3040 Vol. 7, 3040–3046, October 2001 Clinical Cancer Research Phase I Study of Doxil-Cisplatin Combination Chemotherapy in Patients with Advanced Malignancies1 Olga Lyass, Ayala Hubert, and cancer patients. In four of seven responders, the time to 2 Alberto A. Gabizon disease progression exceeded 1 year. Doxil 1-h (Cmax equiv- Department of Oncology, Hadassah-Hebrew University Medical alent) levels were assessed in 20 patients. The mean Doxil Center, Jerusalem 91120, Israel Cmax (mg/l plasma) increased gradually with dose escalation ,from 14.7 ؎ 1.9 for 40 mg/m2, to 17.3 ؎ 3.0 for 50 mg/m2 2 2 ؎ and 23.3 5.5 for 60 mg/m . The 60 mg/m Cmax was similar ABSTRACT to data obtained in parallel clinical studies at our institution Purpose: Our first objective was to evaluate the feasi- with single-agent Doxil at 60 mg/m2. However, the 7-day bility of administering a combination of Doxil, a pegylated Doxil postinfusion levels were significantly lower in patients liposome formulation of doxorubicin, and cisplatin and to receiving the Doxil-cisplatin combination than in those re- determine the maximum tolerated dose of the combination. ceiving single-agent Doxil. A secondary objective was to examine Doxil peak and 7-day Conclusion: Doxil can be administered at full maximum postinjection plasma levels at the various dose levels tested. tolerated dose (50 mg/m2 every 4 weeks) in combination with Methods: Patients with advanced solid tumors were 60 mg/m2 cisplatin, with no evidence of major overlapping treated every 4 weeks with cisplatin on day 1 and Doxil on toxicities. Palmar-plantar erythrodysesthesia incidence and day 2. In the first three dose levels, the dose of Doxil was severity appears to be diminished, in comparison with data fixed at 40 mg/m2, whereas the dose of cisplatin was esca- available for single-agent Doxil. Plasma concentration data lated from 40 to 50 and 60 mg/m2. At the fourth and fifth point to an accelerated clearance of Doxil when adminis- dose levels, the dose of cisplatin was fixed at 60 mg/m2, tered after cisplatin. whereas the dose of Doxil was escalated to 50 and to 60 mg/m2. Plasma Doxil (doxorubicin-equivalent) levels were measured by a high-performance liquid chromatography INTRODUCTION assay with fluorescence detection at 1 h and 7 days after The anthracycline antibiotic doxorubicin is one of the most infusion of Doxil. widely used antineoplastic agents and the mainstay of chemo- Results: Twenty-six patients entered the study. Twenty- therapy for lymphomas and a variety of solid tumors. Unfortu- four patients completed a minimum of 2 courses and were nately, toxicity limits the therapeutic activity of doxorubicin and fully assessable for toxicity and efficacy. Eighteen patients may preclude adequate dosing. Development of doxorubicin had received prior chemotherapy, 11 of them with anthra- encapsulation in liposomes is one of the attempts to improve the cycline-containing regimens. A total of 177 courses were therapeutic index of the drug. administered within the study. In 12 patients, cisplatin was Pegylated liposomal doxorubicin (Doxil, also known as discontinued after 1 to 13 courses, and Doxil was continued Caelyx) is a novel formulation of doxorubicin in long-circulat- alone for 1–22 courses. All other patients received both ing (Stealth) liposomes that drastically changes the drug phar- drugs until discontinuation of therapy. The dose-limiting macokinetics and biodistribution (1). The formulation markedly toxicities were neutropenia and mucositis. Grade 4 neutro- lengthens liposome circulation time by retarding reticulo-endo- penia was seen in 3 patients (one with neutropenic fever) at thelial system clearance. Eventually, large numbers of lipo- dose levels 4 and 5. Grade 3 mucositis was observed in 4 somes are extravasated through the abnormally permeable ves- patients at dose levels 3, 4, and 5. In contrast, the most sels characteristic of many tumors, resulting in enhanced severe palmar-plantar erythrodysesthesia manifestation was liposome deposition in tumors (2, 3). The toxicity profile of grade 2 seen in 1 patient only. Tumor responses included Doxil is characterized by dose-limiting mucocutaneous toxici- seven partial responses, of which three were in ovarian ties, mild myelosuppression, minimal alopecia, and no apparent cardiac toxicity (4). Doxil appears to be the most active agent available for Kaposi’s sarcoma (5, 6) and has shown significant activity against a variety of solid tumors (reviewed in Ref. 7), Received 3/30/01; revised 6/8/01; accepted 7/9/01. specifically in recurrent epithelial ovarian carcinoma (8, 9) and The costs of publication of this article were defrayed in part by the metastatic breast cancer (10, 11). payment of page charges. This article must therefore be hereby marked Cisplatin is one of the most potent chemotherapeutic agents advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. available and forms the basis of many standard combination 1 Supported by ALZA Corporation. A preliminary report on this study chemotherapy regimens. Cisplatin is used in combination with was presented in poster form at the 1999 European Conference on doxorubicin in the treatment of a variety of solid tumors. These Clinical Oncology (Lyass, O., Hubert, A., Tzemach, D., et al., Eur. J. two agents have different mechanisms of action, show no cross- Cancer, 35: S287, 1999). 