A Phase I and Pharmacokinetic Study of Losoxantrone and Paclitaxel in Patients with Advanced Solid Tumors1

Vol. 5, 299–308, February 1999 Clinical Cancer Research 299

Sami G. Diab,2 Sharyn D. Baker, Amita Joshi, enced DLT during the first two courses of therapy. DLTs, Howard A. Burris,3 Patrick W. Cobb,3 mainly myelosuppression, occurring during the first course Miguel A. Villalona-Calero, S. Gail Eckhardt, of therapy were noted in four of six and five of eight patients treated with 40 mg/m2 losoxantrone and 135 mg/m2 pacli- Geoffrey R. Weiss, Gladys I. Rodriguez, taxel over 24 and 3 h, respectively, without G-CSF. DLTs 4 Ronald Drengler, Maura Kraynak, during the first two courses of therapy were observed in one Lisa Hammond, Michael Finizio, of six patients at the 50/175 (losoxantrone/paclitaxel) mg/m2 Daniel D. Von Hoff, and Eric K. Rowinsky dose level, two of four patients at the 50/200 mg/m2 dose 2 The University of Texas Health Science Center at San Antonio level, one of four patients at the 50/225 mg/m dose level, and [S. G. D., G. R. W., R. D.], Institute for Drug Development and two of five patients at the 60/225 mg/m2 dose level. The Cancer Therapy and Research Center [S. D. B., M. A. V-C., S. G. E., degree of thrombocytopenia was worse, albeit not statisti- G. I. R., M. K., L. H., D. D. V. H., E. K. R.], and Brooke Army cally significant, when 24-h paclitaxel preceded losox- Medical Center [H. A. B., P. W. C.], San Antonio, Texas 78234; and DuPont Pharmaceuticals Company, Wilmington, Delaware 19880 antrone, with a mean percentage decrement in platelet count [A. J., M. F.] during course 1 of 80.7%, compared to 43.8% with the Losoxantrone clearance was .(0.19 ؍ reverse sequence (P not significantly altered by the sequence or schedule of ABSTRACT paclitaxel. Cardiac toxicity was observed; however, it was A Phase I and pharmacological study was performed to not related to total cumulative dose of losoxantrone. An evaluate the feasibility, maximum tolerated dose (MTD), unacceptably high rate of DLTs at the first dose level of 40 dose-limiting toxicities (DLTs), and pharmacokinetics of the mg/m2 losoxantrone and 135 mg/m2 paclitaxel administered anthrapyrazole losoxantrone in combination with paclitaxel as either a 24- or 3-h i.v. infusion precluded dose escalation in adult patients with advanced solid malignancies. Losox- without G-CSF support. The addition of G-CSF to the reg- antrone was administered as a 10-min infusion in combina- imen permitted further dose escalation without reaching the tion with paclitaxel on either a 24- or 3-h schedule. The MTD. Losoxantrone at 50 mg/m2 followed by paclitaxel (3-h starting dose level was 40 mg/m2 losoxantrone and 135 i.v. infusion) at 175 mg/m2 with G-CSF support is recom- mg/m2 paclitaxel (as a 24- or 3-h i.v. infusion) without mended for further clinical trials. granulocyte colony-stimulating factor (G-CSF). Administra- tion of these agents at the starting dose level and dose escalation was feasible only with G-CSF support. The fol- INTRODUCTION lowing dose levels (losoxantrone/paclitaxel, in mg/m2)of The anthrapyrazole losoxantrone (C1–941; DuPont Phar- losoxantrone and paclitaxel as a 3-h infusion were also maceuticals Company, Wilmington, DE) was synthesized with evaluated: 50/135, 50/175, 50/200, 50/225, and 60/225. The the rationale of developing cytotoxic agents with a similar sequence-dependent toxicological and pharmacological ef- chemical structure to anthracyclines but with the distinctive fects of losoxantrone and paclitaxel on the 24- and 3-h feature of dissociation between antitumor activity and cardio- schedules of paclitaxel were also assessed. The MTD was toxicity (1). Mechanistically, the cardiotoxicity of anthracy- defined as the dose at which >50% of the patients experi- clines is related, at least in part, to their ability to undergo one electron reduction at the quinone oxygen to form a semiquinone. The enzymatic interaction between the semiquinone and molec- ular oxygen yields a superoxide anion, which gives rise to a highly reactive oxygen species (2, 3). Losoxantrone lacks the Received 9/15/98; revised 11/10/98; accepted 11/11/98. sugar moiety of doxorubicin, retains the aromatic ring structure The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked that is responsible for its intercalation into DNA (4), and differs advertisement in accordance with 18 U.S.C. Section 1734 solely to from the anthracendione mitoxantrone in the central quinone indicate this fact. moiety by having an imino group instead of a keto group (Fig. 1 Presented, in part, at the Annual Meeting of the American Society of 1), which precludes the formation of free radicals (5). Indeed, in Clinical Oncology, held May 14–17, 1994, in Dallas, TX. the fetal mouse heart model, losoxantrone caused substantially 2 To whom requests for reprints should be addressed , at The University of Texas Health Science Center at San Antonio, Division of Medical less free radical formation in rat liver microsomal preparations Oncology, 7703 Floyd Curl Drive, San Antonio, TX 78284. Phone: and fewer cardiotoxic effects than did doxorubicin (5, 6). (210) 567-4777; Fax: (210) 567-6687. Losoxantrone, like doxorubicin and mitoxantrone, intercalates 3 H.A.B. and P.W.C. were United States government employees while into DNA (4), induces single- and double-stranded DNA breaks this study was being performed. The views expressed in this article are those of the authors and do not reflect the official policy of the Depart- (7), and inhibits topoisomerase II (8). ment of Defense or other departments of the United States government. Losoxantrone demonstrated remarkable and broad antitu- 4 Deceased. mor activity in preclinical studies. In the National Cancer Insti-

