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.

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 xenografts 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.

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. MTD was defined as the dose level at which no more CML-BP 1 (4%) ALL 2 (8%) than two of six patients experienced DLT, with the next higher a dose level having at least two of three or three of six patients ECOG performance score 0–1 12 (48%) encountering DLT. Any Grade 3 or worse extramedullary ad- 2 13 (52%) verse event was considered a DLT. Salvage status Response Criteria. CR was defined as normalization of First 6 the blood and bone marrow with 5% or less blasts, normocel- Second 11 1 Third 2 lular or hypercellular bone marrow, a granulocyte count above Fourth or more 4 9 9 10 /liter and a platelet count above 100 ϫ 10 /liter. Patients who Age median (range) yr 54 (11–76) met these criteria but still had 6–25% marrow blasts were Baseline: Hb (median, range) g/dl 8.7 (6.4–11.2) considered to have a PR. HI was defined as for CR, but with WBC, median (range) ϫ109/liter 3.4 (0.4–60.2) platelet counts remaining below 100 ϫ 109/liter. Other re- ϫ 9 sponses were considered as failures and categorized as: (a) early Plts, median (range), 10 /liter 26 (6–240) death if death occurred within 2 weeks from start of therapy; (b) a ECOG, Eastern Cooperative Oncology Group; Hb, hemoglobin; aplastic death if death occurred during therapy without evidence Plts, platelets. of hematological recovery and with less than 20% MLI (percentage of blasts ϫ marrow cellularity; (c) secondary resistance if MLI was reduced below 20% but increased later; and (d) primary resistance if MLI did not decrease below 20%. model. The slope (b) is the residual variability associated with PK. The PK of DX-8951f were determined during the each concentration (i.e., the sum of the intraindividual variabil- first course of therapy in all of the consenting patients. Hepa- ity and the sum of all experimental errors), and the intercept (a) rinized blood samples were collected on day 1 before the start of is related to the limit of detection of the analytic assay. Esti- infusion (time 0), at 29 min (1 min before the end of DX-8951f mates from previous studies were used as beginning priors and infusion), at 1, 4, and 24 h from the end of infusion; samples were updated iteratively during the population PK analysis were collected on day 5 immediately before the start of infusion (VARUP; IT2S) until stable values were found. (time 0), and at 1 h from the end of infusion. The limited Pharmacodynamic Analysis. The relationship between sampling time points were determined based on PK results the maximum observed decrease in which blood count (WBCs) obtained in prior Phase I studies performed in patients with solid at nadir compared with baseline values versus the exposure of tumors. Blood was immediately centrifuged at 3000 rpm for 15 patients to DX-8951 [area under the curve (area-under the time min, and plasma was transferred to 1.5-ml sample tubes and curve from time zero to infinity.)] was determined by using an stored at Ϫ20°C until needed for analysis. All of the collected inhibitory Emax model. plasma samples were analyzed at MDS Pharma Services in Montreal, Canada. DX-8951 in plasma was quantified using a RESULTS validated high-performance liquid chromatography method (43, Patient Characteristics. The characteristics of the 25 44). The lower limit of DX-8951 quantification was 0.20 ng/ml. patients treated on study are shown in Table 1. Their median age PK Analyses. PK parameters were characterized using was 54 years (range, 11–76 years); and performance status was compartmental analyses of data obtained from 18 patients (72%) 0 or 1 in 12 patients (48%) and 2 in 13 (52%) patients. Twenty- who consented to give PK specimens. Total DX-8951 plasma one patients had AML. A total of 25 patients received 27 concentration data were also analyzed using model-dependent courses of therapy (i.e., 2 patients received an additional methods. After visual inspection of plasma concentration-time course). DX-8951f was given as second salvage to 11 AML curves, individual data sets were fit with either two- or three- patients, fourth or more salvage to 4 patients. Six patients with compartment models using nonlinear least-squares regression AML received DX-8951f as their first salvage attempt: two after (45). The goodness of model fit (i.e., two- versus three- a first CR lasting less than 6 months, two with a first CR of 6–12 compartment model) was guided by inspection of the weighted months, and two with primary refractory disease. All of the sum of squares, dispersion of the residuals, SEs of the fitted PK patients with AML had previously received intermediate- or parameters, and the Akaike information criterion (46). The high-dose ara-C as part of induction, consolidation, or salvage parameters were systematically superior in fitting all of the therapy. Two patients with ALL were given DX-8951f as a third plasma concentrations when estimated by the two-compartmen- or subsequent salvage attempt for refractory disease, and one tal model and were, thus, used as prior values for the population patient with refractory CML-BP received DX-8951f as a first PK analysis. The population PK analysis was performed using salvage attempt. an IT2S. All of the concentrations were modeled using a weight- Toxicity. The dose escalation scheme of DX-8951f is ϩ 2 2 2 ing procedure of Wj 1/Sj , where the variance of Sj was shown in Table 2. DLT was initially defined at the 1.35 mg/m / 2 ϭ ϩ ϫ calculated for each observation using the equation Sj (a b day- -5-day dosage (two of two patients having grade 3grade * Y)2, where a and b are the intercept and slope of each variance three stomatitis) and then also at the 1.2 mg/m2/day-ϫ-5-days

