A phase II study of extended dose temozolomide and thalidomide in previously treated patients with metastatic melanoma

Laber, Damian A.; Okeke, Roseline I.; Arce-Lara, Carlos; Taft, B.; Schonard, Cassandra; McMasters, Kelly M.; Kloecker, Goetz; Miller, Donald M.

doi:10.1007/s00432-006-0114-8

Cited by 19 publications

(13 citation statements)

References 23 publications

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“…In the majority of our patients, we were unable to increase the dose of thalidomide as planned because of the dose-limiting side effects attributed to the drug: peripheral neuropathy, constipation, peripheral edema, rash and severe fatigue. This is in contrast to previously published trials using thalidomide in metastatic melanoma patients, where most patients were able to tolerate a daily dose of at least 400 mg [19][20][21][22][23][24] . An unexpected interaction between DTIC and thalidomide would be one explanation for this finding.…”

Section: Discussioncontrasting

confidence: 53%

“…Temozolomide combined with thalidomide at the same doses as described above was also investigated in a phase II, single-institution trial enrolling metastatic melanoma patients (including 23% with brain metastases) who were heavily pretreated. The overall clinical benefit (CR + PR + SD) in that study was 31%, the response rate 12% [24] .…”

Section: Discussionmentioning

confidence: 95%

“…In the last few years, a number of studies have been reported where thalidomide was investigated in combination with temozolomide in stage IV melanoma patients [19][20][21][22][23][24] . Of note, dacarbazine remains the reference standard agent and the only Food and Drug Administration-approved chemotherapy agent for the treatment of stage IV melanoma [4] .…”

Section: Discussionmentioning

confidence: 99%

“…The apparent single-agent activity of temozolomide led to the investigation of thalidomide combined with temozolomide in metastatic melanoma patients, with response rates between 0 and 32% [19][20][21][22][23][24] . Thalidomide has not been studied in combination with dacarbazine, which remains the reference chemotherapy in patients with malignant melanoma.…”

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confidence: 99%

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Phase II Trial of Dacarbazine and Thalidomide for the Treatment of Metastatic Melanoma

et al. 2009

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Objective: This phase II study evaluated the efficacy and tolerability of dacarbazine in combination with thalidomide in metastatic melanoma patients. Methods: Chemotherapy-naïve patients with histologically confirmed, measurable metastatic melanoma with no evidence of brain metastases and adequate hematologic and organ function received dacarbazine (1,000 mg/m² i.v. every 3 weeks) and thalidomide (starting dose of 200 mg/day orally at night, escalated every 3 weeks) as tolerated. The primary endpoint was objective tumor response, evaluated after every 3 cycles of treatment. Fifteen patients, age range 29–77 years, were accrued for this study. All had stage IV disease (1 M1a, 5 M1b, 9 M1c). Nine patients had had no prior adjuvant therapy, 6 had received prior immunotherapy. The median number of cycles was 5 (range 1–18), with 8 patients receiving ≥3 cycles. The median thalidomide dose administered was 200 mg/day with a maximum tolerated dose of 400 mg/day. Results: Of the 13 patients evaluable for response, 1 patient had a partial response, 3 patients had stable disease and 9 patients had progressive disease. No complete responses were seen. Two patients were not evaluable for response: 1 withdrew due to toxicity and 1 died of unrelated causes. Grade III neutropenia, thrombocytopenia and nausea were attributed to dacarbazine. Grade III/IV constipation, peripheral neuropathy, fatigue, edema and rash were attributed to thalidomide. Conclusion: The addition of thalidomide to dacarbazine in metastatic melanoma yielded activity insufficient to proceed with additional trials of this combination. Thalidomide dose escalation beyond 200 mg/day was limited by unacceptable toxicity. Therefore, this combination does not warrant further investigation.

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Section: Discussioncontrasting

confidence: 53%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Phase II Trial of Dacarbazine and Thalidomide for the Treatment of Metastatic Melanoma

et al. 2009

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“…While biochemotherapy regimens yield significantly higher response rates, this has not translated into a survival advantage, and high-dose IL-2 and biochemotherapy are associated with significant treatmentrelated toxicity (7)(8)(9). Antiangiogenic agents such as sorafenib and bevacizumab, administered as single agents or in combination, have also been used to treat advanced melanoma with varying degrees of success (10)(11)(12)(13)(14). Recently, vemurafenib has been reported to improve OS and PFS compared with dacarbazine in patients with previously untreated melanoma with a mutation in the BRAF gene (15).…”

