A phase I clinical and pharmacokinetic study (LIPOTEC - GP PHARM/DOXO 01) of a new liposomal doxorubicin given as 3-week schedule in patients with solid tumors

Abstract

As a dose-finding phase I study of a new liposomal formulation of doxorubicin (LipD), patients (n = 39; median age: 60 years; range, 41–75; median ECOG performance status, 1; range, 0–2) with refractory cancer had a starting dose of LipD administered at 30 mg/m² as a 1-hour iintravenous infusion. Cycle duration was 21 days. At the recommended dose (RD), patients received a first cycle of nonliposomal doxorubicin (non-LipD) to evaluate intrapatient pharmacokinetic differences between non-LipD and LipD. The most frequent diagnosis was head and neck tumor (7 patients). Tolerance and safety of dose levels of 30, 40, 50, 60, 70, 80, and 90 mg/m² were evaluated. A total of 131 cycles were administered (median per patient, 3; range, 1–6). Of the 39 patients, 8 completed the planned six cycles. Febrile neutropenia was dose limiting and defined the toxic dose of LipD as 70 mg/m². Other significant toxicities included asthenia (G2: 31%; G3: 8%), neutropenia (G3: 35%; G4: 29%), thrombopenia (G3: 15%; G4: 2%), anemia (G1–G2: 67%; G3–G4: 5%), mucositis (G1–G2: 32%, G3: 4%), and acute allergic reactions (G1–G2: 36%). Comparison of pharmacokinetic profiles of non-LipD and LipD showed that higher exposure was achieved with LipD. Stable disease was observed in 14 patients. We conclude that the LipD regimen, given as a 1-hour infusion every 3 weeks, is well tolerated and has a favorable pharmacokinetic profile. The recommended dose is 70 mg/m² with prophylactic antihistamines and corticoids to preempt allergic reaction.

Keywords::

• Liposomal doxorubicin
• pharmacokinetics
• phase I clinical trial

Acknowledgments

This work was sponsored by Lipotec S.A. The investigated drug for this study, liposomal doxorubicin, was supplied by GP-Pharm. GP-Pharm S.A. has obtained, from Lipotec S.A., the property and all rights over the investigated drug, liposomal doxorubicin (patent number: ES 2072223 B1).

Declaration of interest: RM and CS are employees of GP-Pharm. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the manuscript, and the decision to publish.