Phase I study of temozolomide plus paclitaxel in patients with advanced malignant melanoma and associated in vitro investigations

Abstract

The purpose of this study was to determine activity of temozolomide combined with paclitaxel or epothilone B in vitro, and to investigate the combination of temozolomide with paclitaxel in a Phase I clinical trial. Melanoma cell lines A375P and DX3 were treated with temozolomide and either paclitaxel or epothilone B. Combination indices were determined to assess the degree of synergism. In a clinical study, 21 patients with malignant melanoma were treated with increasing doses of temozolomide (orally, days 1 -5), in combination with a fixed dose of paclitaxel (i.v. infusion day 1), followed by dose escalation of the latter drug. Cycles of treatment were repeated every 3 weeks. Pharmacokinetics of both agents were determined on day 1, with temozolomide pharmacokinetics also assessed on day 5. All three compounds were active against the melanoma cell lines, with epothilone B being the most potent. There was a strong degree of synergism between temozolomide and either paclitaxel or epothilone B. In the clinical study, no pharmacokinetic interaction was observed between temozolomide and paclitaxel. Dose escalation of both drugs to clinically active doses was possible, with no dose-limiting toxicities observed at 200 mg m À2 day À1 temozolomide and 225 mg m À2 day À1 paclitaxel. There were two partial responses out of 15 evaluable patients. One patient remains alive and symptom-free at 4 years after treatment. Temozolomide and paclitaxel may be administered safely at clinically effective doses. Further evaluation of these combinations in melanoma is warranted.

Evaluating the cytotoxic effects of the water extracts of four anticancer herbs against human malignant melanoma cells

“…Temozolomide, an oral analog of DTIC, has been extensively evaluated in treating advanced MM 48–52. However, its new drug application (NDA 21-051) for melanoma was denied by FDA due to a lack of evidence showing therapeutic advantage over DTIC.…”

Combination of paclitaxel thermal gel depot with temozolomide and radiotherapy significantly prolongs survival in an experimental rodent glioma model

“…To overcome this limitation, we explored the potential anti-tumor effect of the combination chemotherapy of TMZ and paclitaxel. These two chemotherapeutic drugs have: (1) Different mechanisms of action; (2) different resistance mechanisms; (3) non-overlapping toxicity profiles; (4) established efficacy in glioma; and (5) known synergistic effect in melanoma [26–28]. …”

“…In this regard, it has been shown that the administration of paclitaxel has no effect on the in vitro sensitivity of different glioma cell lines to alkylating agents including TMZ [33]. Recent clinical studies have demonstrated that the combination of TMZ with Taxanes (paclitaxel or docetaxel) has a synergistic effect in metastatic melanoma [26–28]. Consistent with our expectations, all combinations of OncoGel with TMZ significantly prolonged survival in the rodent tumor model and no signs of systemic or neurological toxicity were observed.…”

F2A sequence linking MGMTP140K and MDR1 in a bicistronic lentiviral vector enables efficient chemoprotection of haematopoietic stem cells

“…48 TMZ and paclitaxel for malignant melanoma. 49 The IC 50 values for mono-and combination therapies of HL-60 cells with ACNU and paclitaxel are shown in Table 2. Transgene expression of the bicistronic vectors HR'SIN-MDR1-F2A-MGMT P140K (no.…”