Section: Introductionmentioning

confidence: 99%

Multicenter, Phase II Study of Axitinib, a Selective Second-Generation Inhibitor of Vascular Endothelial Growth Factor Receptors 1, 2, and 3, in Patients with Metastatic Melanoma

Fruehauf

Lutzky

McDermott

et al. 2011

Clinical Cancer Research

102

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Purpose: This multicenter, open-label, phase II study evaluated the safety and clinical activity of axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, 2, and 3, in patients with metastatic melanoma.Experimental Design: Thirty-two patients with a maximum of one prior systemic therapy received axitinib at a starting dose of 5 mg twice daily. The primary endpoint was objective response rate.Results: Objective response rate was 18.8% [95% confidence interval (CI), 7.2-36.4], comprising one complete and five partial responses with a median response duration of 5.9 months (95% CI, 5.0-17.0). Stable disease at 16 weeks was noted in six patients (18.8%), with an overall clinical benefit rate of 37.5%. Six-month progression-free survival rate was 33.9%, 1-year overall survival rate was 28.1%, and median overall survival was 6.6 months (95% CI, 5.2-9.0). The most frequently (>15%) reported nonhematologic, treatment-related adverse events were fatigue, hypertension, hoarseness, and diarrhea. Treatment-related fatal bowel perforation, a known class effect, occurred in one patient. Axitinib selectively decreased plasma concentrations of soluble VEGFR (sVEGFR)-2 and sVEGFR-3 compared with soluble stem cell factor receptor (sKIT). No significant association was noted between plasma levels of axitinib and response. However, post hoc analyses indicated potential relationships between efficacy endpoints and diastolic blood pressure of 90 mm Hg or higher as well as baseline serum lactate dehydrogenase levels.Conclusions: Axitinib was well tolerated, showed a selective VEGFR-inhibitory profile, and showed single-agent activity in metastatic melanoma. Further evaluations of axitinib, alone and combined with chemotherapy, are ongoing. Clin Cancer Res; 17(23); 7462-9. Ó2011 AACR.

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Results of a multicenter, randomized, double‐blind phase 2/3 study of lenalidomide in the treatment of pretreated relapsed or refractory metastatic malignant melanoma

Eisen

Trefzer

Hamilton

et al. 2009

Cancer

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BACKGROUND:The results of an international, multicenter, randomized, double-blind, controlled study assessing the efficacy and safety of lenalidomide treatment in patients with refractory stage IV metastatic malignant melanoma are reported. METHODS: The study compared treatment with lenalidomide (25 mg/d on Days 1-21 of a 28-day cycle) to placebo in 306 patients with metastatic malignant melanoma. Treatment was continued until progression of disease or unacceptable toxicity. RESULTS: There were no significant differences between lenalidomide and placebo in overall survival (median 5.9 months vs 7.4 months, respectively; P ¼ .32), time to progression (median 3.0 months vs 2.1 months; P ¼ .19), or Response Evaluation Criteria in Solid Tumors tumor response (5.3% vs 5.8%; P ¼ .82). None of the patients given placebo discontinued treatment because of treatment-related adverse events, compared with 4.6% of those treated with lenalidomide. Treatment-related myelosuppression was observed in 2.0% of patients treated with placebo and 7.3% of patients treated with lenalidomide. CONCLUSIONS: This study showed that treatment with lenalidomide (25 mg/d) has a manageable safety profile in patients with previously treated metastatic malignant melanoma but no benefit in tumor response, time to progression, or overall survival in these patients. Future trials for treatment of metastatic malignant melanoma with lenalidomide should focus on its use in combination therapies.

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A phase II study of extended dose temozolomide and thalidomide in previously treated patients with metastatic melanoma

Abstract: The combination of temozolomide and thalidomide is well tolerated in patients with very advanced heavily pretreated metastatic melanoma. It has modest activity in this population with grave prognosis.

Cited by 19 publications

References 23 publications

Phase II Trial of Dacarbazine and Thalidomide for the Treatment of Metastatic Melanoma

Phase II Trial of Dacarbazine and Thalidomide for the Treatment of Metastatic Melanoma

Multicenter, Phase II Study of Axitinib, a Selective Second-Generation Inhibitor of Vascular Endothelial Growth Factor Receptors 1, 2, and 3, in Patients with Metastatic Melanoma

Results of a multicenter, randomized, double‐blind phase 2/3 study of lenalidomide in the treatment of pretreated relapsed or refractory metastatic malignant melanoma

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