Table 2 Toxicities by dose level of DX-8951f Toxicity grade 2, 3, or 4 (no. of patients with toxicity) Dose level No. of Nausea/ (mg/m2) patients Mucositis Vomiting Diarrhea Skin CNSa Other 0.6 ϫ 54 0.9 ϫ 5 9 2 (3) 2 (2) 2 (1) 2 (2) 1.2 ϫ 5 3 4 (2) 2 (1) 2 (1) 0.9 ϫ 7 7 3 (1) 2 (1) Weakness, grade 3, 1 patient 1.35 ϫ 5 2 3 (2) 2 (1) 2 (1) a CNS, central nervous system.

Table 3 Response to DX-8951f treatment (n ϭ 25) Response n % CR 0 PR 1 4 HI 1 4 Early death 1 4 Aplastic death 0 Secondary resistance 12 48 Primary resistance 8 32 Inevaluable 1 4 Resistance type (primary versus 14 secondary) unknown

dosage (two of three patients having grade 4 stomatitis). With the absence of grade 3 toxicity at the next lower dose level, we defined 0.9 mg/m2/daily for 5 days as the MTD. We then assessed a 0.9 mg/m2/daily-for-7-days schedule to investigate whether a more prolonged regimen would allow an increase in the total dosage administered. However at this dose level, two of six evaluable patients experienced grade 3 toxicities: one experienced stomatitis, and the other experienced weakness. Fifteen patients had 18 febrile episodes during the first course of therapy. These included six episodes of fever of unknown origin; five pneumonias; and three septicemic episodes. Two patients received a second course of DX-8951f that was begun at 28 and Fig. 2 Changes in WBC counts (n ϭ 25 patients) after administration 36 days after the start of course 1. No grade 3 toxicities occurred of DX-8951f (mean Ϯ SD). in these second courses. Response. Twenty-four patients (96%) were evaluable for response; overall responses were as per Table 3. One patient had a HI; one patient had a PR, whereas no CRs were observed inhibition of drug clearance based on visual inspection of indi- in this study. Neither of the patients with ALL showed a vidual plasma concentration-time curves, linear PK models were significant response. WBC nadir occurred between days 9 and evaluated for quality of fit. A two-compartment model was 16, with a tendency to recover thereafter. (Fig. 2). systematically superior in fitting all of the plasma concentration- PK and Pharmacodynamic Studies. Representative time data sets for total DX-8951 on both days 1 and 5. There- plasma concentration-time profiles are shown in Fig. 3, and fore, PK parameters derived from the biexponential model were mean total DX-8951 PK parameters derived using a compart- used to develop a population PK model using an IT2S approach. mental method are listed in Table 4. The PK of total DX-8951 A representative patient’s plasma concentration data fit to this on day 1 were characterized by a moderately large volume of population model are shown in Fig. 3. Pertinent PK parameters distribution at steady-state averaging 14.36 liter/m2 (CV, for total DX-8951 derived from this model were nearly identical

