oncology Group performance score of Յ2; serum bilirubin of Յ1.5 mg/dl; alanine aminotransferase (ALT) or aspartate aminotransferase levels (AST) Ͻ two times the upper limit of normal (ULN), serum creatinine Յ1.5 mg/dl, and no chemotherapy and/or radiation therapy for 2 weeks before entering this study with recovery from the toxic effects of that therapy. Patients with AML included those receiving first salvage with primary refractory disease, a first CR duration of less than 12 months, or those receiving second or subsequent salvage therapy. All of the patients gave signed informed consent indi- cating that they were aware of the investigational nature of this study in keeping with the policies of the M. D. Anderson Cancer Center. Dosage and Drug Administration. DX-8951f was given as a 30-min i.v. infusion once per day for 5 consecutive days, once every 21–28 days. DX-8951f, the methane sulfonic salt of DX8951, was supplied by Daiichi Pharmaceutical Cor- poration (Montvale, NJ) in vials containing 2 mg of lyophilized drug, (calculated as the anhydrous free-base equivalent, 50 or 125 mg of maltose monohydrate), and a proper quantity of hydrochloric acid (pH 3.3 to 4.7). The drug was diluted in the vial with 0.9% saline solution to obtain a 0.5-mg/ml stock solution. An appropriate volume of the stock solution, to yield the required dose, was further diluted in a polyvinyl chloride Fig. 1 Structures of camptothecin, DX-8951f, CPT-11, and SN-38. infusion bag with 0.9% saline solution to a total volume of 100 ml, which was administered over 30 min. The starting dose of DX-8951f was 0.6 mg/m2 daily for 5 days, i.e., 3.0 mg/m2 per more potent than SN-38 and topotecan, respectively, at inhibit- course. ing topo I extracted from murine P388 leukemia cells (25, 27). Treatment was given on an out-patient basis unless the In a study of camptothecin analogues against a panel of 32 patient was an in-patient for other reasons. Toxicity was graded cancer cell lines, including hematopoietic neoplasms, the IC50 on a scale of 0 to 4 using the Common Toxicity Criteria, Version (concentration that inhibits 50%) values of DX-8951f averaged 2.0, of the National Cancer Institute. All of the patients who 6- and 28-fold lower than SN-38 and topotecan, respectively received at least one dose of DX-8951f were considered evalu- (25). In the human tumor cloning assay, DX-8951f and topote- able for toxicity. Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2002 American Association for Cancer Research. 2136 DX-8951f Phase I in Leukemia Patients were assessed on each day of therapy, and at least Table 1 Baseline characteristics of 25 study patients three times weekly and as clinically indicated while on protocol. Characteristics n AML MDS ALL DX-8951f doses were increased by 50% per level until grade 2 Diagnosis toxicity occurred; then doses were increased by 30–35% (de- AML 21 (84%) pending on ease of dose “rounding”) until MTD was deter- MDS 1 (4%) mined.

Load more