Vol. 5, 299–308, February 1999 Clinical Cancer Research 299 A Phase I and Pharmacokinetic Study of Losoxantrone and Paclitaxel in Patients with Advanced Solid Tumors1 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 reverse sequence (P 5 0.19). Losoxantrone clearance was 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- Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 1999 American Association for Cancer Research. 300 Phase I Study of Losoxantrone and Paclitaxel Fig. 1 Chemical structures of doxo- rubicin, mitoxantrone, and losox- antrone. 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 mitox- antrone 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 $18 years; (b) WHO performance status of 2 55 mg/m (11). Two Phase II studies of losoxantrone in patients #2; (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 $ 1500/ml, platelet count of $100,000/ml), hepatic (serum larger of the two studies (13), 1% of the patients developed bilirubin of #1.5 mg/dl), and renal (serum creatinine of #2.0 . 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 ,45%, as determined by radionuclide thracycline regimens have notable antitumor activity in women scanning or $10% 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 .400 mg/m2 or dose of mitoxantrone of .125 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.