Effect of temozolomide on central nervous system relapse in patients with advanced melanoma.

Temozolomide has shown efficacy in the treatment of metastatic melanoma similar to that of dacarbazine (DTIC), the standard chemotherapy, but with the added benefit of penetration into the central nervous system (CNS). Isolated CNS relapse is increasingly a problem for patients who respond to biochemotherapy. By replacing DTIC with temozolomide in treatment regimens, the incidence of CNS relapse might be reduced. This hypothesis is difficult to test in a prospective randomized controlled trial because of the large number of patients that would be required. We have examined this question in a retrospective case control study, observing the rates of CNS relapse in advanced metastatic melanoma patients responding to DTIC- or temozolomide-based chemotherapy in three institutions. Twenty-one DTIC and 20 temozolomide responders were identified, and have been followed up for a median of 19.0 months (range 6.0-74.3 months). CNS relapse occurred in nine DTIC- and two temozolomide-treated patients, a statistically significant difference in favour of the new agent (P = 0.03). These results support the investigation of temozolomide as a replacement for DTIC in systemic treatment regimens for melanoma.

O6-methylguanine-DNA methyltransferase in pretreatment tumour biopsies as a predictor of response to temozolomide in melanoma.

Resistance of tumour cells to methylating and monochloroethylating agents in vitro and in vivo has been linked to levels of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). In a clinical trial of temozolomide in advanced malignant melanoma, the relationship between pretreatment MGMT levels in biopsies of cutaneous tumours and involved lymph nodes and clinical response to the drug has been studied. Among 50 evaluable patients, there were three complete responses (CR), four partial responses (PR), six with stable disease (SD) and 37 with progressive disease (PD), with an overall response rate of 14%. In 33 patients in whom MGMT level and clinical response could be evaluated, the tumour MGMT levels (fmol mg(-1) protein) were: CR, 158 +/- 119; PR, 607 +/- 481; NC, 171 +/- 101; PD, 185 +/- 42.3. Thus, measurements of pretreatment levels of MGMT in melanoma did not predict for response to temozolomide.

Phase I trial of temozolomide using an extended continuous oral schedule.

Temozolomide, a methylating imidazotetrazinone, has antitumor activity against gliomas, malignant melanoma, and mycosis fungoides and is presently administered as a 5-day oral schedule every 4 weeks. This Phase I study aimed to determine the maximum tolerated dose of temozolomide administered as a single oral daily dose for a continuous 6- or 7-week period, evaluate the plasma pharmacokinetics on this schedule, and compare total plasma exposure over 7 weeks with the conventional 5-day regimen. Twenty-four patients with varying tumor types (17 of 24 gliomas) received temozolomide. All had clinically evaluable, refractory disease; normal renal, hepatic, and bone marrow function; and WHO performance status < or = 2. Temozolomide was administered at 50 mg/m2/day, increasing by 25 mg/m2/day/cohort until at 100 mg/m2/day grade 4 myelotoxicity forced dose reductions to 85 mg/m2/day, then 75 mg/m2/day. At 75 mg/m2/day the regimen was extended to 7 weeks, allowing the future potential combination with irradiation for primary gliomas. Patient responses (standard Union International Contre Cancer criteria; for gliomas objective response) and toxicity were assessed. Temozolomide plasma pharmacokinetics were determined on day 1 and at the beginning of the final week of administration (n = 5). The most frequent toxicities were myelosuppression and grades 1 and 2 nausea and vomiting. Grade 4 leucopenia and thrombocytopenia occurred in one of four patients receiving 100 mg/m2/day temozolomide and in one of seven patients receiving 85 mg/m2/day. These hematological toxicities did not exceed grade 2 in 10 patients receiving 75 mg/m2/day temozolomide. One of 4 malignant melanoma patients and 7 of 17 glioma patients (41%) demonstrated tumor responses. The overall response rate for this prolonged schedule was 33% (objective response, 7 of 24 patients; partial response, 1 of 24 patients); also, 6 of 17 glioma patients maintained SD. Peak plasma temozolomide concentrations were obtained 30-90 min after oral administration. Elimination in plasma was best described by a monoexponential equation with an elimination half-life of 96 +/- 16 min. No plasma accumulation of temozolomide occurred. Toxicity was greatest in higher dose cohorts, with a resultant maximum tolerated dose of 85 mg/m2/day, whereas lower dose cohorts tolerated the schedule well. The area under the temozolomide plasma versus time curve was noncumulative between the first and last week of the schedule. Temozolomide administration of 75 mg/m2/day over a 7-week period permits a 2.1-fold greater drug exposure/4 weeks in comparison with the 5-day schedule of 200 mg/m2/day repeated every 28 days. The overall response rate was 33% (glioma patients, 41% and a further 25% SD). Temozolomide (75 mg/m2/day) for 7 weeks is the recommended starting dose for further assessment of this schedule.

