Phase 1 study of temozolamide (TMZ) combined with procarbazine (PCB) in patients with gliomas

Abstract

Temozolomide (TMZ) is an oral alkylating agent with a good safety profile and proven efficacy in the treatment of malignant glioma. Procarbazine (PCB) has been used for treating gliomas for many years and here both agents were combined in the treatment. This phase I study was designed to evaluate the efficacy and safety of TMZ alone (course 1) and TMZ in combination with PCB in subsequent courses in chemotherapy-naïve patients with malignant glioma. Patients with anaplastic astrocytoma (AA), glioblastoma multiforme (GBM) and low-grade glioma were treated with TMZ 200 mg m À2 on days 1 -5 on a 28-day cycle for course 1. Beginning with course 2, cohorts of patients received TMZ at full dose with escalating doses of PCB (50/75/100/125 mg m À2 days 1 -5 given 1 h prior to TMZ). A total of 28 patients were enrolled with three patients each at dose level 1 and 2, 16 patients at dose level 3 and six patients at dose level 4 received 182 þ cycles of treatment and were included in this analysis. In all, 16 patients had GBM, seven patients had AA, five had grade 1 or 2 glioma and the median age was 47 years. The patients had received prior surgery and radiotherapy. Responses were seen at all dose levels. Overall, there were 10 (36%) responses lasting from 2 to 17 þ months. Treatment was generally well tolerated with few grade 3 or 4 toxicities, except at dose level 4, where four patients had grade 3/4 had thrombocytopaenia at this dose and several patients had moderate-to-severe lethargy. TMZ 200 mg m À2 and PCB 100 mg m À2 were well tolerated on a daily 5 Â and four weekly cycle in patients with malignant glioma and clearly had antitumour activity. Prognosis with patients with glioma, and in particular, high-grade (anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM)) tumours is poor. Studies have confirmed the beneficial effect of postoperative cranial irradiation, but in most series, survival beyond 2 years is 15% or less (Walker et al, 1978;Stewart, 1989;Fine et al, 1993). The most widely used combination in treating gliomas is procarbazine, CCNU (lomustine), vincristine (PCV). This has a limited effect on survival (Levin et al, 1980;Sandberg-Wollheim et al, 1991). The most active agents identified until recently were the nitrosoureas (BCNU, CCNU, methyl-CCNU and HECNU), and have been reported to induce responses in the range of 35 -55%. However, the majority of these responses were of short duration (Rodriguez and Levin, 1987;Georges et al, 1988;Stewart, 1989).Temozolomide came from a synthetic programme of a number of imidazotetrazine derivatives, which exhibited broad-spectrum antitumour activity against murine models (Stevens et al, 1984). TMZ was selected for further clinical development in view of its good experimental antitumour activity and low toxicity in the pre-clinical screen. In addition, its antitumour activity was also schedule-dependent (Stevens et al, 1987). In the early clinical development of TMZ, administration of a single dose induced myelosupression but did not have any antitumour activi...

Prognostic Significance of O6-Methylguanine-DNA Methyltransferase Protein Expression in Patients with Recurrent Glioblastoma Treated with Temozolomide

“…One of the most potent agents, O 6 -benzylguanine, has been investigated in combination with TMZ in a couple of phase I studies with evidence of activity against refractory malignant gliomas (45,46). Similarly, clinical trials to evaluate the activity of procarbazine or cisplatin combined with TMZ have been conducted in patients with recurrent GBM (47,48). Whether these approaches can overcome resistance to TMZ through downregulation of MGMT activity needs to be verified in comparison with the standard TMZ regimen in patients with GBM having high MGMT expression.…”

The Safety of the Temozolomide in Patients with Malignant Glioma

“…The toxic effects Grade 3 and 4 lymphocytopenia have been observed in most studies [19,35,37,44] with incidence between 4 and 57%. At present is not clear if this toxic effect is due to temozolomide administration or to the frequent corticosteroid co-medications used as anti cerebral oedema [35,44].…”

Contribution of DNA repair mechanisms to determining chemotherapy response in high-grade glioma

“…Combination therapy with multiple chemotherapeutic drugs known to deplete MGMT (specifically procarbazine and temozolomide) has been successfully assessed in a Phase I trial 27 but as yet has not been shown to confer a benefit in survival. O 6 benzylguanine (O 6 BG), a substrate for MGMT has also been used to decrease MGMT levels.…”