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© 2003 American Society for Clinical Oncology Phase II Study of Temozolomide Plus Thalidomide for the Treatment of Metastatic MelanomaFrom the Memorial Sloan-Kettering Cancer Center, New York, NY. Address reprint requests to Wen-Jen Hwu, MD, PhD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: hwuw{at}mskcc.org.
Purpose: To further investigate the efficacy and safety of temozolomide plus thalidomide in patients with metastatic melanoma without brain metastases.
Patients and Methods: Patients with histologically confirmed advanced-stage metastatic melanoma were enrolled in an open-label, phase II study. The primary end point was response rate. Patients received temozolomide (75 mg/m2/d x 6 weeks with a 2-week rest between cycles) plus concomitant thalidomide (200 mg/d with dose escalation to 400 mg/d for patients < 70 years old, or 100 mg/d with dose escalation to 250 mg/d for patients Results: Thirty-eight patients (median age, 62 years) with stage IV (three patients with M1a, eight with M1b, and 26 with M1c) or stage IIIc (one patient) melanoma and a median of four metastatic sites were enrolled, and received a median of two cycles of therapy. Twelve patients (32%) had an objective tumor response, including one with an ongoing complete response of 25+ months’ duration and 11 with partial responses. Five patients achieving partial response with a more than 90% reduction of disease were converted to a complete response with surgery. Treatment was generally well tolerated. Median survival was 9.5 months (95% confidence interval, 6.05 to 19.38 months), with a median follow-up among survivors of 24.3 months. Conclusion: The combination of temozolomide plus thalidomide seems to be a promising and well-tolerated oral regimen for metastatic melanoma that merits further study.
ADVANCED-STAGE METASTATIC melanoma is associated with a poor prognosis, with 10-year survival rates of only 2.5% to 15.7%.1 In 2002, an estimated 7,400 patients in the United States died of melanoma.2 Current treatment options have provided no improvement in overall survival. Standard therapies include dacarbazine- (DTIC-) based chemotherapy regimens (eg, Dartmouth regimen) and biochemotherapy. Standard chemotherapy regimens produce response rates of only 10% to 20% with very few complete or durable responses,3 and the Dartmouth regimen does not improve survival compared with DTIC alone.4 The addition of biologic therapy with agents such as interleukin-2 and interferon alfa increases response rates at the expense of increased toxicity, but it has not been shown to provide a significant survival advantage compared with standard chemotherapy regimens in randomized trials.5–7 Treatment failure in the CNS is a clinically important problem in patients with advanced melanoma. Temozolomide is a well-tolerated oral alkylating agent with excellent CNS penetration8,9 that has demonstrated activity in patients with recurrent gliomas, and has been shown to improve progression-free survival compared with DTIC alone in patients with metastatic melanoma.10 Temozolomide may also reduce the incidence of CNS relapse in patients with metastatic melanoma.11,12 Myelosuppression is the primary toxicity associated with temozolomide, but it is noncumulative, and manageable in the majority of patients and infrequently causes dose delays or discontinuation. Temozolomide is typically administered for 5 consecutive days every 28 days at a dose of 150 to 200 mg/m2/d, but can also be safely administered on an extended daily regimen at a dose of 75 mg/m2/d.13 Thalidomide is also orally bioavailable, has a range of biologic modulatory activities including antiangiogenic effects,14–16 and has demonstrated clinical activity against a range of solid tumors.17 Although single-agent low-dose thalidomide (100 mg/d) did not yield objective tumor responses in 17 patients with advanced melanoma,18 melanoma is a highly vascular tumor, suggesting a possible role for an antiangiogenic agent such as thalidomide. Therefore, we hypothesized that the combination of temozolomide plus thalidomide would be a well-tolerated regimen, with potential for improved antitumor activity compared with chemotherapy alone.
We have previously reported the results of a phase I, dose-finding study demonstrating that extended daily dosing of temozolomide at 75 mg/m2/d (for 6 weeks, followed by 2 weeks of rest) can be safely combined with thalidomide, at daily doses of 400 mg (250 mg for patients
Patients Eligible adult (18 years of age) patients had histologically confirmed, measurable, unresectable melanoma of stage III or IV per the new American Joint Committee on Cancer staging criteria.1 Eligible patients were required to have the following: Karnofsky performance status  70%; absolute granulocyte count 1,500/µL; platelet count 150,000/µL; serum bilirubin and serum creatinine  1.5 times the upper limit of laboratory normal; and AST, ALT, and alkaline phosphatase 3 times the upper limit of laboratory normal. All patients were required to use appropriate birth control methods and to provide informed written consent. All patients were required to have either magnetic resonance imaging or computed tomography of the brain, and patients with brain metastases were excluded from this study. Patients were also excluded if they were pregnant or lactating, or had any of the following: ongoing toxicity from prior therapy or pre-existing neurotoxicity grade 2; any medical condition that would interfere with intake of oral medication; a history of cardiac disease; or other concurrent malignancy, with the exception of nonmelanoma skin cancer or in situ cervical cancer. Patients could have received no prior systemic chemotherapy for metastatic melanoma, and prior radiotherapy, interstitial brachytherapy, or radiosurgery must have been completed at least 4 weeks before study entry. Patients were allowed no other concurrent chemotherapy, immunotherapy, or radiotherapy.
Study Design
A dose-modification plan was prospectively developed to allow for modification of the temozolomide dose in the event of grade 4 hematologic toxicity or any grade 3 or 4 nonhematologic toxicities (National Cancer Institute common toxicity criteria). The dose-modification plan also allowed for escalation of the thalidomide dose as tolerated or de-escalation if grade 3 or 4 nonhematologic toxicities developed. Patients were started at a low-dose of thalidomide (administered at bedtime), and the dose was escalated every 2 weeks to allow patients to adjust to its sedative effects. In the event of grade 3 or 4 neurotoxicity, the thalidomide dose was de-escalated stepwise to a minimum of 50 mg/d. The dose was held until the toxicity decreased to
Tumor response was evaluated by physical examination, chest x-ray, computed tomography scan, or other diagnostic tests, as appropriate, after every 8-week cycle of therapy. Standard World Health Organization response criteria were used. A complete response (CR) was defined as complete disappearance of all evidence of tumor and symptoms of disease for at least 4 weeks. Partial response (PR) was defined as a
Statistical Analysis
Patients A total of 38 patients were entered in the phase II protocol from October 2000 to September 2001, including three patients carried over from the phase I study who were treated at the same dose level used in the phase II study. Demographics and baseline disease characteristics are presented in Table 1  . Median age was 62 years (range, 21 to 83 years), and median Karnofsky performance status was 90%. Eleven patients were 70 years of age. Twenty-seven patients had cutaneous melanoma (including four with acral lentiginous melanoma), nine patients had unknown primaries, and one patient each had melanoma of the vulva and of the rectum. One patient had stage IIIc disease with multiple in-transit metastases, and the remaining patients all had stage IV disease (three patients with M1a, eight with M1b, and 26 with M1c). The most common sites of visceral metastases were lung and liver, and the median number of metastatic sites was four (range, 1 to 9 sites). Patients completed a median of two cycles of therapy (range, zero to seven cycles; Table 2), and five patients did not complete the first cycle.
Response Twelve patients (32%; 95% confidence interval [CI], 17.2%, 46.8%) had an objective tumor response (intent-to-treat analysis), including one patient with an ongoing CR of 25+ months’ duration and 11 patients with a PR. The median time to first response was 8 weeks, and the median duration of response was 5 months (range, two to 25+ months). Responses are presented in Table 3 .
Among patients with a PR, five patients had a more than 90% reduction of disease and were converted to a CR with surgery (one patient with in-transit metastases, three with soft tissue/lymph node metastases, and one with lung metastases). Among the five patients with a surgical CR, two remain disease-free at, respectively, 24+ and 21+ months from study entry; two patients are alive with disease at, respectively, 26+ and 20+ months from study entry; and one patient died of melanoma 26 months after study entry. Objective responses were seen in lung, soft tissue, and liver metastases. The one clinical CR occurred in lung and cutaneous metastases in a patient with M1b disease. One patient with numerous in-transit metastases (stage IIIc) had a more than 90% regression and was subsequently rendered disease-free by resection. This patient developed recurrent disease 4 months after achieving a surgical CR, and remains alive with disease at 20+ months from study entry. Three patients with M1a disease had a PR in soft tissue and lymph node metastases. One of these patients had surgical resection of residual disease and remains disease-free at 21+ months from study entry, and one patient had resolution of all distant metastases but had progression at the primary site and underwent resection of the primary tumor. Two months afterward, this patient developed a small soft tissue metastasis and remains alive with disease at 26+ months from study entry. The third patient experienced disease progression 2 months after achieving a PR. Five patients with M1b disease had a PR in lung, soft tissue, and lymph node metastases, and 2 of these patients were rendered disease-free after surgical resection of residual disease (one with soft tissue or lymph node metastases and one with lung metastases). The patient who had resection of residual soft tissue or lymph node metastases remains disease-free at 24+ months, and the patient who underwent resection of residual lung metastases had a recurrence in the lung 6 months after surgery and died of disease 26 months after study entry. The other three patients had disease progression at 4, 12, and 15 months, respectively, after achieving a PR. Finally, two patients with M1c disease had a PR in lung, liver, spleen, mesentery, and lymph node metastases, with response durations of 2 and 4 months.
Survival
Brain Metastases Brain metastases developed in nine of 38 (24%) patients after a median follow-up of 24.3 months. The median time from start of treatment to the development of brain metastases was 12 months (range, 2 to 28 months). In most cases, brain metastases developed long after the study drug regimen was discontinued (median, 11 months posttreatment; range, 7 to 20 months). One patient with M1a disease achieved a PR as best response and developed brain metastasis 9 months after discontinuation of therapy. Among four patients with M1b disease (three PR and one SD) who developed brain metastasis, one developed brain metastasis while on study, and three developed brain metastasis 16, 12, and 7 months, respectively, after treatment was discontinued. Similarly, among three patients with M1c disease (two SD and one progressive disease) who developed brain metastasis, only one case occurred while on study, and two occurred 20 and 14 months, respectively, after discontinuation of therapy. One patient with M1c disease who progressed rapidly and did not complete one cycle of therapy, developed brain metastasis 11 months after removal from the study. Overall, four (33%) of 12 patients who achieved an objective response to treatment later developed brain metastases, and only one responder developed brain metastasis while on study treatment. Two patients with M1c disease who developed brain metastases remain alive at 29.5 and 21.5 months, respectively, from the start of treatment.
Safety
Seven patients required dose reductions, delayed dose-escalation of thalidomide, or discontinued thalidomide primarily as a result of thalidomide-associated neurotoxicity, rash, or constipation. Only one patient had a dose delay because of temozolomide-associated lymphopenia. Five patients did not complete the first cycle of therapy because of either toxicity (rash in one patient, rash and grade 3 deep vein thrombosis in one patient, and grade 4 thrombocytopenia in one patient) or complications that prevented further treatment (atrial fibrillation and bowel obstruction in one patient each). The latter patient was unable to continue oral therapy because of intermittent bowel obstruction associated with bulky intestinal metastases. Nine patients discontinued after completing at least one cycle of therapy because of neurotoxicity or fatigue (two patients); dyspnea and pneumonia or pneumonitis (two patients); fever, rash, and dyspnea (one patient); persistent lymphopenia (one patient); edema and constipation (one patient); and gastrointestinal bleeding (one patient). In addition, one patient with pre-existing hypertension died of hemorrhagic stroke after achieving a minor response in lung, liver, spleen, and soft tissue metastases after one cycle of therapy.
The results of this study suggest that the combination of a low-dose daily schedule of temozolomide with thalidomide has significant clinical activity in patients with advanced-stage metastatic melanoma. Six patients (16%) had either a clinical or a surgical CR. The five surgical CRs were made possible by the greater than 90% tumor regression of soft tissue, lymph node, and lung metastases that was achieved with treatment. The overall objective response rate of 32% is higher than that typically achieved with DTIC alone and compares favorably with DTIC plus cisplatin regimens in patients with similarly advanced disease.3 The responses achieved in this study were also reasonably durable. Moreover, the median survival of 9.5 months is good for such an advanced-stage patient population. This daily regimen of concomitant temozolomide plus thalidomide was generally well tolerated by all patients, including the elderly patients in this trial (11 patients were > 70 years of age). The majority of patients were able to tolerate the planned escalation of the thalidomide dose, and few patients discontinued therapy because of treatment-associated toxicity. In particular, hematologic toxicity associated with temozolomide (mainly grade 3 lymphopenia) led to dose delay in only one patient, and led to discontinuation in only two patients. Thalidomide-associated neurotoxicity and rash led to discontinuation in several patients, but was mild to moderate in severity (consisting mainly of grade 2 drowsiness and neurosensory dysfunction) and manageable in the majority of patients. This regimen has a number of important advantages over existing treatments for metastatic melanoma, particularly for older patients. Because both drugs are oral agents and have favorable side-effect profiles, patients are able to self-administer treatment at home and need only periodic clinic visits for follow-up. Therefore, this regimen may provide important quality-of-life benefits to patients with advanced cancer and significant comorbidity. Secondly, one can speculate that combining a cytotoxic agent such as temozolomide with an immunomodulatory and antiangiogenic agent such as thalidomide may provide enhanced antitumor activity. Thirdly, in contrast to DTIC and other standard agents such as cisplatin, temozolomide readily crosses the blood-brain barrier and has the potential to reduce the risk of progression in the CNS. Brain metastases develop in approximately 50% of patients with metastatic melanoma during the course of their disease.21,22 In this study, after a median follow-up of more than 24 months, brain metastases developed in nine patients (24%), including one patient who did not complete one cycle of therapy. In most cases, brain metastases developed 1 year or more after patients discontinued therapy. Moreover, brain metastases developed in only four (15%) of 26 patients with M1c disease, two of whom remain alive with disease at 29.5 and 21.5 months, respectively. Therefore, it is reasonable to hypothesize that this regimen may reduce CNS progression. In a recent phase II pilot study of a biochemotherapy regimen containing temozolomide in place of DTIC, brain metastases developed in only two (9%) of 22 responding patients as their initial site of relapse, compared with 12 (63%) of 19 patients treated with the regimen containing DTIC.12 Temozolomide is also being investigated in melanoma patients with brain metastases and has demonstrated promising activity in this setting.23–25 We have observed several objective responses in brain metastases among melanoma patients enrolled in a phase II study of temozolomide plus thalidomide currently ongoing at Memorial Sloan-Kettering Cancer Center. Lastly, because of temozolomide’s favorable safety profile and the flexibility of its dosing schedules, it can easily be combined with other chemotherapy agents or immunotherapy. For example, a phase I study has shown that temozolomide can be safely combined with interferon alfa.26 The Hellenic Cooperative Oncology Group also reported a 27% overall response rate (five CRs and 12 PRs) in patients with melanoma, and a PR in three (38%) of eight patients with brain metastases who were treated with temozolomide plus docetaxel.23 In summary, the combination of continuous daily oral temozolomide plus thalidomide seems to be a promising regimen for the treatment of metastatic melanoma, and further study is warranted.
1. Balch CM, Buzaid AC, Soong S-J, et al: Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 19:3635–3648, 2001