Multicentre CRC phase II trial of temozolomide in recurrent or progressive high-grade glioma.

PURPOSE: Patients with progressive or recurrent supratentorial high-grade gliomas were entered into a multicentre phase II trial to evaluate the efficacy and toxicity of temozolomide. METHODS: The treatment schedule was 150-200 mg/m2 per day orally for 5 days repeated every 28 days. Response evaluation was by a combination of neurological status evaluation (MRC scale) and imaging. RESULTS: Of 103 eligible patients enrolled, 11 (11%) achieved an objective response and a further 48 (47%) had stable disease. The median response duration was 4.6 months. Response rates were similar for anaplastic astrocytomas (grade III) and glioblastoma multiforme (grade IV) tumours. Predictable myelosuppression was the major toxicity. CONCLUSIONS: The observation of objective responses and tolerable side effects in this heterogeneous population of patients supports the further investigation of this agent in high-grade gliomas.

The Charing Cross Hospital experience with temozolomide in patients with gliomas.

Temozolomide, a new oral cytotoxic agent, was given to 75 patients with malignant gliomas. The schedule used was for the first course 150 mg/m2 per day for 5 days (i.e. total dose 750 mg/m2), escalating, if no significant myelosuppression was noted on day 22, to 200 mg/m2 per day for 5 days (i.e. total dose 1000 mg/m2) for subsequent courses at 4-week intervals. There were 27 patients with primary disease treated with two courses of temozolomide prior to their radiotherapy and 8 (30%) fulfilled the criteria for an objective response. There were 48 patients whose disease recurred after their initial surgery and radiotherapy and 12 (25%) fulfilled the criteria for an objective response. This gave an overall objective response rate of 20 (27%) out of 75 patients. Temozolomide was generally well tolerated, with little subjective toxicity and predictable myelosuppression. However, the responses induced with this schedule were of short duration and had relatively little impact on overall survival. In conclusion, temozolomide given in this schedule has activity against high grade glioma. However, studies evaluating chemotherapy in primary brain tumours should include a quality-of-life/performance status evaluation in addition to CT or MRI scanning assessment.

Phase I trial of elactocin.

Elactocin is a novel anti-tumour antibiotic which has potent activity in vitro against a range of tumours. This phase I trial of elactocin identified the dose-limiting toxicity as profound anorexia and malaise. The schedules used included 1 h infusion 3 weekly, 24 h infusion 3 weekly, 1 h infusion daily x 5 (3 weekly), 1 h infusion weekly and finally continuous 5 day intravenous infusion. On all these schedules dose-limiting toxicity was the same and as no partial or complete responses were identified, we do not recommend that further trials of elactocin are performed.

Phase I study of etoposide with SDZ PSC 833 as a modulator of multidrug resistance in patients with cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD) and toxicity of PSC 833 infusion administered with etoposide for 5 days in patients with cancer, and to determine the effect of PSC 833 on etoposide pharmacokinetics. PATIENTS AND METHODS: Thirty-five patients were entered onto the study, one of whom was ineligible. Etoposide was delivered from day 1 as a 2-hour infusion over 5 consecutive days at a dose of 75 to 100 mg/m2/d. PSC 833 was administered from day 2 as a 2-hour loading dose and as a 5-day continuous infusion. Doses were escalated from 1 to 2 mg/kg (loading dose) and 1 to 15 mg/kg/d (continuous infusion). RESULTS: Thirty-four patients were treated with 53 cycles of PSC 833 and etoposide. Steady-state blood PSC 833 levels more than 1,000 ng/mL were achieved in all patients treated at PSC 833 doses > or = 6.6 mg/kg/d by continuous infusion. Myelosuppression was the most common toxicity. The major dose-related toxicity of PSC 833 was reversible hyperbilirubinemia, which occurred in 83% of cycles. The dose-limiting toxicity of PSC 833 was severe ataxia, which occurred in two of nine patients treated at 12 mg/kg/d and in both of the single patients treated at 13.5 and 15 mg/kg/d. PSC 833 concentrations more than 2,000 ng/mL resulted in an increase in etoposide area under the curve (AUC) of 89%, a decrease in etoposide clearance (Cl) of 45%, a decrease in volume of steady-state distribution (Vss) of 41%, and an insignificant increase in alpha half-life (t 1/2 alpha) and significant increase of beta half-life (t 1/2 beta) of 19% and 77%, respectively. CONCLUSION: PSC 833 can be administered in combination with etoposide with acceptable toxicity. The recommended continuous infusion dose of PSC 833 for this schedule is 10 mg/kg/d over 5 days. PSC 833 results in an increase in etoposide exposure and etoposide doses should be reduced in patients receiving PSC 833.