30.08%) and a mean elimination t1/2 of 8.75 h (CV, 48.34%). to those derived using noncompartmental methods in a previous Ͼ 2 There were no significant differences (P 0.05) between PK Phase I study, with mean CL and z-t1/2 values of 2.13 liter/h/m parameters derived from paired concentration data sets obtained (CV, 60%) and 9.87 h (CV, 77%), respectively (12, 19, 29). on days 1 and 5; mean CL values were 1.86 (CV, 56%) and 2.05 Mean values for volume of the central compartment (Vc) and (CV, 72%) liter/h/m2, respectively. Because there was no evi- volume of distribution at steady-state were 2.40 liter/m2 (CV, dence of nonlinear drug elimination, nor autoinduction, nor 40%) and 19.0 liter/m2 (CV, 23%), respectively.

selectively stabilized by albumin under physiological condi- tions. The requirement of many camptothecins for enzymatic activation accentuates interindividual variability in their behavior. However, DX-8951f does not require enzymatic activation (25). Additionally, the broad preclinical antitumor spectrum of DX-8951f may be partially attributable to its not being a PGP substrate, in contrast to topotecan, 9-aminocamptothecin, and SN-38 (27). In addition, the antitumor activity of DX-8951f is similar against human pancreatic cancers and their respective Fig. 3 Observed (⅐) and model-predicted (-) plasma concentrations sublines with acquired resistance to CPT-11 in vivo and SN-38 versus time for representative patient. in vitro (27, 28). We thus considered DX-8951f to be potentially active in topotecan-resistant AML, an important consideration because topotecan is a component of some front-line AML regimens (20). WBC counts were well explained by an inhibitory Emax We have recently reported on the efficacy and toxic effects model. The Emax (maximal decrease in WBC precursor pro- of DX8951f in a human AML SCID mouse model (37). Six- ϫ duction in bone marrow) for the WBC nadir compared with the week-old female ICR SCID mice were given injections of 20 106 viable KBM3 cells in the tail vein. The mice were then predose value was 89% and the DX-8951 exposure (AUC50) associated with one-half of the Emax value was 57 ␮g/h/liter divided into groups of five and treated with different doses of (Fig. 4). DX-8951f 7 days after inoculation. Animals dying within 2 weeks from treatment had no molecular evidence of leukemia and were counted as toxic deaths. In control groups, all of the DISCUSSION animals died of disseminated leukemia with a median survival The topo 1 inhibitors are a potent class of antileukemic of 35–37 days. With a single 20 mg/kg dose of DX8951f dose, agents (12, 19, 29). DX-8951f, a hexacyclic synthetic water- no survival advantage was seen. Median survival improved with soluble derivative of camptothecin, is a novel topo 1 inhibitor single doses of 40 and 50 mg/kg and was significantly pro- (25). The antitumor activities of DX-8951f have been studied longed at 60 mg/kg as compared with the control group. Further both in vitro and in vivo in a number of different model systems dose escalation was technically not feasible. Toxicity data sug- (31, 47). DX-8951f was approximately 3 times more potent than gest schedule-dependent effects because the same total dose of SN-38 (the active metabolite of CPT-11), 10 times more potent 20 mg/kg produced three of five deaths when given over a than topotecan, and 20 times more potent than camptothecin as period of 5 days in contrast to none in five animals when given an inhibitor of topo 1 in vitro and 5 times more potent than over a period of 1 or 3 days. The 20-mg/kg dose was well SN-38 as an inhibitor of DNA synthesis (25, 31). In cell-based tolerated but was not effective in the one-day schedule. When cytotoxicity assays, DX-8951f was 3–10 times more active than given in a three-day schedule, a total dose of 20 mg/kg was still SN-38, topotecan, or camptothecin in its antiproliferative activ- well tolerated and survival was significantly improved. In a ity against a wide range of breast, colon, gastrointestinal, and five-day schedule the 20-mg/kg dose was toxic and did not lung human tumor cell lines (25, 27). prolong survival. DX-8951F had dose-schedule-dependent ac- Toxicology studies in mice, rats, and dogs have shown that tivity and toxicity in this AML in vivo model, as has been hematopoietic, gastrointestinal, lymphatic, and reproductive tis- recently observed with other topo I inhibitors (49, 50). sues are most prone to the adverse effects of DX-8951f (48). Rowinsky et al. (39) have recently reported on a solid Noncumulative myelosuppression has been the principal dose- tumor Phase 1 study of Dx-8951f given on the same schedule as limiting effect of DX-8951f in both single- and multiple-dosing the currently reported study. The MTD, defined as the highest regimen studies in both rodents and dogs. There is considerable dose level at which the incidence of DLT did not exceed 20%, interspecies differences in drug tolerance, with dogs being more was calculated separately for minimally pretreated (MP) and susceptible to toxicity than mice or rats. In dog and rodent heavily pretreated (HP) patients. Thirty-six patients were treated pharmacology studies using 14C-DX-8951f and high-perfor- with 130 courses of DX-8951f at six dose levels ranging from mance liquid chromatography for differential quantification of 0.1 to 0.6 mg/m2/day. Brief, noncumulative neutropenia was the