Fig. 1 Chemical structures of doxorubicin, mitoxantrone, and losoxantrone.

tute drug evaluation screen, losoxantrone was active against a of the combination of paclitaxel and losoxantrone; (b) charac- variety of cell lines derived from central nervous system, leu- terize the principal DLTs of the combination of paclitaxel and kemias, and lung tumors, among others (8). Losoxantrone was losoxantrone; (c) describe the pharmacokinetics of both losox- more active than several other anthrapyrazoles and mitoxantrone and paclitaxel in combination; (d) determine whether antrone and was as effective as doxorubicin against various the sequence of drug administration results in significantly murine tumors, including mammary adenocarcinoma 16C, co- different toxicological and pharmacological profiles; and (e) lon adenocarcinoma 11a, the Ridgway osteogenic sarcoma (9), seek preliminary evidence of antitumor activity in patients with and mammary carcinomas arising in ras transgenic mice (10). advanced solid malignancies. The activity of losoxantrone in preclinical models and its potential to induce less cardiotoxicity than most anthracyclines, PATIENTS AND METHODS anthracendiones, and other anthrapyrazoles provided the impe- Eligibility. Patients with solid tumors that were refrac- tus for the clinical development of this agent. A Phase I study of tory to conventional therapy or for whom no standard therapy 5 losoxantrone demonstrated that the DLT was leukopenia and existed were candidates for this study. Eligibility requirements that its MTD on a short-infusion, every-3-weeks schedule was included: (a) age of Ն18 years; (b) WHO performance status of 2 55 mg/m (11). Two Phase II studies of losoxantrone in patients Յ2; (c) a life expectancy of at least 8 weeks; (d) no chemother- with advanced breast cancer demonstrated significant antitumor apy in the preceding 3 weeks; (e) adequate hematopoietic (ANC activity, with an overall response rate of 43–63% (12, 13). In the of Ն 1500/␮l, platelet count of Ն100,000/␮l), hepatic (serum larger of the two studies (13), 1% of the patients developed bilirubin of Յ1.5 mg/dl), and renal (serum creatinine of Յ2.0 Ͼ congestive heart failure, and 4% experienced 20% asymptom- mg/dl) functions; and (f) no coexisting medical problems that atic decline in LVEF. might compromise compliance with the study. Due to concern In light of the increasing recognition that paclitaxel, par- about the potential for cardiotoxicity of the study drug combi- ticularly on a 3-h infusion schedule, enhances the potential for nation, patients were ineligible for treatment if they had: (a)a anthracycline-related cardiotoxicity (14) and that paclitaxel-an- pretreatment LVEF of Ͻ45%, as determined by radionuclide thracycline regimens have notable antitumor activity in women scanning or Ն10% absolute reduction in LVEF within 6 months with metastatic breast cancer, with CR rates as high as 40% prior to this study; (b) prior treatment with a cumulative dose of (14), a combination of paclitaxel and losoxantrone combination doxorubicin of Ͼ400 mg/m2 or dose of mitoxantrone of Ͼ125 is a seemingly rational developmental alternative with a poten- mg/m2;or(c) a history of congestive heart failure, myocardial tially greater therapeutic index than doxorubicin and paclitaxel. infarction within 1 year of study entry, unstable angina, active The enhancement of doxorubicin’s cardiotoxicity by paclitaxel, cardiomyopathy, or ventricular arrhythmia requiring therapy. which is likely due to reduced hepatic clearance and/or in- Dosage, Dose Escalation, and Sequencing. The study creased cellular retention of doxorubicin and doxorubicinol by was designed to escalate the doses of both paclitaxel and losox- paclitaxel itself and/or its polyoxyethylated castor oil formula- antrone until the MTD was reached. Initially, the sequence of tion vehicle (Cremophor EL; Ref. 15) may not be operative with administration of paclitaxel and losoxantrone was alternated to paclitaxel-losoxantrone regimens. This reason and the remark- evaluate any sequence-dependent toxicity. In addition, pacli- able single-agent activities of losoxantrone (12, 13) and paclitaxel was initially administered i.v. over 24 h; however, when a taxel (16, 17) in patients with breast cancer and other neo- 3-h i.v. infusion schedule was demonstrated to be safe and plasms, the vastly different mechanisms of cytotoxic actions of possibly less toxic (18), the paclitaxel infusion was shortened to these agents, and the lack of overlapping nonhematological 3 h. Losoxantrone was administered i.v. over 10 min at all dose toxicities were the impetus to evaluate the feasibility of admin- levels. Patients were retreated every 3 weeks, provided they had istering losoxantrone and paclitaxel in combination. The prin- recovered to grade Յ1 from drug-related toxicities, except alo- cipal objectives of this study were to: (a) determine the MTDs pecia. At least three patients were treated at each dose level. The first three patients were treated with 40 mg/m2 losoxantrone followed by 135 mg/m2 paclitaxel administered over 24 h. The next three patients were treated at the same dose level and 5 The abbreviations used are: DLT, dose-limiting toxicity; MTD, max- schedule, but with paclitaxel administered prior to losoxantrone. imum tolerated dose; LVEF, left ventricular ejection fraction; CR, complete response; ANC, absolute neutrophil count; G-CSF, granulo- The following eight patients were treated with losoxantrone 40 2 2 cycte colony-stimulating factor; PR, partial response; AUC, area under mg/m and paclitaxel 135 mg/m administered over 3 h instead the concentration-time curve; CHF, congestive heart failure. of 24 h, with four receiving losoxantrone prior to paclitaxel and

the other four receiving the reverse sequence. When myelosup- study termination in patients who received more than eight pression precluded dose escalation, the study was amended to courses. Tumors were measured after every two courses, and require prophylactic administration of G-CSF, and four patients therapy was continued in the absence of evidence of disease were treated with losoxantrone 40 mg/m2 followed by paclitaxel progression. A CR was defined as the absence of any symptoms 135 mg/m2 administered over 3 h with G-CSF. With the addi- related to the cancer and a complete disappearance of all disease tion of G-CSF, dose escalation continued with the following on two separate measurements performed at a minimum interval dose levels of losoxantrone/paclitaxel (mg/m2) evaluated: 50/ of 4 weeks. A PR required at least 50% decrease from baseline 135, 50/175, 50/200, 50/225, and 60/225. All patients received in the sum of the bidimensional product of all measurable losoxantrone followed by paclitaxel administered over3hand tumors on two separate measurements performed at a minimum prophylactic G-CSF. Dose reduction of 10% for losoxantrone interval of 4 weeks. and/or paclitaxel in subsequent courses was allowed for patients Pharmacokinetic Sampling and Assay Methodologies. experiencing DLT. Intrasubject dose escalation was not permit- Blood samples for pharmacokinetic analyses of losoxantrone ted. and paclitaxel were obtained from indwelling venous catheters Toxicities were graded according to the NCI Common placed in the arm contralateral to the drug infusion. Losox- Toxicity Criteria. DLT was defined as at least one of the antrone pharmacokinetics were determined in 13 patients during following: (a) ANC of Ͻ500/␮l for Ͼ5 days or associated with the first course of therapy following administration of losox- fever exceeding 38°C; (b) platelet count of Ͻ25,000/␮l; or (c) antrone 40 mg/m2 and paclitaxel 135 mg/m2 as a 3- or 24-h grade 3 or 4 nonhematological toxicity (excluding alopecia, infusion either before or immediately after losoxantrone admin- nausea, or vomiting). istration. None of these patients received G-CSF. Blood samples The MTD was defined as the dose at which Ͼ50% of the were obtained pretreatment and at the following times from the patients (or two of three patients, if only three patients were start of losoxantrone infusion: 5, 10, 20, 30, 40, 65, and 90 min treated at a dose level) experienced DLT during courses 1 and 2 and 2, 3, 4, 6, 8, 12, 14, 24, 30, 48, 72, and 96 h. Blood samples of therapy. The recommended dose for Phase II–III studies was for losoxantrone pharmacokinetics were collected without anti- one dose level below the MTD. coagulant, immediately transferred to plastic centrifuge tubes Drug Administration. Losoxantrone was supplied by containing a citrate buffer, and centrifuged. Next, plasma was DuPont Pharmaceuticals Company (Wilmington, DE) in vials separated and stored at Ϫ20°C until analysis. Losoxantrone containing 25 mg of lyophilized powder for injection. Each vial plasma levels were determined using a high-performance liquid was reconstituted with 2.5 ml of sterile water to achieve a chromatographic method with a visible detection at 492 nm and concentration of 10 mg/ml. The calculated total dose was further a lower limit of sensitivity of 1.3 ng/ml, as described previously diluted in 50 ml of 0.9% sodium chloride and administered i.v. (19). The precision and accuracy of the method was within 15%, over 10 min. All patients received prophylactic antiemetics with with a mean extraction efficiency of 99.7 Ϯ 12.7%. The stand- serotonin antagonists and dexamethasone. ard curves were linear over a concentration range of 1.3–17 Paclitaxel (Taxol®; Bristol Myers Squibb Company, Prin- ng/ml in plasma. ceton, NJ) was supplied as a concentrated sterile solution of 6 Paclitaxel pharmacokinetics were determined in 17 patients mg/ml in 50% polyoxyethylated castor oil (Cremophor EL) and during their first course of therapy. The 17 patients received 50% dehydrated alcohol, USP. The total dose of paclitaxel was doses ranging from 175 to 225 mg/m2. Losoxantrone pharma- diluted in 500 ml of 5% dextrose or 0.9% sodium chloride. cokinetics were not simultaneously characterized in these pa- Paclitaxel was administered as a continuous i.v. infusion over tients. All patients received their respective paclitaxel dose as a 24 h in the first six patients and as a 3-h i.v. infusion in all 3-h infusion immediately after a 10-min losoxantrone infusion, subsequent cohorts. Prior to paclitaxel administration, all pa- followed by G-CSF support. Blood samples for paclitaxel phar- tients were premedicated with 20 mg of dexamethasone p.o. 12 macokinetics were obtained pretreatment and at the following and 6 h prior to paclitaxel and both 50 mg of diphenhydramine times from the start of paclitaxel infusion: 1.5, 3, 3.3, 3.6, 4, 4.5, i.v. and 300 mg of cimetidine i.v. 30 min prior to paclitaxel. 5, 7, 9,12, 16, 24, 36, 48, and 72 h. Blood samples for paclitaxel Recombinant methionyl human G-CSF (Neupogen; Am- pharmacokinetics were collected with anticoagulant and imme- gen, Thousand Oaks, CA) was supplied in ampules that con- diately centrifuged at 3000 rpm for 12 min. The separated tained 0.6 mg of cytokine in 2 ml of sterile water. When the plasma was then transferred to 5-ml polypropylene cryovials feasibility of further dose escalation of the combination with using a plastic pipette and stored at Ϫ20° C. Paclitaxel plasma G-CSF was explored, 5 ␮g/kg G-CSF was administered s.c., concentrations were determined using high-performance liquid starting at 24 h after chemotherapy and continuing until day 12 chromatography with UV detection and a sensitivity limit of 10 or until the ANC increased to Ͼ10,000/␮l. ng/ml. The precision and accuracy of the method was within Pretreatment and Follow-up Studies. Medical histo- 15%, with a mean extraction efficiency of 90 Ϯ 9%. The ries, physical examinations, electrocardiograms, and routine he- standard curves were linear over a concentration range of 10.0– matology and chemistry studies were performed prior to each 2500 ng/ml. treatment. Complete blood counts and differential white blood Pharmacokinetic and Pharmacodynamic Analysis. In- counts were obtained weekly in patients who were not assigned dividual losoxantrone and paclitaxel pharmacokinetic parameters to G-CSF, biweekly in patients assigned to G-CSF, and every were calculated using standard model-independent methods (20). other day in patients with grade 3–4 myelosuppression. The AUC values were calculated using the linear trapezoidal method as chemistry tests were repeated prior to each course of therapy. implemented in PK-IMS Version 2.0 (DuPont Pharmaceuticals MUGA scans were obtained after every two courses and at Company), and were extrapolated to infinity. Other calculated

