Clinical StudyPhase 2 trial of temozolomide and pegylated liposomal doxorubicin in the treatment of patients with glioblastoma multiforme following concurrent radiotherapy and chemotherapy
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.
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Patient eligibility
Eligible patients were >18 years old with histologically proven GBM. All patients had completed concurrent irradiation and T chemotherapy, and were planning to continue with adjuvant T treatment as per current approved indications. Patients were required to have a post-radiation MRI scan.
The eligibility criteria included: Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0–2; serum creatinine ⩽ 1.5 times the upper limit of normal; total granulocyte count ⩾ 1500/μL; platelet count ⩾
Patient characteristics
Patient characteristics are shown in Table 1. Forty patients were enrolled from four Australian sites between April 2007 and August 2008. Six patients did not have residual disease on post-radiation MRI (no measurable lesions) and were therefore not included in the response efficacy endpoint (Table 2), but were included in time to disease progression.
All patients had completed concurrent irradiation with 60 Gy in 30 fractions and T chemotherapy, and planned to continue with adjuvant T as part of
Discussion
The value of conventional chemotherapy for malignant gliomas has been modest and GBM has been considered refractory to most cytotoxic agents.[15], [16] Occasional responses have been documented but these have generally been short-lived with the rapid emergence of resistance. The blood–brain barrier (BBB) has been a major obstacle to the effective delivery of chemotherapy, especially to the infiltrating component of the tumour that is intercalated with normal brain parenchyma.[17], [18] Usually
Acknowledgments
This investigator-initiated trial was supported by an unrestricted grant from Schering–Plough (S–P) and by Cancer Australia (CA). The study was conducted and analysed independently of S–P and CA.
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