Objectives: Paclitaxel and doxorubicin are among the most active chemotherapeutic agents in various types of tumors. Pegylated liposomal doxorubicin (Caelyx) has a more favorable pharmacokinetic and toxicity profile than the free drug. We conducted a phase I study to determine the maximum tolerated doses (MTD) and the dose limiting toxicities (DLT) of the combination administered every 2 weeks in patients with advanced solid tumors. Patients and Methods: Treatment consisted of escalating doses of Caelyx (12.5–17.5 mg/m2) administered as a 30-min intravenous infusion on day 1 and paclitaxel (90–115 mg/m2) as a 3-hour intravenous infusion on day 2 every 2 weeks without growth factor support. One cycle was considered as the administration of two consecutive treatments in 28 days. Twenty-six patients with histologically confirmed advanced stage solid tumors have been enrolled. Treatment was first-line treatment for 38% of patients, second-line for 31% and third-line for 31%. Results: The DLT were evaluated during the first 4 weeks of treatment (2 treatment administrations) and consisted in all but one case of grade 2–3 neutropenia resulting in treatment delay. One patient died of cardiac arrest 1 day after the first treatment. A total of 86 cycles have been administered with only 1 episode of febrile neutropenia. Hematologic toxicity was generally mild. Only 1 patient at the first and another at the highest dose level developed grade 4 neutropenia. At the highest dose level, 3 of 6 patients developed grade 3 neutropenia. Grade 4 anemia or grade 3–4 thrombocytopenia was not observed. Non-hematologic toxicity included grade 2–3 nausea/vomiting in 10%, grade 2–4 diarrhea in 7% and grade 2–3 neurotoxicity in 8% of cycles. Mucositis grade 3 complicated 1 cycle. Palmar-plantar erythrodysesthesia grade 2–3 was observed in 3 patients and was the reason for treatment discontinuation in 1 patient. Cardiotoxicity as the development of congestive heart failure or more than 10% reduction in left ventricular ejection fraction was not observed. The most common non-hematologic toxicity was grade 2–3 asthenia complicating 31% of the cycles. Among 18 evaluable patients, 1 complete and 4 partial responses were observed primarily in patients with breast cancer. The MTD which are the recommended doses for further use in phase II trials were Caelyx 15 mg/m2 on day 1 and paclitaxel 115 mg/m2 on day 2 administered every 2 weeks. Conclusion: The administration of Caelyx and paclitaxel every 2 weeks is a feasible regimen and is associated with acceptable toxicity.

1.
Gianni L, Munzone E, Capri G, Fulfaro F, Tarenzi E, Villani F, Spreafico C, Laffranchi A, Caraceni A, Martini C: Paclitaxel by 3-hour infusion in combination with bolus doxorubicin in women with untreated metastatic breast cancer: High antitumor efficacy and cardiac effects in a dose-finding and sequence-finding study. J Clin Oncol 1995;13:2688–2699.
2.
Gehl J, Boesgaard M, Paaske T, Vittrup Jensen B, Dombernowsky P: Combined doxorubicin and paclitaxel in advanced breast cancer: Effective and cardiotoxic. Ann Oncol 1996;7:687–693.
3.
Sparano JA, Hu P, Rao RM, Falkson CI, Wolff AC, Wood WC: Phase II trial of doxorubicin and paclitaxel plus granulocyte colony-stimulating factor in metastatic breast cancer: An Eastern Cooperative Oncology Group Study. J Clin Oncol 1999;17:3828–3834.
4.
Holmes FA, Madden T, Newman RA, Valero V, Theriault RL, Fraschini G, Walters RS, Booser DJ, Buzdar AU, Willey J, Hortobagyi GN: Sequence-dependent alteration of doxorubicin pharmacokinetics by paclitaxel and doxorubicin in patients with metastatic breast cancer. J Clin Oncol 1996;14:2713–2721.
5.
Gianni L, Vigano L, Locatelli A, Capri G, Giani A, Tarenzi E, Bonadonna G: Human pharmacokinetic characterization and in vitro study of the interaction between doxorubicin and paclitaxel in patients with breast cancer. J Clin Oncol 1997;15:1906–1915.
6.
Colombo T, Parisi I, Zucchetti M, Sessa C, Goldhirsch A, D’Incalci M: Pharmacokinetic interactions of paclitaxel, docetaxel and their vehicles with doxorubicin. Ann Oncol 1999;10:391–395.
7.
Sledge GW, Robert N, Sparano JA, Cogleigh M, Goldstein LJ, Neuberg D, Rowinsky E, Baughman C, McCaskill-Stevens W: Eastern Cooperative Oncology Group studies of paclitaxel and doxorubicin in advanced breast cancer. Semin Oncol 1995;22(3 suppl 6):105–108.
8.
Working PK, Newsman MS, Huang SK: Pharmacokinetics, biodistribution and therapeutic efficacy of doxorubicin encapsulated in Stealth liposomes (Doxil). J Liposom Res 1994;4:667–687.