Table 1 Dose escalation scheme No. of patients No. of courses Losoxantrone dose, Paclitaxel dose, mg/m2 mg/m2 (infusion time, h) Sequencea Total With DLT Total With DLT Without G-CSF 40 135 (24) L3P3 2 115 P3L3 3 139 40 135 (3) L3P4 3 187 P3L4 2 148 With G-CSF 40 135 (3) L3P4 1 181 50 135 (3) L3P4 0 120 50 175 (3) L3P6 2 255 50 200 (3) L3P4 3 93 50 225 (3) L3P4 2 282 60 225 (3) L3P5 2 142 Total 41 162 a L, losoxantrone; P, paclitaxel.

pharmacokinetic parameters included the half-lives (t1/2), mean Table 2 Patient characteristics residence time (MRT), the apparent volume of distribution (Varea), Characteristic No. of patients the volume of distribution at steady-state (V ), and systemic clear- ss Total no. of patients 41 ance (Cl). Values for maximum plasma concentration (Cmax) were Median age, yr (range) 60 (25–79) the observed peak plasma concentrations. WHO performance status Losoxantrone and paclitaxel pharmacokinetic parameters 014 were also estimated using model-dependent methods. Individual 124 losoxantrone and paclitaxel concentrations were fitted with a 23 Tumor type linear three-compartment model using the method of weighted Non-small cell lung 13 least squares regression, as implemented in PCNONLIN (SCI Head and neck 6 Software; Statistical Consultants, Inc., Lexington, KY). Esti- Melanoma 5 mated pharmacokinetic parameters included the disposition of Colorectal 5 Esophagus 3 half-lives (t1/2␣, t1/2␤, and t1/2␥) and the central volume of Sarcoma, unknown primary, bladder 2 each distribution (Vc). Small cell lung, stomach, liver 1 each The relationships between losoxantrone and paclitaxel sys- Previous treatment Radiation and chemotherapy 14 temic exposure (Cmax and AUC) and toxicity during course 1 were explored. Parameters reflecting toxicity included NCI Chemotherapy only 13 No treatment 5 Common Toxicity Criteria grade neutropenia and thrombocyto- Radiation only 4 penia, grade 4 neutropenia for Ͼ5 days or with fever, the Chemotherapy ϩ immunotherapy 2 occurrence of DLT, and percentage decrement in ANC or plate- Chemotherapy ϩ hormone 1 ϩ ϩ lets during course 1. The relationships between the absolute Chemotherapy hormone immunotherapy 1 Chemotherapy ϩ radiation ϩ hormone ϩ 1 decrement in LVEF from baseline to lowest value documented immunotherapy during all courses of treatment and losoxantrone drug exposure during course 1 and the total cumulative dose of losoxantrone were also evaluated. Statistical Analyses. The Wilcoxon rank sums test was of doses was four (range, one to nine). Thirty-seven patients used to evaluate the effects of study drugs sequence on hema- received at least two courses of study drugs. The median total tological toxicity and the influence of losoxantrone and pacli- losoxantrone dose was 160 mg/m2 (range, 40–400 mg/m2). taxel sequence on losoxantrone’s pharmacokinetics and to com- pare values of systemic exposure between different categories of Toxicity toxicity. The JMP statistical software program (Version 3.1; SAS institute, Cary, NC) was used in the statistical analyses. Hematological Toxicity Myelosuppression was the main toxicity of losoxantrone RESULTS and paclitaxel. Tables 3 and 4 depict the incidences of hemato- Clinical Study logical toxicities per patient and course, respectively. The com- The characteristics of the 41 patients entered on the study bination of 40 mg/m2 losoxantrone and 135 mg/m2 paclitaxel are listed in Table 1. Six patients had received prior doxorubi- over 24- or 3-h infusion, without G-CSF, produced significant cin, with a median dose of 110 mg/m2 (range, 90–380 mg/m2). toxicity with DLTs (grade 4 neutropenia of Ͼ5 days, grade 4 A total of 162 courses of losoxantrone and paclitaxel were thrombocytopenia, or febrile neutropenia) occurring in 5 of 6 administered at five dose levels (Table 2). The median number patients (83%) and 14 of 24 courses (58%) when paclitaxel was

Table 3 Hematological toxicity (patients) No. of patients Neutropenia grade Thrombocytopenia grade Losoxantrone Paclitaxel, mg/m2 Febrile dose, mg/m2 (infusion time, h) Sequencea Total With DLT 3 4 4, Ͼ5 days neutropeniab 3 4 Without G-CSF 40 135 (24) L3P3 2032 2 0 0 P3L3 3033 1 0 1 40 135 (3) L3P4 3132 2 1 0 P3L4 2132 1 0 0 With G-CSF 40 135 (3) L3P4 1111 0 0 0 50 135 (3) L3P4 0130 0 0 0 50 175 (3) L3P6 2222 0 0 1 50 200 (3) L3P4 3032 1 1 0 50 225 (3) L3P4 2121 0 1 1 60 225 (3) L3P5 2232 0 0 0 a L, losoxantrone; P, paclitaxel. b Fever of Ͼ38°C and grade 4 neutropenia.

