Vol. 6, 2279–2287, June 2000 Clinical Cancer Research 2279 Dose-finding and Pharmacologic Study of Chronic Oral Idarubicin Therapy in Metastatic Breast Cancer Patients1 Giuseppe Toffoli, Roberto Sorio, Paola Aita, observed between absolute neutrophil count at nadir and ؊؍ ؍ Diana Crivellari, Giuseppe Corona, IDA area under the curve (P 0.022; r 0.33), IDA Cmax ؍ ؊0.38), IDOL area under the curve (P؍ r ;0.0067 ؍ P) ؊؍ ؍ ؊؍ ,Alessandra Bearz, Isabel Robieux 0.0009; r 0.43), and IDOL Cmax (P 0.0016; r 0.41), Anna Maria Colussi, Franco Stocco, and respectively. By multivariate analysis, IDA C was the 2 max .(0.01 ؍ P ;0.14 ؍ Mauro Boiocchi strongest determinant for neutropenia (R2 Divisions of Experimental Oncology 1 [G. T., P. A., G. C., M. B.] Among the 21 patients evaluable for response, 3 (14.3%) had and Medical Oncology [R. S., D. C., A. B., I. R., A. M. C.], Centro di partial response (lasting 3, 6, and 8 months, respectively), Riferimento Oncologico, 33081 Aviano, and Pharmacia & Upjohn, and 6 (28.6%) had a complete arrest of disease progression 20152 Milan [F. S.], Italy (lasting 2–6 months). In conclusion, the MTD of this sched- ule is 10 mg/day and the DLTs are neutropenia and diar- ABSTRACT rhea. Tolerance was good, and the treatment is feasible as Oral idarubicin (IDA) is an active drug in metastatic home therapy. Some objective measurable responses were breast cancer, but its role in the management of this tumor documented in this group of anthracycline-pretreated pa- is yet not established completely. To investigate a new mo- tients. IDOL could have a role for the pharmacological dality of IDA administration, a dose-finding study was de- effect. Further evaluation of this schedule is warranted to signed with hyperfractionated doses. The purpose was to assess the activity and toxicity of prolonged oral IDA ad- determine the maximum tolerated dose (MTD), the dose- ministration. limiting toxicity (DLT), and the pharmacokinetics of this schedule. IDA was administered twice daily as outpatient INTRODUCTION therapy in cycles of 3 weeks followed by a 1-week rest. IDA3 is a DAU analogue that has achieved a clinical role Thirty-one patients with progressive metastatic breast can- in the treatment of some hematological malignancies (1–7). cer and pretreated with chemotherapy (including epirubicin Recently, IDA has been also proposed in the management of and doxorubicin) were enrolled. DLT was defined as G4 adult solid tumors (8–13). IDA is endowed with greater biolog- hematological toxicity or any other toxicity G3 or higher ical activity and lower cardiotoxicity than DAU (2). Our and (Bloom and Richardson grading). Inter- and intrapatient other in vitro studies have indicated that IDA is more effective dose increases were studied. Pharmacokinetics of IDA and than DAU in tumor cell lines displaying the multidrug-resistant its metabolite idarubicinol (IDOL) were evaluated. IDA dose phenotype, thus suggesting that IDA could be useful in circum- was increased from 2 mg/day to 10 mg/day, by steps of 1 venting multidrug resistance (3, 14). mg/day, with the larger dose given in the evening. MTD was IDA therapy generally is well tolerated. The main IDA reached at 10 mg/day. Overall, the therapy cycles were 69 adverse effect is myelosuppression. Gastrointestinal toxicity is (median/patient, 2; range, 1–6). DLTs were G4 neutropenia also common. This includes nausea, vomiting, and stomatitis of associated with leukopenia and thrombocytopenia in one different WHO grades, according to the IDA dose schedule patient and G3 diarrhea in another of the 5 patients in the 10 used. G1-G2 diarrhea occurs in ϳ10% of patients after a single mg/day cohort. The two patients developing DLT at the i.v. dose (10–15 mg/m2) and in 10–30% of patients after oral daily dose of 10 mg received a dose normalized for body administration (40–45 mg/m2; Ref. 9). surface of 6.85 and 5.65 mg/m2/day, respectively. We con- The pharmacokinetics of IDA have been evaluated in can- sidered 5.5 mg/m2/day to be the MTD. Other toxicities were cer patients after i.v. or oral administration (10, 15). IDA has a nausea, vomiting, neutropenia, and diarrhea, grades G1 to large volume of distribution, which probably indicates extensive G2. By univariate analysis, significant correlations were tissue accumulation. IDA is metabolized, mainly in the liver after oral administration, to IDOL (10). IDOL retains good cytotoxic activity in vitro (15). Variability in oral absorption has been reported both between patients and within the same patient (10). Received 12/30/99; revised 2/29/00; accepted 3/1/00. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 3 The abbreviations used are: IDA, idarubicin; DAU, daunorubicin; 1 Supported in part by a grant from the Ministry of Health (“Ricerca IDOL, idarubicinol (4-demethoxy-13-dihydrodaunorubicin); AUC, area Finalizzata” FSN 1997). under the curve; t1/2, half-life; MTD, maximum tolerated dose; FEC, 2 To whom requests for reprints should be addressed, at Centro di fluorouracil-epirubicin- cyclophosphamide; LVEF, left ventricular ejec- Riferimento Oncologico, Via Pedemontana Occidentale 12, 33081 Avi- tion fraction; ANC, absolute neutrophil count; DLT, dose-limiting tox- ano (PN), Italy. Phone: 39-0434-659300; Fax: 39-0434-659428; E-mail: icity; Cmax, maximum plasma concentration; CL, clearance; Vd, volume [email protected]. of distribution; P-gp, P-glycoprotein. Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2000 American Association for Cancer Research. 2280 Chronic Oral IDA IDA is the first anthracycline that can be given both p.o. vious treatments were 440 mg/m2 (range, 155–765 mg/m2) and i.v. Oral IDA has been used in advanced breast cancer (11, and 180 mg/m2 (range, 140–317 mg/m2), respectively. 16). However, the role of oral IDA in this tumor needs to be The patients should not have received chemotherapy and/or better clarified. The oral route is useful in palliative treatment of radiation within 4 weeks before IDA treatment and were not patients with poor venous access and may be particularly ap- receiving concurrent hormonal therapy. Patients with a history propriate for older patients (17). Oral IDA in solid tumors was of cardiac disease were excluded. Other inclusion/exclusion administered over 1, 3, or 5 days (9). However, as demonstrated criteria were: normal baseline (Ն50%) LVEF; life expectancy previously for other antineoplastic drugs (18, 19), the effective- of at least 8 weeks; Eastern Cooperative Oncology Group per- ness of IDA might improve by low-dose continuous exposure. formance status of 0, 1, or 2; WBC count Ն4,000/␮l; platelet Although IDA is not a typical cell cycle phase-specific drug, it count Ն150,000/␮l; ANC Ն2,000/␮l; bilirubin level Յ1.5 mg/ exerts some antitopoisomerase II activity (1). It has been dem- dl; aspartate aminotransferase level two times normal or lower, Յ onstrated that the commitment to cell killing by antitopoisomer- serum creatinine level 1.5 mg/dl, and creatinine clearance Ն ase II agents predominantly occurs in S-phase cells (20). There- 60 ml/min. Written informed consent was obtained before fore, prolonged treatments with this drug increase the number of study entry and the protocol was approved by the local Ethical cells exposed to the drug during the most chemosensitive phase Committee. of the cell cycle. The increased ratio of IDOL/IDA AUC after Pretreatment and Treatment Evaluation. Pretreatment oral compared with i.v. administration represents another ad- evaluation included history and physical examination, chest vantage of prolonged low-dose treatments because IDA and its X-ray, liver ultrasound, electrocardiogram, determination of resting baseline LVEF by echocardiography and computed to- metabolite can cooperate in determining cytotoxic effects. Fi- mography, total body Tcm bone scan when clinically indicated, nally, the long plasmatic t of IDA and the longer t of IDOL 1/2 1/2 full blood cell count, electrolytes, blood urea nitrogen, creati- (10) are pharmacological characteristics extremely favorable in nine clearance (24-h urinary collection), liver function tests, protracted oral drug administration. In fact, they reduce the prothrombin time-international normalized ratio (PT-INR), and fluctuations in the plasmatic concentrations of the drug, allow- partial thromboplastin time (PTT). Laboratory tests were per- ing cells to be exposed to steadier drug concentrations, as with formed on a weekly base. Toxicities were graded using the continuous i.v. infusion therapy. WHO criteria. The compliance to therapy was assessed through To investigate a simple modality of IDA administration weekly pill counts in addition to a patient diary and evaluation instead of the cumbersome and costly continuous i.v. infusion, was according to the criteria of Miller et al. (21). a dose escalation of oral IDA was devised. The drug was given Treatment Plan. IDA was provided by Pharmacia Up- p.o. in hyperfractionated doses over a long period of time with john (Milan, Italy) in powder oral capsules of 1 and 5 mg. Each the purpose of determining the MTD, toxicity profile, and therapy course was administered for 21 days every 28 days, The pharmacokinetics of IDA this schedule. starting dose of 1 mg was taken around either 8.30 a.m. or 8.30 p.m. In the subsequent cycles, the dose was increased by 1 PATIENTS AND METHODS mg/day (with the larger dose given in the evening) until disease progression, refusal, or DLT. The 1-mg capsule to be added was Patients. Thirty-one patients, ages 39–73 years, with given alternatively in the morning or in the evening.