9.
Papahadjopoulos D, Allen T, Gabizon A, Mayhew E, Matthay K, Huang SK, Lee KD, Woodle MC, Lasik DD, Redemann C: Sterically stabilized liposomes: Improvement in pharmacokinetics and antitumor therapeutic efficacy. Proc Natl Acad Sci USA 1991;88:11460–11464.
10.
Ranson MR, Carmichael J, O’Byrne K, Stewart S, Smith D, Howell A: Treatment of advanced breast cancer with sterically stabilized liposomal doxorubicin: Results of a multicenter phase II trial. J Clin Oncol 1997;15:3185–3191.
11.
Muggia FM, Hainsworth JD, Jeffers S, Miller P, Groshen S, Tan M, Roman L, Uziely B, Muderspach L, Garcia A, Burnett A, Greco FA, Morrow CP, Paradiso LJ, Liang LJ: Phase II study of liposomal doxorubicin in refractory ovarian cancer: Antitumor activity and toxicity modification by liposomal encapsulation. J Clin Oncol 1997;15:987–993.
12.
Northfelt DW, Dezube BJ, Thommes JA, Levine R, Von Roenn JH, Dosil GM, Rios A, Krown SE, DuMond C, Mamelok RD: Efficacy of pegylated-liposomal doxorubicin in the treatment of AIDS-related Kaposi’s sarcoma after failure of standard chemotherapy. J Clin Oncol 1997;15:653–659.
13.
Uziely B, Jeffers S, Isacson R, Kutsch K, Wei-Tsao D, Yehoshua Z, Libson E, Muggia FM, Gabizon A: Liposomal doxorubicin: Antitumor activity and unique toxicities during two complementary phase I studies. J Clin Oncol 1995;13:1777–1785.
14.
Miller AB, Hoogstraten BB, Staquet M, Winkler A: Reporting results of cancer treatment. Cancer 1981;47:207–214.
15.
Symon Z, Peyser A, Tzemach D, Lyass O, Sucher E, Shezen E, Gabizon A: Selective delivery of doxorubicin to patients with breast carcinoma metastases by stealth liposomes. Cancer 1999;86:72–78.
16.
Stewart S, Harrington KJ: The biodistribution and pharmacokinetics of stealth liposomes in patients with solid tumors. Oncology 1997;10:33–37.
17.
Krishna R, Mayer LD: Liposomal doxorubicin circumvents PSC 833-free drug interactions, resulting in effective therapy of multidrug-resistant solid tumors. Cancer Res 1997;57:5246–5253.
18.
Muggia FM: Clinical efficacy and prospects for use of pegylated liposomal doxorubicin in the treatment of ovarian and breast cancers. Drugs 1997;54(suppl 4):22–29.
19.
Gabizon A, Martin F: Polyethylene glycol-coated (pegylated) liposomal doxorubicin. Rationale for use in solid tumours. Drugs 1997;54(suppl 4):15–21.
20.
Amantea M, Newman MS, Sullivan TM, Forrest A, Working PK: Relationship of dose intensity to the induction of palmar-plantar erythrodysesthesia by pegylated liposomal doxorubicin in dogs. Hum Exp Toxicol 1999;18:17–26.
21.
Dombernowsky P, Boesgaard M, Andersen E, Jensen BV: Doxorubicin plus paclitaxel in advanced breast cancer. Semin Oncol 1997;24(5 suppl 17):15–18.
22.
Moore MR, Srinivasiah J, Feinberg BA, Bordoni RE, Lesesne JB, Carr D, Spinolo J, Galleshaw J, Moseley L, Lefler J, McKenzie P: Phase II randomised trial of doxorubicin plus paclitaxel (AT) versus doxorubicin HCL liposome injection (Doxil) plus paclitaxel (DT) in metastatic breast cancer (abstr 614). Proc Am Soc Clin Oncol 1998;17:160a.
23.
Safra T, Muggia F, Jeffers S, Groshen S, Tsao-Wei D, Angeles A, Lyass O, Henderson RW, Berry G, Gabizon A: Pegylated liposomal doxorubicin (Doxil) reduced clinical cardiotoxicity in patients reaching or exceeding 500 mg/m2 cumulative doses of Doxil (abstr 804). Proc Am Soc Clin Oncol 2000;19:206a.
24.
Caponigro F, Comella P, Budillon A, Bryce J, Avallone A, De Rosa V, Ionna F, Comella G: Phase I study of Caelyx (doxorubicin HCL, pegylated liposomal) in recurrent or metastatic head and neck cancer. Ann Oncol 2000;11:339–342.
25.
Ernst DS, Winquist E, Moore M, Jonker D, Friel C: Activity of pegylated liposomal doxorubicin (Caelyx) advanced transitional cell carcinoma (abstr 1431). Proc Am Soc Clin Oncol 2000;19:363a.
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