A Phase I/II Trial of Temozolomide and Escalating Doses of Oral VP-16 for Children and Young Adults with Recurrent Brain Tumours
The prognosis for children with recurrent central nervous system malignancies such as medulloblastoma, ependymoma, or glioblastoma multiforme is dismal. Although survival may be prolonged using innovative techniques such as image-guided surgery, stereotactic radiosurgery, or high-dose chemotherapy with autologous stem cell rescue, the majority of children still succumb to their recurrent disease. Efforts to cure children of these recurrences have been hampered by resistance of the tumour to radiation therapy, local dissemination of the tumour beyond radiation therapy fields, resistance to chemotherapy, and inability of chemotherapy to penetrate the blood-brain barrier.
Although clinicians have investigated numerous chemotherapeutic agents for the treatment of recurrent brain tumours in children, the outcome for these children remains poor. Newer agents are needed, and combination therapy using new and old agents must be explored.
Temozolomide is a recently-developed cytotoxic agent that is currently being tested against a broad spectrum of malignancies. In animal models Temozolomide has been shown to penetrate into the central nervous system (CNS). This appears to be the case in humans as well. Many patients with newly diagnosed or recurrent malignant gliomas have responded to the drug.
There are few studies of temozolomide in children. Although there were few responses in children with high-grade or low-grade glioma, a number of patients had prolonged stable disease. Because overall responses to temozolomide have been modest and short-lived, temozolomide may prove to be more effective in combination with other agents.
Etoposide (VP-16) is a type II topoisomerase inhibitor which, like temozolomide, penetrates the central nervous system and has activity against brain tumours. While VP-16 has proven effective when administered intravenously, it has been shown in several studies that its efficacy is schedule-dependent and that it may be more effective when given as several small doses rather than as a single larger one.
Orally-administered VP-16 has been remarkably effective against a broad spectrum of pediatric brain tumours when administered as a 3 week course at a dose of 50 mg/m2/day. VP-16, like Temodar, may be more effective when used in combination with other agents. There may be a synergistic effect when temozolomide and VP-16 are used in combination.
This clinical trial proposes a combination therapy with temozolomide and oral VP-16 for children with recurrent or progressive brain tumours. This combination holds great appeal because:
- Both agents have established efficacy against a broad spectrum of brain tumors;
- There may be synergy when the 2 are used together;
- Their mechanisms of cytotoxicity are completely different;
- There is only mild toxicity when each is used alone;
- Both agents can be administered orally, thus increasing their appeal to patients and treating physicians.
Because the 2 agents have not been given together in children, the trial will be conducted as a phase I study with a fixed dose of temozolomide (180 mg/m2/day for 5 days) and a dose escalation of oral VP-16 (from 50 mg/m2/day for 8 days to 50 mg/m2/day for 20 days). Toxicity may be more pronounced in children who received craniospinal irradiation; thus children in this study will be stratified into two groups – those who received CSI and those who did not. Once the maximum tolerated dose of oral VP-16 is established in each of these groups, subsequently enrolled patients will be treated at that dose.
- To determine whether the investigational drug temozolomide can be given safely in combination with a standard drug VP-16. (to determine the maximum tolerated dose and dose limiting toxicity of oral VP-16 in combination with a fixed dose of temozolomide in children and young adults with recurrent brain tumours)
- To determine whether these two drugs in combination will be of benefit in controlling the growth of brain tumors. (to determine the response of children and young adults with recurrent brain tumors to temozolomide and oral VP-16)
- To evaluate the good and bad effects of different doses of VP-16.