2 To whom requests for reprints should be addressed, at Department of resistance, and their toxicities do not overlap. Because Doxil Oncology, Hadassah Medical Center, Kiryat Hadassah, Jerusalem appears to be a promising form of delivering doxorubicin with 91120, Israel. Fax: 972-2-643-0622; E-mail: [email protected]. decrease of some of the most problematic toxicities (cardiac Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2001 American Association for Cancer Research. Clinical Cancer Research 3041 Table 1 Dose levels clide ventriculography (MUGA scan) or echocardiography. No. of Cisplatin, Doxil, Prior treatment with anthracyclines was allowed only if the 2 Dose level patients mg/m2, day 1a mg/m2, day 2a cumulative dose of doxorubicin was Ͻ400 mg/m . The study 1 5 40 40 was approved by the Hadassah institutional review board, and 2 4 50 40 patients were required to provide signed, witnessed informed 3 4 60 40 consent. 4 5 60 50 Pretreatment evaluation included a complete history and 5 8 60 60 physical examination and documentation of performance status. a Cycles every 4 weeks. Laboratory evaluation included a complete blood count, chem- istry panel with liver and renal function tests, prothrombin time, and serum tumor marker levels if relevant to tumor condition. toxicity and myelosuppression), a combination with cisplatin is All patients had a pretreatment 12-lead electrocardiogram and likely to be tolerated without enhanced toxicity, which may cardiac ejection fraction evaluation. Radiographic evaluation enable us to deliver to patients optimal doses of both agents and included a chest radiograph and any other imaging examinations achieve significant advantages over standard cisplatin-doxoru- (computed tomography scan and ultrasonography) indicated by bicin combination. the type and site of the malignancy. Before each new treatment The principal objectives of the present study were to eval- cycle, vital signs, weight, symptom-oriented physical check, uate the feasibility of administering a combination of Doxil and Karnofsky status assessment, complete blood count, chemistry cisplatin and to determine the MTD3 of the combination. In panel with liver and renal function tests, and report on adverse addition, Doxil plasma levels were assessed in subgroup of events occurring after the previous dose were obtained. During patients and compared with our records for patients receiving the first cycle, a complete blood count was repeated on a weekly Doxil as single agent (11, 12). basis. From the second cycle and onward, a complete blood count was performed before treatment and 2 weeks after each 2 PATIENTS AND METHODS dose. After a 300 mg/m cumulative dose of Doxil, cardiac ejection fraction was reevaluated by MUGA scan or echocar- Study Design. The study reported herein was a single- diography. institution Phase I trial at the Hadassah Medical Center. Be- Treatment was administered until disease progression or tween February 1997 and October 1998, 26 patients were en- dose-limiting toxicity. All patients who received one or more rolled. courses of cisplatin and Doxil were evaluable for toxicity. The starting dose of Doxil was 40 mg/m2 combined with Toxicity was graded according to the National Cancer Institute 40 mg/m2 cisplatin every 4 weeks. Doses of Doxil and cisplatin Common Toxicity Criteria. For the sake of clarity, PPE grades were escalated according to a planned sequence (Table 1), 3–4 always entailed a situation in which simple physical activ- covering a range of 40–60 mg/m2 for both drugs. A minimum ities (writing, clenching fists, and walking with closed shoes) of 4 patients receiving at least 2 courses of treatment were were highly painful or unfeasible. enrolled per dose level. At each dose level, the study progressed For stomatitis and PPE, dose-limiting toxicity was defined to the next level if no patient experienced nonhematological as any grade 3 or 4. For patients with grade 3 or 4 toxicity, the toxicity of grade 3 or hematological toxicity of grade 4 during dose of subsequent courses was reduced by 25%. Patients were the two first dosing cycles. If only one patient experienced grade retreated only after the toxicity grade returned to 0 to 1. If 3 or 4 toxicity, up to 4 subsequent patients were to be accrued necessary, the dosing intervals could be increased by 1 or 2 at the same dose level until the dose tolerance could be accu- weeks to enable resolution of toxicity. rately assessed. If two or more patients experienced grade 3 or For myelosuppression, dose-limiting toxicity was defined 4 toxicity per dose level, then this level was declared as the as grade 4.