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A phase II trial of O6-benzylguanine and carmustine in patients with advanced soft tissue sarcoma
Christopher W Ryan1, M Eileen Dolan, Bruce B Brockstein
1Division of Hematology and Medical Oncology, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd. CR145, Portland, OR 97239, USA. ryanc@ohsu.edu
Purpose:
Tumor resistance to alkylating agents such as carmustine (BCNU) has been found to be associated with intracellular expression of O6-methylguanine-DNA methyltransferase (MGMT). Administration of O6-benzylguanine (O6-BG), a substrate that inactivates MGMT, may help overcome chemotherapy resistance. We performed a phase II study to explore the activity of O6-BG in combination with BCNU in patients with advanced soft tissue sarcoma.
Experimental Design:
Informed consent was obtained from patients with metastatic soft tissue sarcoma naïve to systemic chemotherapy (adjuvant chemotherapy allowed). Patients received O6-BG 120 mg/m2 I.V. followed by BCNU 40 mg/m2 I.V. Treatment was repeated every 6 weeks until disease progression or development of unacceptable toxicity.
Results:
No objective responses were observed in 12 enrolled patients. Four patients exhibited stable disease lasting 11-25+ weeks. The median overall survival was 16.9 months (95% CI, 2.9-NR). The most common grade 3-4 toxicities were neutropenia, thrombocytopenia, and anemia. Depletion of MGMT activity was demonstrated in peripheral blood mononuclear cells. Immunohistochemical estimation of MGMT expression from archival tissue ranged from 20 to 99% positive staining cells.
Conclusions:
Observed toxicities were consistent with previous studies of O6-BG plus BCNU. The degree of MGMT expression was variable in this small sample of heterogeneous sarcomas. Further development of this regimen and dose for the treatment of soft tissue sarcoma is not warranted due to the lack of objective responses.
Insights
This study found that combining O6-benzylguanine (O6-BG) with carmustine (BCNU) did not improve treatment response in advanced soft tissue sarcoma patients. The combination showed toxicities but no objective tumor responses, suggesting it is not a viable treatment option.
Area of Science:
- Oncology
- Pharmacology
- Cancer Biology
Background:
- Tumor resistance to carmustine (BCNU) is linked to O6-methylguanine-DNA methyltransferase (MGMT).
- O6-benzylguanine (O6-BG) inactivates MGMT and may overcome resistance.
- Soft tissue sarcoma treatment often faces challenges with chemotherapy resistance.
Purpose of the Study:
- To evaluate the efficacy of O6-BG combined with BCNU in advanced soft tissue sarcoma.
- To assess the safety and tolerability of this combination regimen.
- To explore the role of MGMT expression in treatment response.
Main Methods:
- Phase II clinical trial.
- 12 patients with metastatic soft tissue sarcoma received O6-BG followed by BCNU every 6 weeks.
- MGMT activity depletion was measured; MGMT expression was assessed via immunohistochemistry.
Main Results:
- No objective tumor responses were observed in the 12 patients.
- Four patients achieved stable disease for 11-25+ weeks.
- Median overall survival was 16.9 months; common toxicities included neutropenia, thrombocytopenia, and anemia.
Conclusions:
- The combination of O6-BG and BCNU demonstrated toxicities consistent with prior studies.
- MGMT expression varied significantly in this patient cohort.
- Due to a lack of objective responses, further development of this regimen for soft tissue sarcoma is not recommended.