Table 4 Hematological toxicity (courses) No. of courses Neutropenia grade Thrombocytopenia grade Losoxantrone Paclitaxel, mg/m2 Febrile dose, mg/m2 (infusion time, h) Sequencea Total With DLT 3 4 4, Ͼ5 days neutropeniab 3 4 Without G-CSF 40 135 (24) L3P115 1104 3 0 0 P3L139 0117 2 0 1 40 135 (3) L3P187 585 3 1 0 P3L148 298 2 0 0 With G-CSF 40 135 (3) L3P181 111 0 2 0 50 135 (3) L3P120 130 0 0 1 50 175 (3) L3P255 465 0 1 1 50 200 (3) L3P9 3162 1 1 0 50 225 (3) L3P282 621 0 3 1 60 225 (3) L3P142 452 0 0 0 a L, losoxantrone; P, paclitaxel. b Fever of Ͼ38°C and grade 4 neutropenia.

administered as a 24-h infusion and in 5 of 8 patients (62%) and (P ϭ 0.56), the degree of thrombocytopenia was worse, albeit 15 of 32 courses (47%) when paclitaxel was administered as a not statistically significant, when 24-h paclitaxel preceded 3-h infusion. DLT occurring during the first course of therapy losoxantrone with a mean percentage decrement in platelet was noted in four of six and five of eight patients treated with 40 count during course 1 of 80.7% compared to 43.8% with the mg/m2 losoxantrone and 135 mg/m2 paclitaxel over 24 or 3 h, reverse sequence (P ϭ 0.19). This trend of more severe throm- without G-CSF, respectively. Prior to G-CSF prophylaxis, dose bocytopenia was not noted with the 3-h schedule of paclitaxel reduction of paclitaxel to 100 mg/m2 after the first course was with the mean percentage decrement in platelet counts during common and occurred in 8 of 13 patients who received more course 1 of 37.7% when paclitaxel preceded losoxantrone com- than one course of therapy. The ANC nadir during course 1 of pared to 40.5% with the reverse sequence (P ϭ 0.9). therapy tended to be lower with paclitaxel administered on a These toxicity data provided the rationale for prophylactic 24-h schedule (mean, 182/␮l) compared to a 3-h infusion (mean, G-CSF support, for administering losoxantrone before pacli- 301/␮l); however, the difference did not reach statistical signif- taxel, and for administering paclitaxel as a 3-h infusion in all icance (P ϭ 0.2). subsequent cohorts. The combination of losoxantrone 40 mg/m2 The sequence-dependent toxicity of losoxantrone and pa- followed by paclitaxel 135 mg/m2 and G-CSF prophylaxis was, clitaxel was explored prior to G-CSF support at the first dose indeed, much better tolerated with only 1 of 18 courses associ- level. Although the degree of neutropenia was not related to the ated with a DLT (grade 4 neutropenia for Ͼ5 days). sequence of study drugs administration on either the 24- or 3-h With the first dose level well tolerated, dose escalation schedule of paclitaxel, with the mean percentage decrement in proceeded with ascending losoxantrone dose to 50 mg/m2 and a ANC during course 1 of 96.6% when paclitaxel over 24-h fixed dose of paclitaxel at 135 mg/m2. With these doses not infusion preceded losoxantrone, 100% with the reverse se- producing DLT in any course, the paclitaxel dose was escalated quence (P ϭ 0.31), 95% when paclitaxel over 3-h infusion in three subsequent cohorts to 175, 200, and 225 mg/m2, re- preceded losoxantrone, and 92.5% with the reverse sequence spectively, and a fixed dose of losoxantrone at 50 mg/m2. These

