Phase 2 trial of temozolomide and pegylated liposomal doxorubicin in the treatment of patients with glioblastoma multiforme following concurrent radiotherapy and chemotherapy

Abstract

Concurrent and post-radiotherapy temozolomide (T) significantly improves survival in patient with newly diagnosed glioblastoma multiforme. We aimed to assess the activity of the combination of T and pegylated liposomal doxorubicin (PLD) in this population. A combination of T (days 1–5, 200 mg/m² orally) and PLD (day 1, 40 mg/m² intravenous) was given every 4 weeks for six cycles following chemo-radiotherapy as a post-operative treatment. The primary endpoint was 6-month progression free survival (6PFS). Of the 40 patients who enrolled (53 years median age, 73% male), the 6PFS was 58% (95% confidence interval [CI], 41–72%). The median time to progression was 6.2 months (95% CI, 5.6–8.0 months) and overall survival (OS) was 13.4 months (95% CI, 12.7–15.8 months). Thirty-four patients had measurable disease: one had a complete response (3%), 28 had stable disease (82%), and five had progressive disease (15%). Treatment was well tolerated: hematological toxicity included grade 3 neutropenia (8%). Grade 3 non-hematologic toxicity included nausea and vomiting (8%) and palmar–plantar toxicity (5%). We concluded that combination T and PLD is well tolerated but does not add significant clinical benefit regarding 6PFS and OS.

Introduction

The annual incidence of malignant gliomas is approximately five cases per 100,000 people, with more than 14,000 new cases diagnosed annually and 13,000 deaths in the United States.[1], [2], [3] The current standard of care for suitable patients with newly diagnosed glioblastoma multiforme (GBM) is maximum surgical resection followed by concurrent temozolomide (T) and irradiation, followed by 6 months of T. The 2-year and 5-year survival rates from initial diagnosis with this regimen are 26.5% and 9.8%, respectively; more effective treatments are needed.[4], [5]

Pegylated liposomal doxorubicin (PLD) is a formulation of doxorubicin in which the drug is encapsulated in liposomes (stealth liposomes) that can avoid uptake by the reticuloendothelial system.⁶ Liposomal encapsulation may ameliorate the toxicity of doxorubicin by reducing both the non-specific drug delivery to normal tissues and the high peak plasma levels of free drug. Once concentrated in tumours, the liposomes of PLD may deliver high levels of doxorubicin locally, reducing toxicity without compromising efficacy, and improving the therapeutic index.⁷ Liposomal doxorubicin has been tested in preclinical glioma models and appears to have significantly improved penetration compared with doxorubicin itself.[8], [9], [10] However, there are only limited data regarding its use in the treatment of recurrent high grade glioma. One Phase 1/2 study demonstrated that it is well tolerated and several patients achieved stabilisation of their disease.⁹

The combination of PLD and T is appealing given the documented efficacy of T coupled with the preclinical and clinical data supporting PLD in the treatment of GBM. A Phase 1 study of PLD and T in patients with advanced cancer demonstrated that the regimen was well tolerated and recommended a Phase 2 dose of PLD 40 mg/m² on day 1 and T 200 mg/m² on days 1–5, every 4 weeks.¹¹

We have previously published a Phase 2 pilot study of T and PLD in recurrent GBM. Our data demonstrated good tolerability, modest myelosuppression, and an objective response rate of 19% in 22 patients.¹² More striking were the high disease stabilisation rates of 50% and 6-month progression free interval (6PFS) in 32% of patients. In view of the apparent efficacy of the combination in the recurrent setting, we chose to evaluate the combination of PLD and T in the adjuvant setting.