lactone and total drug, the half-life (t1/2) of the lactone ranged most common toxicity observed. Severe myelosuppression was from ϳ20 to 30 min, and systemic exposure to the lactone was the DLT in both MP and HP patients. Nonhematological toxic- ϳ50% of total drug exposure. In rats treated with a single i.v. ities (nausea, vomiting, and diarrhea) were rarely severe. The dose of 14C-DX-8951f, urine and fecal recovery averaged 15 recommended doses for Phase II studies of DX-8951f as a and 78% of the administered dose, respectively. Hydroxylated 30-min infusion daily for 5 days every 3 weeks were 0.5 and 0.3 metabolites predominated after coincubation of DX-8951f and mg/m2/day, respectively, for MP and HP patients with solid human liver microsomes in vitro, and the rate of metabolite tumors. formation was decreased by inhibitors of CYP3A; the use of In the currently reported Phase 1 study of DX-8951f in known CYP3A inhibitors was avoided in patients on the cur- patients with leukemia, the MTD was 0.9 mg/m2/daily for 5 rently reported study. DX-8951f is highly plasma protein in both days with stomatitis being the DLT at higher doses. This rep- rats and dogs; spectrometric studies indicate that the lactone is resents an approximate doubling of the MTD established in

Table 4 Calculated compartmental PK parameters adjusted for body surface area

a Vc Vp Vss Cl Cld Cmax pred Total pred AUC Dose level No. of Mean CV Mean CV Mean CV Mean CV Mean CV Mean CV Mean CV (mg/m2/day) patients (liter/m2) (%) (liter/m2) (%) (liter/m2) (%) (liter/h/m2) (%) (liter/h/m2) (%) (mcg/ml) (%) (mcg/l) (%) 0.6 2 8.56 3.8 16.27 31.9 24.83 22.2 4.47 24.1 2.60 60.4 57.95 0.6 688.60 24.0 0.9b 11 9.07 14.9 9.20 40.1 18.27 23.5 2.04 45.5 9.25 19.6 78.65 14.8 3464.20 53.3 1.2 2 8.69 6.4 9.34 7.2 18.03 6.8 0.67 65.8 10.50 13.1 107.06 6.3 11398.72 65.9 1.35 2 10.06 0.9 7.85 35.5 17.91 16.1 1.76 54.0 10.68 18.1 106.72 2.92 4537.30 55.0 Mean 9.08 12.8 9.89 41.3 18.97 22.9 2.13 60.4 8.78 32.8 a Vc, volume of the central compartment; Vp, plasma volume of distribution; Vss, volume of distribution at steady-state; Cl, total plasma clearance; Cld, clearance; pred, predicted; AUC, area under the curve. b Two of 11 patients received 7 days of treatment.