dose levels were associated with DLTs in Յ25% of all courses and dose escalation continued with the final dose level exploring 60 mg/m2 losoxantrone and 225 mg/m2 paclitaxel. This dose level was associated with DLTs in 2 of 5 patients and 2 of 14 courses. DLTs during the first two courses of therapy with paclitaxel/losoxantrone were observed in one of six patients at the 50/175 mg/m2 dose level, two of four patients at the 50/200 mg/m2 dose level, one of four patients at the 50/225 mg/m2 dose level, and two of five patients at the 60/225 mg/m2 dose level. Grade 4 thrombocytopenia developed in 1 patient at each of the following dose levels of losoxantrone/paclitaxel (in mg/ m2): 40/135 (24 h), 50/175, and 50/225. Grade 3 thrombocytopenia was the highest grade of thrombocytopenia, developing in one patient at each of the following dose levels of losoxantrone and paclitaxel (in mg/m2): 40/135 (3 h, no G-CSF), 40/135 (with G-CSF), 50/200, and 50/225. No grade 3 or 4 thrombocytopenia Fig. 2 The relationship between total losoxantrone dose and absolute occurred in any of the five patients treated at the highest dose of decrease in LVEF. losoxantrone/paclitaxel (60/225 mg/m2). Red cell toxicity was minimal. Grade 4 anemia (hemoglobin, Ͻ6.5 mg/dl) occurred in 1 patient treated with 40 mg/m2 losoxantrone followed by 135 mg/m2 paclitaxel (3-h infusion) LVEF exceeding 20%, but without symptoms of congestive without G-CSF. Grade 3 anemia (hemoglobin, 6.5–7.9 mg/dl) heart failure. He had colon carcinoma, no prior anthracycline developed in three patients at 40 mg/m2 losoxantrone and 135 therapy, and received six courses of losoxantrone 50 mg/m2 mg/m2 paclitaxel, one patient at 50 mg/m2 losoxantrone and 200 (total cumulative dose, 300 mg/m2) and 175 mg/m2 paclitaxel. mg/m2 paclitaxel, and one patient at 50 mg/m2 losoxantrone and The LVEF was 58% at baseline, 53% after cycle 4, declined to 225 mg/m2 paclitaxel. No grade 3 or 4 anemia was seen at the 33% about 14 days after course 6 (grade 2 toxicity), and the highest dose level of losoxantrone and paclitaxel. patient was taken off study due to this decline in LVEF. A repeat MUGA 3 months later revealed an increase in LVEF to 47%. Nonhematological Toxicity Finally, eight patients had asymptomatic declines in LVEF of Cardiac Toxicity. Two patients developed congestive between 10 and 20%. heart failure. The first patient with congestive heart failure, No relationship was found between the cumulative dose of which was not likely to be related to the study drugs, was a losoxantrone and absolute change in LVEF (Fig. 2). 61-year-old woman with metastatic lung cancer and no prior Other Significant Nonhematological Toxicity. The anthracycline therapy, who was treated at 40 mg/m2 losox- combination of losoxantrone and paclitaxel was mildly emeto- antrone followed by 135 mg/m2 paclitaxel (24 h), with a dose genic, with only one patient developing severe (grade 3) nausea reduction of paclitaxel to 100 mg/m2 after course 1 secondary to and vomiting at losoxantrone and paclitaxel doses of 50 mg/m2 myelosuppression. Her total cumulative dose of losoxantrone and 200 mg/m2, respectively. The incidence of mucositis was over five courses of therapy was 200 mg/m2. At baseline, LVEF 9.8%, with four patients developing grade 1 mucositis. Neuro- was 61%, and after course 4, it was 67%. Following course 5, logical toxicities, principally paresthesia and hyperesthesia, she developed cellulitis of the left arm while she was neutro- were mild and occurred in eight (19.5%) and seven (17.1%) penic and was hospitalized. Twenty-four h later, she developed patients, respectively. Pronounced or total alopecia (grade 2) hypotension and received i.v. fluids and packed RBCs. She then developed in 18 patients (29%) and mild alopecia (grade 1) developed increasing dyspnea and an echocardiogram revealed occurred in five patients (12%). Two patients developed grade significant mitral regurgitation with an estimated LVEF of 61%. 3–4 hyperbilirubinemia. One patient with a mucoepidermoid Her dyspnea was probably related to fluid overload in the setting tumor of the parotid gland, who received eight courses of 50 of significant mitral insufficiency. mg/m2 losoxantrone and 225 mg/m2 paclitaxel, developed grade The second patient with congestive heart failure was a 4 hyperbilirubinemia (peak bilirubin, 4.6 mg/dl) and elevation in 47-year-old woman with pleural mesothelioma. She had previ- LDH after a RBC transfusion and therefore the elevations were ously received doxorubicin at a total cumulative dose of 100 possibly due to transfusion-related hemolysis. The hyperbiliru- mg/m2 and received seven courses of losoxantrone 50 mg/m2 binemia resolved prior to the next course of therapy, and the (total cumulative dose, 350 mg/m2, and 225 mg/m2 paclitaxel). patient received five additional courses of study drugs with no At baseline and after course 6, LVEF was 51 and 52%, respec- dose reduction and no further hyperbilirubinemia. The sec- tively. After course 7, she developed congestive heart failure ond patient, with colon cancer and no liver metastases, de- manifested by dyspnea with a decrease in LVEF to between 39 veloped grade 3 hyperbilirubinemia (peak bilirubin, 2.3 mg/ and 43%. She was treated with furosemide and digoxin with dl) after the second course of 40 mg/m2 losoxantrone and 100 significant clinical improvement and received additional therapy mg/m2 paclitaxel (dose reduction from 135 mg/m2 in course with paclitaxel alone and, subsequently, after progression, with 1 secondary to fever and neutropenia), and the hyperbiliru- BCNU and temozolomide. binemia resolved prior to the next course of therapy. The In addition, one patient had a decline from pretreatment patient received three additional courses of therapy, with a

Table 5 Losoxantrone pharmacokineticsa L3Pb P3L 403135c (24 h) 403135 (3 h) 135 (24 h)340 135 (3 h)340 No. of patients 2 4 3 4

Cmax (ng/ml) 4049 (1811–6286) 4409 (840–8920) 1856 (1226–2455) 3145 (2463–3960) AUC (ng ⅐ h/ml) 2367 (2249–2484) 1735 (1268–2821) 1851 (1419–2195) 2544 (1527–3075) Cl (ml/min/m2) 282 (268–296) 425 (236–526) 373 (304–470) 283 (217–437) 2 Varea (liters/m ) 850 (749–951) 1196 (561–2057) 1333 (1104–1524) 1119 (720–1384) 2 Vss (liters/m ) 304 (165–444) 480 (212–1257) 570 (339–865) 470 (251–710) MRT (h) 18 (10–25) 18 (8.1–42) 25 (19–31) 32 (14–55)

t1/2 (h) 35 (32–37) 33 (15–48) 42 (37–52) 49 (34–74) t1/2␣ (h) 0.12 (0.08–0.15) 0.09 (0.04–0.14) 0.18 (0.12–0.23) 0.12 (0.06–0.16) t1/2␤ (h) 1.2 (1.2–1.3) 1.1 (0.38–1.8) 2.4 (1.7–3.2) 1.3 (0.84–1.6) t1/2␥ (h) 37 (34–39) 29 (13–48) 36 (31–41) 39 (27–53) 2 Vc (liters/m ) 4.1 (2.9–5.2) 7.6 (1.4–14) 14 (8.3–24) 6.5 (2.9–9.4) a Values are means (ranges). b L, losoxantrone; P, paclitaxel. c Doses are in mg/m2 (values in parentheses are infusion times).

