Phase II multicentre study of temozolomide in combination with interferon alpha-2b in metastatic malignant melanoma

García, Margarita; Muro, Xavier García del; Trés, A.; Crespo, Carmen; Valladares, Manuel; López, Juan José; Rifà, Julio; Pérez, Xavier; Filipovich, Elena; Germá-Lluch, J. R.

doi:10.1097/01.cmr.0000215042.53683.40

Cited by 13 publications

(4 citation statements)

References 25 publications

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“…By analogy with previous trials displaying an increase in response rate in stage IV melanoma with a combination of DTIC and interferon a compared with DTIC alone (although with no significant difference in overall survival) [2,3], the association of TMZ with interferon a-2b either pegylated or not has been evaluated previously in seven clinical trials, the data of which are summarized in Table 5 [14][15][16][17][18][19][20]. Overall, they show overall response rates comprised between 12.5 and 27.5%, comparable with the results usually obtained with DTIC alone, with the notable exception of the association of TMZ with pegylated interferon reported by Hwu et al [20] that achieved a response rate of 32.5% and a median survival time of 12 months, far above the mean figures of the other trials, but on a limited number of patients in an open study.…”

Section: Discussionmentioning

confidence: 97%

Temozolomide associated with PEG-interferon in patients with metastatic melanoma: a multicenter prospective phase I/II study

et al. 2008

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Metastatic melanoma treatment remains disappointing, and a combined approach by chemotherapy and immunotherapy might increase the response rates through a synergistic action. Accordingly, a clinical trial using oral temozolomide (TMZ) and subcutaneous PEG-interferon alpha-2b (PEG) in patients with metastatic melanoma was designed to determine the maximal tolerated dosage of both drugs and the antitumoral response. A multicenter, prospective, phase I/II study was conducted in 31 metastatic melanoma patients, without cerebral metastasis. Dose escalation was performed according to the modified continual reassessment method scale and resulted in four cohorts of patients: TMZ 150 mg/m2 5 days/week each 4 weeks and PEG 0.5 microg/kg/week - TMZ 150 mg/m2 5 days/week and PEG 1.0 microg/kg/week - TMZ 200 mg/m2 5 days/week and PEG 0.5 microg/kg/week - TMZ 200 mg/m2 5 days/week and PEG 1.0 microg/kg/week. Patients received a maximum of six cycles. Thirty-three patients were enrolled in this study: one in the first dose level, one in the second one, 18 in the third one and 11 in the fourth one. At level 4, four of 11 patients experienced dose-limiting toxicity and four nondose-limiting toxicity; toxicity was mainly hematologic (grade IV thrombocytopenia). An objective response was observed in five patients (two complete response and three partial response) receiving level 3 or 4 of treatment. The disease remained stable in three patients, and six of 31 patients were alive 24 months after enrollment. The association of oral TMZ with subcutaneous PEG in metastatic melanoma displayed an unacceptable hematological toxicity with the dosages of 200 mg/m2 5 days/week and 1 microg/week, respectively. At a lower level, this treatment was effective and deserves further investigations to define its indications in metastatic melanoma patients.

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Section: Discussionmentioning

confidence: 97%

Temozolomide associated with PEG-interferon in patients with metastatic melanoma: a multicenter prospective phase I/II study

et al. 2008

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“…Presently, these combinations are being modified in the hope of maximizing clinical effi cacy and minimizing toxicity. A recent Phase II trial combined TMZ at 150 mg/m 2 /day for 5 days with IFNa2b at 10 MU/m 2 3 days a week [121] (Table 6). Overall, 18.5% of patients responded, and those who did respond had met astatic disease limited to lymph nodes or lungs.…”

Section: Multimodal Combination Therapeutics Biochemotherapymentioning

confidence: 99%

Novel Therapeutics for The Treatment of Metastatic Melanoma

Mansfield

Markovic

2009

Future Oncol.

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Metastatic malignant melanoma is an incurable disease with a median survival of 8.5 months and a probability of surviving 5 years after the diagnosis of less than 5%. To date, no systemic therapy has meaningfully changed these survival end points. Currently, in the USA the FDA has approved three agents for the treatment of metastatic melanoma: hydroxyurea, dacarbazine and interleukin-2. None of these have demonstrated a meaningfully prolonged survival of patients with metastatic melanoma. Therefore, a number of innovative therapeutic strategies have been pursued to improve outcomes, including immune therapy, tyrosine kinase inhibitors and angiogenesis inhibitors. Herein, we review some of the recent advances in novel therapeutic developments for the treatment of metastatic melanoma.

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“…TMZ in combination with IFN-α2 has been investigated in metastatic melanomas (21)(22)(23)(24)(25). Treatment with a combination of TMZ and IFN-α can increase the median survival of patients with metastatic melanomas (26); however, a combination treatment with TMZ and IFN-β has rarely been investigated in malignant melanomas (15).…”

Section: Interferon-β Sensitizes Human Malignant Melanoma Cells To Tementioning

confidence: 99%

Interferon-β sensitizes human malignant melanoma cells to temozolomide-induced apoptosis and autophagy

et al. 2019

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Malignant melanoma is a highly aggressive skin cancer that is highly resistant to chemotherapy. Adjuvant therapy is administered to patients with melanoma that possess no microscopic metastases or have a high risk of developing microscopic metastases. Methylating agents, including dacarbazine (DTIC) and temozolomide (TMZ), pegylated interferon (IFN)-α2b and interleukin-2 have been approved for adjuvant immuno-chemotherapy; however, unsatisfactory results have been reported following the administration of methylating agents. IFN-β has been considered to be a signaling molecule with an important therapeutic potential in cancer. The aim of the present study was to elucidate whether antitumor effects could be augmented by the combination of TMZ and IFN-β in malignant melanoma. We evaluated the efficacy of TMZ and IFN-β by comparing O 6-methylguanine-DNA transferase (MGMT)-proficient and-deficient cells, as MGMT has been reported to be associated with the resistance to methylating agents. Cell viability was determined by counting living cells with a Coulter counter, and apoptosis was analyzed by dual staining with Annexin V Alexa Fluor ® 488 and propidium iodide. The expression of proteins involved in the cell cycle, apoptosis and autophagy was evaluated by western blot analysis. The combined treatment with TMZ and IFN-β suppressed cell proliferation and induced cell cycle arrest. We also demonstrated that a combination of TMZ and IFN-β enhanced apoptosis and autophagy more efficiently compared with TMZ treatment alone. These findings suggest that antitumor activity may be potentiated by IFN-β in combination with TMZ.

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Phase II multicentre study of temozolomide in combination with interferon alpha-2b in metastatic malignant melanoma

Abstract: Temozolomide in combination with interferon is a well-tolerated palliative regimen that has moderate activity against metastatic melanoma. Further evaluation of this regimen in comparative studies or in combination with other drugs is warranted.

Cited by 13 publications

References 25 publications

Temozolomide associated with PEG-interferon in patients with metastatic melanoma: a multicenter prospective phase I/II study

Temozolomide associated with PEG-interferon in patients with metastatic melanoma: a multicenter prospective phase I/II study

Novel Therapeutics for The Treatment of Metastatic Melanoma

Interferon-β sensitizes human malignant melanoma cells to temozolomide-induced apoptosis and autophagy

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