Phase II trials of rhizoxin in advanced ovarian, colorectal and renal cancer.

Rhizoxin is a tubulin-binding anti-neoplastic agent which is active in a range of murine tumour models. The recommended schedule, of intravenous (i.v.) bolus administration at a dose of 2 mg m-2 every 3 weeks, has been assessed in three phase II trials of ovarian, renal and colorectal cancer. In general terms the drug was fairly well tolerated, but the response rate was disappointing: 0/18, colorectal cancer; 0/18, renal cancer; 1 partial response (PR)/17, ovarian cancer.

Phase II trial of temozolomide in low-grade non-Hodgkin's lymphoma.

Temozolomide, an imidazotetrazine derivative, was given to 18 patients with low-grade non-Hodgkin's lymphoma (NHL) at a dose of 750 mg m-2 orally, divided over five consecutive days, escalated to 1000 mg m-2 over 5 days (i.e. 200 mg m-2 day-1) if no significant myelosuppression was noted at day 22 of the 28 day cycle. Fifty-six treatment cycles were given to 18 patients. The drug was well tolerated. Only one partial tumour response was documented. The patients were heavily pretreated but had chemoresponsive disease, as shown by a response rate of 69% among 13 patients who went on to receive alternative cytotoxic regimens. We conclude that temozolomide given in this schedule is inactive in previously treated low-grade NHL.

Phase I trial of temozolomide (CCRG 81045: M&B 39831: NSC 362856).

Temozolomide (CCRG 81045: M&B 39831: NSC 362856) is an analogue of mitozolomide displaying similar broad spectrum activity in mouse tumours, but showing considerably less myelosuppression in the toxicology screen. Temozolomide was initially studied intravenously at doses between 50-200 mg m-2 and subsequently was given orally up to 1,200 mg m-2. A total of 51 patients were entered on the single dose schedule. Temozolomide exhibits linear pharmacokinetics with increasing dose. Myelotoxicity was dose limiting. Experimentally, temozolomide activity was schedule dependent and therefore oral administration was studied as a daily x 5 schedule between total doses of 750 and 1,200 mg m-2 in 42 patients. Myelosuppression was again dose limiting. The recommended dose for Phase II trials is 150 mg m-2 po for 5 days (total dose 750 mg m-2) for the first course, and if no major myelosuppression is detected on day 22 of the 4 week cycle, the subsequent courses can be given at 200 mg m-2 for 5 days (total dose 1 g m-2) on a 4 week cycle. Mild to moderate nausea and vomiting was dose related but readily controlled with antiemetics. Clinical activity was detected using the 5 day schedule in four (2CR, 2PR; 17%) out of 23 patients with melanoma and in one patient with mycosis fungoides (CR lasting 7 months). Two patients with recurrent high grade gliomas have also had partial responses. Temozolomide is easy to use clinically and generally well tolerated. In the extended Phase I trial temozolomide only occasionally exhibited the unpredictable myelosuppression seen with mitozolomide.

Phase II trial of didox in advanced breast cancer. Cancer Research Campaign Phase I/II Clinical Trials Committee.

Fourteen patients with advanced breast cancer were treated with the ribonucleotide reductase inhibitor didox 6 g m-2 given by intravenous infusion over 36 h every 3 weeks. None responded and toxicity was minimal. Possibilities for the more effective use of this agent are discussed.