dose reduction in losoxantrone to 30 mg/m2 without further losoxantrone are shown in Fig. 3. All data were optimally hyperbilirubinemia. fitted to a three compartment model with i.v. infusion input

for estimating the half-lives of t1/2␣, t1/2␤, and t1/2␥ and the Antitumor Activity central volume of distribution (VC). One patient had a CR, and three patients had PRs. The Losoxantrone pharmacokinetics were characterized by a ϭ patient with CR had an adenoid cystic carcinoma of the scalp rapid distribution phase (mean t1/2␣ 0.13 h; range, 0.04–0.23 with cervical lymph node metastases. He had prior radiation h), a mean t1/2␤ of 1.5 h (range, 0.38–3.2 h), and a long terminal ϭ therapy to the cervical and supraclavicular nodes and no prior elimination phase (mean t1/2␥ 35 h; range, 13–48 h). The Vss systemic chemotherapy and was treated with 40 mg/m2 losox- was large (mean ϭ 456 liters/m2; range, 165-1257 liters/m2), antrone followed by a 3-h infusion of 135 mg/m2 paclitaxel for and Cl was high (mean ϭ 341 ml/min/m2; range, 217–526 four courses with complete clinical and radiological resolution ml/min/m2). Similarly, paclitaxel pharmacokinetics were char- ϭ of his metastases that lasted for 2 months prior to developing acterized by rapid distribution into tissue (mean t1/2␣ 0.36 h; new pulmonary nodules. The three PRs included: a patient with range, 0.11–0.77 h), a mean t1/2␤ of 2.4 h (range, 1.1–6.1 h), ϭ non-small cell lung carcinoma with prior cisplatin and etoposide and a long terminal elimination phase (mean t1/2␥ 27 h; range, 2 2 therapy who was treated with a 24-h infusion of 135 mg/m 17–78 h). Mean paclitaxel Vss and Cl were 78 liters/m (range, paclitaxel followed by 40 mg/m2 losoxantrone (4-month dura- 45–262 liters/m2) and 166 ml/min/m2 (range, 51–278 ml/min/ tion of response); a patient with transitional cell carcinoma of m2), respectively. the bladder with prior therapy with methotrexate, vinblastine, The sequence-dependence pharmacokinetic effects of doxorubicin, and cisplatin/carboplatin who was treated with 50 losoxantrone were evaluated for different paclitaxel schedules. mg/m2 losoxantrone followed by 3-h infusion of 175 mg/m2 No significant differences (P Ͻ 0.05) in losoxantrone AUC or paclitaxel and G-CSF (unknown duration of response); and a Cl were noted based on the sequences of losoxantrone and patient with adenocarcinoma of the esophagus with prior radi- paclitaxel on either the 24- or 3-h schedule of paclitaxel. ation therapy to the esophagus concomitant with cisplatin and No linear relationship was found between losoxantrone or 2 5-FU who was treated with 50 mg/m losoxantrone followed by paclitaxel Cmax, AUC, or Cl and grade of neutropenia, grade of 3-h infusion of 225 mg/m2 paclitaxel and G-CSF (4-month thrombocytopenia, grade 4 neutropenia for Ͼ5 days, and per- duration of response). centage decrement in ANC or platelets. Similarly, no relationship was found between course 1 losoxantrone exposure and the Pharmacokinetic and Pharmacodynamic Studies percentage decrement in LVEF. Plasma sampling for losoxantrone pharmacokinetics was performed in 13 patients following administration of 40 mg/m2 DISCUSSION losoxantrone and 135 mg/m2 paclitaxel as a 3- or 24-h Myelosuppression was the principal DLT of the combina- infusion either before or immediately after losoxantrone ad- tion of losoxantrone and paclitaxel and prevented dose escala- ministration. Paclitaxel pharmacokinetics were determined in tion from the first dose level of 40 mg/m2 losoxantrone and 135 17 patients who received paclitaxel doses ranging from 175 mg/m2 paclitaxel, without G-CSF support. DLTs were observed to 225 mg/m2 dose over 3 h immediately after losoxantrone. during 14 of 24 (58%) courses and 15 of 32 (47%) courses of Losoxantrone pharmacokinetics were not simultaneously therapy with 40 mg/m2 losoxantrone and 40 mg/m2 paclitaxel characterized in these patients. The pharmacokinetic param- 40 mg/m2 administered over 24 and 3 h, respectively, without eters of losoxantrone and paclitaxel are listed in Tables 5 and G-CSF support. In addition, the doses of paclitaxel after the first 6, respectively, and representative disposition curves of course were reduced in 8 of 13 (62%) patients, indicating that

Table 6 Paclitaxel pharmacokineticsa L3Pb 503175c (3 h) 503200 (3 h) 503225 (3 h) 603225 (3 h) No. of patients 5 4 4 4

Cmax (ng/ml) 4,772 (3,710–5,730) 4,745 (4,210–5,440) 7,328 (5,630–9,680) 5,930 (5,030–6,730) AUC (ng ⅐ h/ml) 21,143 (13,974–33,196) 20,938 (16,815–26,168) 33,162 (13,129–74,436) 20,823 (19,134–22,171) Cl (ml/min/m2) 152 (90–211) 163 (125–194) 169 (51–278) 180 (166–199) 2 Varea (liters/m ) 205 (136–357) 277 (166–543) 177 (24–359) 207 (122–242) 2 Vss (liters/m ) 80 (45–135) 121 (66–262) 51 (4.0–84) 61 (55–68) MRT (h) 11 (6.6–16) 16 (7.2–37) 5.9 (2.9–8.2) 7.3 (6.7–7.7)

t1/2 (h) 16 (10–23) 22 (9.9–50) 11 (5.1–20) 13 (8.2–16) d d t1/2␣ (h) 0.4 (0.2–0.57) 0.26 (0.11–0.57) 0.31 (0.14–0.66) 0.46 (0.25–0.77) d d t1/2␤ (h) 3.4 (2.5–4.3) 1.9 (1.1–3.4) 2.7 (2.1–3.1) 3.5 (2.4–6.1) d d t1/2␥ (h) 21 (17–27) 23 (10–51) 38 (17–78) 24 (10–50) 2 d d Vc (liters/m ) 9.7 (6.8–14) 8.8 (5.9–17) 6.6 (2.8–13) 12.7 (9.2–20) a Values are means (ranges). b L, losoxantrone; P, paclitaxel. c Doses are in mg/m2 (values in parentheses are infusion times). d Pharmacokinetic parameters were from only three patients.

