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G3139 (Genasense) in patients with advanced merkel cell carcinoma
Manisha H Shah1, Kimberly A Varker, Minden Collamore
1Division of Hematology and Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA. Manisha.Shah@osumc.edu
Objectives:
Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine malignancy of the skin. Preclinical studies have identified up-regulation of the critical antiapoptosis gene bcl-2 in MCC. We conducted a multicenter phase II trial of the novel bcl-2 antisense agent (G3139, Genasense) in patients with advanced MCC.
Methods:
Twelve patients (9 men, 3 women) with histologically confirmed metastatic or regionally recurrent MCC were enrolled. Ten patients (83%) had received prior chemotherapy. Eight patients (67%) had Karnofsky performance status of 90 to 100. Patients received continuous IV infusion of G3139 (7 mg/kg/d) via central venous access in an outpatient setting for 14 days, followed by a 7-day rest period. Response was assessed at 6-week intervals. Patients were allowed to continue therapy until unacceptable toxicity or disease progression.
Results:
No objective responses were observed. The best response was stable disease in 3 patients and progressive disease in 9 patients. A median of 4 doses per patient (total 46 doses) was administered. Dose delays and/or reductions were required in 6 patients. One patient developed grade 4 lymphopenia. One patient developed grade 3 renal failure characterized by grade 3-elevated creatinine and grade 4 hyperkalemia. Other grade 3 events included cytopenia (n = 5), aspartate aminotransferase/alanine aminotranferease elevation (n = 3), hypophosphatemia (n = 2), and pain (n = 1). The most frequent grade 1 to 2 toxicities were elevated creatinine, ALT elevation, hypokalemia, lymphopenia, and fatigue.
Conclusions:
Bcl-2 antisense therapy (G3139) was well tolerated among patients with advanced MCC. Although probable antitumor activity was documented in 1 patient, no objective responses per Response Evaluation Criteria in Solid Tumors criteria were observed.
Insights
Bcl-2 antisense therapy showed limited efficacy in advanced Merkel cell carcinoma, with no objective responses observed. The treatment was generally well-tolerated, though some patients experienced dose modifications due to toxicity.
Area of Science:
- Oncology
- Molecular Biology
- Dermatology
Background:
- Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer.
- The antiapoptotic gene bcl-2 is upregulated in MCC, making it a potential therapeutic target.
Purpose of the Study:
- To evaluate the efficacy and safety of the bcl-2 antisense agent G3139 (Genasense) in patients with advanced MCC.
- To assess the response to bcl-2 antisense therapy in a multicenter phase II trial.
Main Methods:
- Twelve patients with advanced MCC received continuous IV infusion of G3139 (7 mg/kg/d).
- Treatment involved 14 days of infusion followed by a 7-day rest period.
- Response was assessed every 6 weeks, and therapy continued until progression or unacceptable toxicity.
Main Results:
- No objective responses were observed in any patients according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
- Three patients achieved stable disease, while nine experienced progressive disease.
- The treatment was associated with toxicities including lymphopenia, renal failure, and cytopenia, requiring dose delays or reductions in 6 patients.
Conclusions:
- Bcl-2 antisense therapy (G3139) was well-tolerated in patients with advanced MCC.
- While one patient showed probable antitumor activity, no objective responses were achieved.
- Further investigation into bcl-2 targeted therapies for MCC may be warranted, potentially with combination strategies or different agents.