Because of the limited number of evaluable subject profiles in certain dosing groups, results have to be interpreted with caution. Nevertheless, the total plasma clearance (Cl) and volume of the central compartment (Vc) appeared to be the same between dosing groups. Patients treated at the dose of 1.25 mg/m2/day had more severe (Grade 4) DLT (stomatitis) than patients receiving the stopping dose of 1.35 mg/m2/day. A 53-year-old male with AML and a Ϫ5, Ϫ7 blast karyotype achieved a PR after he received DX-8951f as second salvage therapy. The patient had primary refractory disease and had failed to achieve a response to either prior cyclophosphamide, ara-C, and topotecan (CAT) or dolostatin therapy. A 51-year-old female with AML and a trisomy 8, Ϫ5, Ϫ7 blast karyotype achieved a HI after she received DX-8951f as first Fig. 4 Percentage decrease in WBCs from baseline values to nadir salvage therapy. Her initial CR duration after induction therapy versus DX-8951 exposure. with CAT was 14 weeks. Although it is very difficult to comment on the relative activity of DX-8951f in comparison with that of other topo 1 patients with solid tumors (39, 41, 48, 51). Although stomatitis inhibitors in patients with acute leukemia based on the data from was the DLT on this study, it was not a feature of the toxicity of this Phase I study, it is noteworthy that both of the responding DX8951f that was given on a variety of schedules in Phase I patients had failed prior topotecan therapy. Phase II studies are studies in patients with solid tumors, in whom lower doses were defined as the MTD on the basis of myelosuppression (39, 40, warranted to define the activity of DX-8951f in patients with 42, 52). Stomatitis is a relatively pronounced toxicity in leuke- hematological malignancies and to place its activity in the mia patients who receive topotecan at higher doses than do solid context of topotecan (53, 54), 9-aminocamptothecin, (55) 9- tumor patients, thus paralleling the experience on this Phase I nitrocamptothecin, (56), and NX-211 (57), all of which have study with DX-8951f (14). antileukemic activity. Relative to our experience with topotecan, DX-8951f seems to cause less diarrhea, nausea, or vomiting (10). No Grade REFERENCES 3 or 4 diarrhea was documented in this study. None of the reported Phase I studies of DX-8951f in patients with solid 1. Wani, M. C., Nicholas, A. W., and Wall, M. E. Plant antitumor agents. 23. Synthesis and antileukemic activity of camptothecin ana- tumors, including those with weekly 24-hour infusions and logues. J. Med. Chem., 29: 2358–2363, 1986. daily-times-5 schedules, have reported any Grade 3 or 4 diarrhea 2. Wall, M. E., Wani, M. C., Natschke, S. M., and Nicholas, A. W. (39–42, 48, 51). Plant antitumor agents. 22. Isolation of 11-hydroxycamptothecin from After repeated dose administration to patients with hema- Camptotheca acuminata Decne: total synthesis and biological activity. tological malignancies, the PK profile of DX-8951 appeared J. Med. Chem., 29: 1553–1555, 1986. linear within the dose range of 0.6–1.35 mg/m2/day. The plasma 3. Hsiang, Y. H., Hertzberg, R., Hecht, S., and Liu, L. F. Camptothecin concentrations were well predicted after the first and fifth daily induces protein-linked DNA breaks via mammalian DNA topoisomer- administration with the same PK parameters. It would have been ase I. J. Biol. Chem., 260: 14873–14878, 1985. impossible to fit data from all of the sampling days simulta- 4. Giovanella, B. C., Stehlin, J. S., Wall, M. E., Wani, M. C., Nicholas, A. W., Liu, L. F., Silber, R., and Potmesil, M. DNA topoisomerase neously if the clearance or elimination had changed over time. I–targeted chemotherapy of human colon cancer in xenografts. Science In this study, the values reported for DX-8951 clearance, vol- (Wash. DC), 246: 1046–1048, 1989. ume of distribution, and elimination half life are very similar to 5. Liu, L. F. DNA topoisomerase poisons as antitumor drugs. Annu. those reported for other Phase I studies (39, 41). Rev. Biochem., 58: 351–375, 1989.

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Francis J. Giles, Jorge E. Cortes, Deborah A. Thomas, et al.

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