each agent in combination has the potential for significant antitumor activity. The preliminary results of a Phase III study comparing 50 mg/m2 losoxantrone and 175 mg/m2 paclitaxel with G-CSF, which was based on the results of this study, to 175 mg/m2 paclitaxel alone as a first-line cytotoxic therapy in patients with metastatic breast cancer, but in whom adjuvant anthracycline or mitoxantrone therapy was allowed, revealed that grade 3 and 4 neutropenia occurred in 69% of patients and grade 4 thrombocytopenia occurred in 11%, which is similar to the incidence of these toxicities in this study, and that there was an overall response rate of 53% (21). The response rate in the paclitaxel arm was only 15%. The response rate to losoxantrone and paclitaxel in the Phase III study is similar to the response Fig. 3 Plasma disposition curves for losoxantrone. ‚, losoxantrone rate (53%) observed in a recent Phase II trial of the combination Ⅺ followed by 24-h paclitaxel infusion; , 24-h paclitaxel infusion fol- of 60 mg/m2 doxorubicin and 200 mg/m2 paclitaxel asa3h lowed by losoxantrone; ᭛, losoxantrone followed by 3-h paclitaxel infusion; E, 3-h paclitaxel infusion followed by losoxantrone. infusion with G-CSF as first-line chemotherapy in patients with metastatic breast cancer and no prior adjuvant doxorubicin (22). This study presented an opportunity to explore the toxicological and pharmacological effects produced by alternate this dose level is intolerable without G-CSF. Because single- sequences of losoxantrone and paclitaxel, which are particu- agent losoxantrone produced grade 4 neutropenia in 74% of larly important because sequence-dependent toxicological patients in a Phase II study (13), the severe degree of myelo- and pharmacological effects between paclitaxel and doxoru- suppression observed when losoxantrone is combined with an- bicin have been observed (23). The administration of pacli- other myelosuppressive agent, paclitaxel, is not surprising. The taxel on a protracted (24-h) schedule followed by doxorubi- addition of prophylactic G-CSF support allowed further dose cin had been demonstrated to be associated with more severe escalation of both losoxantrone and paclitaxel. The MTD was toxicity, which is explained by a reduction in the clearance of defined as the dose at which Ͼ50% of the patients experienced doxorubicin by paclitaxel (15, 23). Although this interaction DLT during course 1 and/or 2 of therapy. On the basis of this occurs on all schedules of paclitaxel, the sequence-dependent definition, the MTD was not reached with DLTs observed in one toxicological and pharmacological effects have been ob- of six patients at the losoxantrone/paclitaxel 50/175 mg/m2 dose served only with a prolonged (24-h infusion) paclitaxel level, two of four patients at the 50/200 mg/m2 dose level, one schedule. Except for a slightly greater magnitude of myelo- of four patients at 50/225 mg/m2 dose level, and two of five suppression, based on percentage decrement in the platelet patients at 60/225 mg/m2 dose level during the first two courses counts during course 1 when paclitaxel is administered prior of therapy with losoxantrone and paclitaxel. On the basis of to losoxantrone over 24 but not 3 h, which did not reach these results, the recommended dose level for further studies is statistical significance, there was no evidence of sequence 50 mg/m2 losoxantrone and 175 mg/m2 paclitaxel with G-CSF dependent toxicological effects. This conclusion however, and was based on the recommended dose for each agent when should be considered preliminary because the sequence- used alone (11, 16). Using the same recommended doses for dependent toxicity was evaluated in a limited number of

patients (six patients on the 24-h schedule of paclitaxel), and ture-activity relationships against murine leukemias. J. Med. Chem., 30: the patients did not serve as their own controls. 121–131, 1987. In this study, losoxantrone pharmacokinetics were charac- 5. Graham, M. A., Newell, D. R., Butler, J., and Hoey, B. The effect of terized by a high total plasma clearance and a slow rate of the anthrapyrazole antitumour agent CI941 on rat liver microsome and cytochrome P-450 reductase mediated free radical processes. Inhibition elimination, suggesting extensive tissue distribution. Paclitaxel of doxorubicin activation in vitro. Biochem. Pharmacol., 36: 3345– pharmacokinetic parameter values were consistent with data 3351, 1987. from previously published studies of paclitaxel given as a 3-h 6. Fisher, G. R., and Patterson, L. H. Lack of involvement of reactive infusion. For example, in the study by Schiller et al. 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Topoi- additional patients experienced Ͼ10% asymptomatic reduction somerase II inhibition and cytotoxicity of the anthrapyrazoles DuP 937 in LVEF. However, no relationship could be established be- and DuP 941 (losoxantrone) in the National Cancer Institute preclinical tween the total cumulative dose of losoxantrone and the change antitumor drug discovery screen. J. Natl. Cancer Inst. (Bethesda), 86: 1239–1244, 1994. in LVEF. Interestingly, cardiotoxicity was also noted in both arms of the Phase III trial comparing the combination of pacli- 9. Leopold, W. R., Nelson, J. M., Plowman, J., and Jackson, R. C. Anthrapyrazoles, a new class of intercalating agents with high-level, taxel and losoxantrone to paclitaxel as a single agent in patients broad spectrum activity against murine tumors. Cancer Res., 45: 5532– with metastatic breast cancer with two patients in the losox- 5539, 1985. antrone and paclitaxel arm and 1 patient in the paclitaxel arm 10. Dexter, D. 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Sami G. Diab, Sharyn D. Baker, Amita Joshi, et al.

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