Phase II Study of Temozolomide Plus Thalidomide for the Treatment of Metastatic Melanoma

Hwu, Wen Jen; Krown, Susan E.; Menell, Jennifer H.; Panageas, Katherine S.; Merrell, Janene; Lamb, Lynne; Williams, Linda; Quinn, Carolyn; Foster, Theresa; Chapman, Paul B.; Livingston, Philip O.; Wolchok, Jedd D.; Houghton, Alan N.

doi:10.1200/jco.2003.02.061

Cited by 137 publications

(76 citation statements)

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“…Temozolomide has been combined with thalidomide (Hwu et al, 2003) or with interferon-a, using schedules similar to that used here, or with daily or three-times daily administration for 6 weeks out of eight. Most promising results have been obtained in combination with thalidomide (Danson et al, 2003), but that combination requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2005

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2005

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“…However, the response rate of melanoma to dacarbazine or TMZ is only ∼20%. Attempts to improve efficacy of TMZ through combination therapy with drugs such as cisplatin, docetaxel, thalidomide, IFN, and irinotecan have shown no clear benefits in response rates, median time to progression, or overall survival (7)(8)(9)(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Antifolate Activity of Pyrimethamine Enhances Temozolomide-Induced Cytotoxicity in Melanoma Cells

Chen

Osman

Orlow

2009

Molecular Cancer Research

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Most metastatic melanoma patients fail to respond to available therapy, underscoring the need to develop more effective treatments. We screened 2,000 compounds from the Spectrum Library in human melanoma cell lines to identify compounds that enhanced the cytotoxic effect of temozolomide, a drug used to treat metastatic melanoma. Screening was done with the temozolomide-resistant melanoma cell line SK-MEL-19, and six compounds were identified that had little or no inherent cytotoxicity but significantly enhanced growth-inhibition by temozolomide. These compounds were tested in five additional melanoma cell lines. Cell proliferation and death assays were used to compare the efficacy of single agent temozolomide versus combination treatments. Effects of combination treatment on levels of DNA double-strand breaks, the DNA repair protein O 6 -methylguanine-DNA-methyltransferase, apoptosis[measured by cleaved caspase-3 and poly(ADP-ribose) polymerase], and cell cycle were examined. Pyrimethamine, an antiparasitic, sensitized melanoma cells to temozolomide. Temozolomide combined with Pyrimethamine synergistically inhibited cell proliferation in melanoma cells with combination index values of 0.7 or less. In addition, combination treatment induced cell cycle arrest and increased both DNA damage and apoptosis. The increase in cell death due to combination treatment was rescued by leucovorin. Other folate antagonists were also effective enhancers of temozolomide-induced cytotoxicity, and the effects of antifolates were also evident in gliomas. Our screening approach led to the identification of Pyrimethamine, an orally available drug that efficiently crosses the blood-brain barrier, as a potent enhancer of the efficacy of temozolomide as an antineoplastic agent via inhibition of folate metabolism. (Mol Cancer Res 2009;7(5):703-12)

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“…In a basic fibroblast growth factor (bFGF)-induced angiogenesis assay performed in rabbit cornea, it was shown that thalidomide significantly decreased the formation of new vessels 7 and inhibited vascular endothelial growth factor (VEGF)-induced angiogenesis. 8 Several clinical studies indicate that thalidomide may possess antineoplastic properties in myeloma, 9 melanoma, 10 hormonerefractory prostate carcinoma, 11 high-grade glioma, and Kaposi sarcoma. 12 Several considerations support the potential use of thalidomide in patients with HCC.…”

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confidence: 99%

Phase II study of thalidomide in patients with unresectable hepatocellular carcinoma

Lin

Brophy

Fisher

et al. 2004

Cancer

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BACKGROUNDThe hypervascular nature of hepatocellular carcinoma (HCC) is well characterized. Recent data have suggested that thalidomide possesses antiangiogenic and immunomodulatory activity. Therefore, the authors initiated a study to assess the efficacy and toxicity of thalidomide in patients with advanced HCC as primary and secondary endpoints, respectively.METHODSInclusion criteria were unresectable HCC with bidimentionally measurable disease, age ≥ 18 years, Eastern Cooperative Oncology Group performance status ≤ 2, and adequate organ function. Thalidomide was administered at a starting dose of 200 mg per day in a 100‐mg‐per‐week dose escalation regimen, up to the maximum tolerated dose or to 800 mg per day. Toxicity was monitored according to the National Cancer Institute Common Toxicity Criteria.RESULTSTwenty‐six of 27 patients were eligible and assessable for toxicity and response. A median daily dose of 300 mg was achieved. One patient experienced near‐complete recovery of α‐fetoprotein levels and a partial radiographic response on computed tomography. Two patients had stable disease during the 16‐week study period. The median duration of progression‐free survival was 42 days. The overall median survival was 123 days. Fatigue and somnolence were the most common side effects, occurring in 81% and 62% of patients, respectively. No Grade 4 hematologic toxicity was observed. Three patients experienced Grade 4 hepatic toxicity (namely, hyperbilirubinemia).CONCLUSIONSWith gradual dose escalation, thalidomide was tolerated in most patients with advanced HCC. However, treatment with thalidomide alone was associated with only a modest response in the treatment of HCC. Cancer 2005. © 2004 American Cancer Society.

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Phase II Study of Temozolomide Plus Thalidomide for the Treatment of Metastatic Melanoma

Abstract: The combination of temozolomide plus thalidomide seems to be a promising and well-tolerated oral regimen for metastatic melanoma that merits further study.

Cited by 137 publications

References 19 publications

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

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

Antifolate Activity of Pyrimethamine Enhances Temozolomide-Induced Cytotoxicity in Melanoma Cells

Phase II study of thalidomide in patients with unresectable hepatocellular carcinoma

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