A phase I study of pegylated liposomal doxorubicin

Authors: Andrea WangGillam Nilay Thakkar A Craig Lockhart Kerry Williams Maria Baggstrom Michael Naughton Rama Suresh Cynthia Ma Benjamin Tan Wooin Lee Xuntian Jiang Tibu Mwandoro Lauren Trull Stefanie Belanger Allison N Creekmore Feng Gao Paula M Fracasso Joel Picus

Publish Date: 2014/06/11

Volume: 74, Issue: 2, Pages: 419-426

PDF Link

Abstract

This study aimed to determine the maximumtolerated dose and doselimiting toxicities of pegylated liposomal doxorubicin PLD in combination with temsirolimus T in patients with refractory solid tumors Using a standard “3+3” dose escalation design 23 patients were enrolled in three dosing cohorts in this phase I study The starting dose level was PLD at 30 mg/m2 every 4 weeks and T at 20 mg weekly Pharmacokinetics PK of doxorubicin were evaluated for patients in the expansion cohort The most common treatmentrelated adverse events of all grades were mucositis/stomatitis 696  anorexia 522  thrombocytopenia 522  and fatigue 478  The recommended doses of this combination for phase II studies are 25 mg/m2 PLD and 25 mg T PK analyses suggested increased exposure of doxorubicin in this combination regimen compared to doxorubicin administered as a single agent possibly due to PK drug interactions Out of 18 patients evaluable for a treatment response two had partial responses PR breast cancer and hepatocellular carcinoma and six had stable disease SD Two patients remained on treatment for more than 1 year The combination of PLD and T is tolerable and the treatment resulted in clinical benefit The combination regimen should be further explored in appropriate tumor typesThe mammalian target of rapamycin mTOR acts downstream of the phosphatidylinositol 3 kinase PI3K/Akt pathway and plays a key role in the signaling of malignant cell proliferation differentiation migration and survival 1 Given that an overactive PI3K pathway is frequently implicated in the development and progression of a variety of malignancies therapeutic targeting of crucial mediators along the PI3K signaling axis such as mTOR is an attractive strategy for cancer therapyTemsirolimus T CCI779 Torisel® Pfizer Inc is a soluble ester analog of sirolimus and exerts its antitumor effect by selectively inhibiting mTOR Temsirolimus received approval from the Food and Drug Administration FDA for treating patients with advanced renal cell carcinoma based on a pivotal Phase 3 study demonstrating that patients receiving T had superior median overall survival when compared to those receiving interferon alpha alone or a combination of the two therapies 109 73 and 84 months respectively p = 0008 2 In addition fewer patients in the T group experienced serious adverse events than the other two groups 2 A second mTOR inhibitor everolimus RAD001 Afinitor® Norvartis Pharmaceuticals Co has also been approved for advanced renal cell carcinoma after sunitinib or sorafenib treatment failure and for progressive neuroendocrine tumors of pancreatic origin Therefore mTOR inhibition is a proven antitumor strategy and is being evaluated in clinical trials for other cancer indicationsDoxorubicin is a cytotoxic anthracycline antibiotic isolated from Streptomyces peucetius var caesius and exerts its antitumor effect via inhibition of topoisomerase II 3 In comparison with conventional or liposomal doxorubicin formulations the pegylated liposomal doxorubicin PLD has extended blood circulation time improved tumor localization and better tolerance than conventional formulations 4 Since its FDA approval PLD is prescribed for refractory metastatic ovarian cancer and AIDSrelated Kaposi Sarcoma 5 6Several reports have indicated that mTOR inhibition may enhance the antitumor effects of cytotoxic agents in an additive or synergistic manner when tested in vitro and in vivo models of multiple types of human cancers 7 8 In particular one preclinical study suggested that mTOR inhibition can reverse doxorubicin resistance conferred by PTEN mutation/Akt activation 9Based on the evidence suggesting potential synergy between mTOR inhibition and doxorubicin we conducted a phase I clinical study evaluating the combination of PLD and T in patients with refractory solid malignancies Here we report the results on the safety tolerability pharmacokinetics PK and efficacy of this combination regimen

Keywords: