A phase II study of bortezomib in the treatment of metastatic malignant melanoma

Abstract

BACKGROUNDBortezomib is a proteasome inhibitor with manageable clinical toxicity and laboratory evidence of anti‐melanoma activity. Therefore, it was considered for clinical testing in patients with metastatic melanoma.METHODSPatients with metastatic melanoma and adequate hematologic, renal, and hepatic function were treated with bortezomib (a 1.5‐mg/m2 intravenous bolus twice weekly for 2 of every 3 weeks). Eligible patients were age ≥ 18 years with an Eastern Cooperative Oncology Group performance status of 0–1. The primary goal of the current study was to evaluate the 18‐week disease progression‐free survival rate and tolerability of bortezomib in these patients.RESULTSThe current study was intended to treat 45 patients. It was closed at the planned interim analysis due to early evidence of insufficient clinical efficacy. Twenty‐seven patients with a median age of 56 years (range, 32–77 years)were accrued. There were no major clinical responses to treatment. Only 6 patients (22%) achieved stable disease. Of these 6 patients, 4 were still stable after 4 cycles of treatment, but were removed from the study due to toxicity. The median time to disease progression was 1.5 months (95% confidence interval [95% CI], 1.4–1.6) with a median overall survival of 14.5 months (95% CI, 9–22). Having failed bortezomib, most patients proceeded to other clinical trials. Twenty‐six patients were evaluable for toxicity. One patient was removed from the study for other reasons and could not return for the cycle evaluation and thus was never evaluated. Of the 26 patients, no Grade 4/5 treatment‐related toxicities (using the National Cancer Institute Common Toxicity Criteria [version 2.0]) were reported. Eleven patients (42%) had Grade 3 toxicities (believed to be at least possibly related to treatment), including sensory neuropathy, thrombocytopenia, constipation, fatigue, ileus, abdominal pain, and infection without neutropenia. The median number of treatment cycles patients received was two (range, one to six treatment cycles). Two patients (7%) had 1 dose delay and 6 patients (22%) had dose reductions during 1 treatment cycle due to adverse events.CONCLUSIONSSingle‐agent bortezomib, administered twice weekly × 2 weeks, every 3 weeks at a dose of 1.5 mg/m2, was not found to be effective in the treatment of patients with metastatic melanoma. Cancer 2005. © 2005 American Cancer Society.

Therapeutic window for melanoma treatment provided by selective effects of the proteasome on Bcl-2 proteins

“…This need is particularly important in metastatic melanoma patients, whose average survival of 6-10 months could not be improved with the current dosing and administration route of bortezomib. 15 The rational design of new treatments to overcome bortezomib resistance in melanoma cells is complicated by several hurdles. First, the ubiquitin/proteasome system controls the half-life of nearly 80% of cellular proteins, both in normal and tumor cells, and no consistent predictive markers of response to bortezomib have been identified in vivo.…”

“…For example, although bortezomib can synergize with various chemotherapeutic agents, this proteasome inhibitor failed to reveal significant efficacy in a recent clinical trial with metastatic melanoma patients. 15 The development of treatments tailored to enhance the efficacy of bortezomib without increasing its secondary toxicity has been complicated by a lack of consensus on the impact of proteasome inhibition on the apoptotic cascade in tumor cells. In particularly, the impact of bortezomib on Bcl-2 family members is unclear.…”

Targeting apoptosis in solid tumors: the role of bortezomib from preclinical to clinical evidence

“…Mackay et al [101] also did not find any objective response in patients with metastatic colorectal cancer treated with bortezomib alone. Markovic et al [102] evaluated patients with metastatic malignant melanoma treated with bortezomib alone. Response rate in this study was also 0% and only six patients achieved stable disease.…”

Immune Mechanism of the Antitumor Effects Generated by Bortezomib

“…It is the first of a novel class of anticancer drugs, known as proteasome inhibitors, to be approved for clinical use. Since its discovery, bortezomib has been used to treat a variety of human tumors, such as multiple myeloma (3)(4)(5)(6)(7)(8), lymphoma (9,10), non-small cell lung cancer (11,12), renal cancer (13,14), prostate cancer (15)(16)(17), pancreatic cancer (18), melanoma (19), breast cancer (20,21), and ovarian cancer (22). Bortezomib inhibits a key regulator of intracellular protein degradation, the 26S proteasome, which has the downstream effect of inducing apoptotic cancer cell death by means of multiple mechanisms.…”