2. Jemal A, Thomas A, Murray T, et al: Cancer statistics, 2002. CA Cancer J Clin 52:23–47, 2002 3. Serrone L, Zeuli M, Sega FM, et al: Dacarbazine-based chemotherapy for metastatic melanoma: Thirty-year experience overview. J Exp Clin Cancer Res 19:21–34, 2000[Medline]
4. Chapman PB, Einhorn LH, Meyers ML, et al: Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol 17:2745–2751, 1999
5. Rosenberg SA, Yang JC, Schwartzentruber DJ, et al: Prospective randomized trial of the treatment of patients with metastatic melanoma using chemotherapy with cisplatin, dacarbazine, and tamoxifen alone or in combination with interleukin-2 and interferon alfa-2b. J Clin Oncol 17:968–975, 1999 6. Dorval T, Negrier S, Chevreau C, et al: Randomized trial of treatment with cisplatin and interleukin-2 either alone or in combination with interferon-alpha-2a in patients with metastatic melanoma: A Federation Nationale des Centres de Lutte Contre le Cancer Multicenter, parallel study. Cancer 85:1060–1066, 1999[CrossRef][Medline]
7. Eton O, Legha SS, Bedikian AY, et al: Sequential biochemotherapy versus chemotherapy for metastatic melanoma: Results from a phase III randomized trial. J Clin Oncol 20:2045–2052, 2002 8. Agarwala SS, Reyderman L, Statkevich P, et al: Pharmacokinetic study of temozolomide penetration into CSF in a patient with dural melanoma. Ann Oncol 9:138, 1998 (abstr 659) 9. Stupp R, Ostermann S, Leyvraz S, et al: Cerebrospinal fluid levels of temozolomide as a surrogate marker for brain penetration. Proc Am Soc Clin Oncol 20:59a, 2001 (abstr 232)
10. Middleton MR, Grob JJ, Aaronson N, et al: Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 18:158–166, 2000 11. Paul MJ, Summers Y, Calvert AH, et al: Effect of temozolomide on central nervous system relapse in patients with advanced melanoma. Melanoma Res 12:175–178, 2002[CrossRef][Medline]
12. Atkins MB, Gollob JA, Sosman JA, et al: A phase II pilot trial of concurrent biochemotherapy with cisplatin, vinblastine, temozolomide, interleukin 2, and IFN-alpha 2B in patients with metastatic melanoma. Clin Cancer Res 8:3075–3081, 2002
13. Brock CS, Newlands ES, Wedge SR, et al: Phase I trial of temozolomide using an extended continuous oral schedule. Cancer Res 58:4363–4367, 1998
14. D’Amato RJ, Loughnan MS, Flynn E, et al: Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A 91:4082–4085, 1994 15. Geitz H, Handt S, Zwingenberger K: Thalidomide selectively modulates the density of cell surface molecules involved in the adhesion cascade. Immunopharmacology 31:213–221, 1996[CrossRef][Medline]
16. Haslett PA, Corral LG, Albert M, et al: Thalidomide costimulates primary human T lymphocytes, preferentially inducing proliferation, cytokine production, and cytotoxic responses in the CD8+ subset. J Exp Med 187:1885–1892, 1998 17. Rajkumar SV: Current status of thalidomide in the treatment of cancer. Oncology (Huntingt) 15:867–874, 2001[Medline] 18. Eisen T, Boshoff C, Mak I, et al: Continuous low dose Thalidomide: A phase II study in advanced melanoma, renal cell, ovarian and breast cancer. Br J Cancer 82:812–817, 2000[CrossRef][Medline]
19. Hwu W-J, Krown SE, Panageas KS, et al: Temozolomide plus thalidomide in patients with advanced melanoma: Results of a dose-finding trial. J Clin Oncol 20:2610–2615, 2002 20. Anderson JR, Cain KC, Gelber RD: Analysis of survival by tumor response. J Clin Oncol 1:710–719, 1983[Abstract] 21. Amer MH, Al-Sarraf M, Baker LH, et al: Malignant melanoma and central nervous system metastases: incidence, diagnosis, treatment and survival. Cancer 42:660–668, 1978[CrossRef][Medline] 22. Patel JK, Didolkar MS, Pickren JW, et al: Metastatic pattern of malignant melanoma: A study of 216 autopsy cases. Am J Surg 135:807–810, 1978[CrossRef][Medline]
23. Bafaloukos D, Gogas H, Georgoulias V, et al: Temozolomide in combination with docetaxel in patients with advanced melanoma: A phase II study of the Hellenic Cooperative Oncology Group. J Clin Oncol 20:420–425, 2002 24. Hwu W-J, Raizer J, Panageas KS, et al: Treatment of metastatic melanoma in the brain with temozolomide and thalidomide. Lancet Oncol 2:634–635, 2001[CrossRef][Medline] 25. Dardoufas C, Miliadou A, Skarleas C, et al: Concomitant temozolomide (TMZ) and radiotherapy (RT) followed by adjuvant treatment with temozolomide in patients with brain metastases from solid tumours. Proc Am Soc Clin Oncol 20:75b, 2001 (abstr 2048) 26. Agarwala SS, Kirkwood JM: Temozolomide in combination with interferon alfa-2b in patients with metastatic melanoma: A phase I dose-escalation study. Cancer 97:121–127, 2003[CrossRef][Medline] Submitted February 13, 2003; accepted June 10, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
