Aki Morikawa1, Milan Grkovski2, Sujata Patil3, Komal L Jhaveri4, Kendrick Tang4, John L Humm2, Andrei Holodny5, Kathryn Beal6, Heiko Schöder5, Andrew D Seidman7. 1. Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA. 2. Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 3. Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 4. Breast Cancer Medicine Service, Evelyn Lauder Breast Center, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, New York, NY, 10065, USA. 5. Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 6. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 7. Breast Cancer Medicine Service, Evelyn Lauder Breast Center, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, New York, NY, 10065, USA. seidmana@mskcc.org.
Abstract
PURPOSE: Sorafenib has demonstrated anti-tumor efficacy and radiosensitizing activity preclinically and in breast cancer. We examined sorafenib in combination with whole brain radiotherapy (WBRT) and explored the [18F] 3'deoxy-3'-fluorothymidine (FLT)-PET as a novel brain imaging modality in breast cancer brain metastases. METHODS: A phase I trial of WBRT + sorafenib was conducted using a 3 + 3 design with safety-expansion cohort. Sorafenib was given daily at the start of WBRT for 21 days. The primary endpoints were to determine a maximum tolerated dose (MTD) and to evaluate safety and toxicity. The secondary endpoint was CNS progression-free survival (CNS-PFS). MacDonald Criteria were used for response assessment with a correlative serial FLT-PET imaging study. RESULTS: 13 pts were evaluable for dose-limiting toxicity (DLT). DLTs were grade 4 increased lipase at 200 mg (n = 1) and grade 3 rash at 400 mg (n = 3). The MTD was 200 mg. The overall response rate was 71%. Median CNS-PFS was 12.8 months (95%CI: 6.7-NR). A total of 15 pts (10 WBRT + sorafenib and 5 WBRT) were enrolled in the FLT-PET study: baseline (n = 15), 7-10 days post WBRT (FU1, n = 14), and an additional 12 week (n = 9). A decline in average SUVmax of ≥ 25% was seen in 9/10 (90%) of WBRT + sorafenib patients and 2/4 (50%) of WBRT only patients. CONCLUSIONS: Concurrent WBRT and sorafenib appear safe at 200 mg daily dose with clinical activity. CNS response was favorable compared to historical controls. This combination should be considered for further efficacy evaluation. FLT-PET may be useful as an early response imaging tool for brain metastases. TRIAL AND CLINICAL REGISTRY: Trial registration numbers and dates: NCT01724606 (November 12, 2012) and NCT01621906 (June 18, 2012).
PURPOSE:Sorafenib has demonstrated anti-tumor efficacy and radiosensitizing activity preclinically and in breast cancer. We examined sorafenib in combination with whole brain radiotherapy (WBRT) and explored the [18F] 3'deoxy-3'-fluorothymidine (FLT)-PET as a novel brain imaging modality in breast cancer brain metastases. METHODS: A phase I trial of WBRT + sorafenib was conducted using a 3 + 3 design with safety-expansion cohort. Sorafenib was given daily at the start of WBRT for 21 days. The primary endpoints were to determine a maximum tolerated dose (MTD) and to evaluate safety and toxicity. The secondary endpoint was CNS progression-free survival (CNS-PFS). MacDonald Criteria were used for response assessment with a correlative serial FLT-PET imaging study. RESULTS: 13 pts were evaluable for dose-limiting toxicity (DLT). DLTs were grade 4 increased lipase at 200 mg (n = 1) and grade 3 rash at 400 mg (n = 3). The MTD was 200 mg. The overall response rate was 71%. Median CNS-PFS was 12.8 months (95%CI: 6.7-NR). A total of 15 pts (10 WBRT + sorafenib and 5 WBRT) were enrolled in the FLT-PET study: baseline (n = 15), 7-10 days post WBRT (FU1, n = 14), and an additional 12 week (n = 9). A decline in average SUVmax of ≥ 25% was seen in 9/10 (90%) of WBRT + sorafenibpatients and 2/4 (50%) of WBRT only patients. CONCLUSIONS: Concurrent WBRT and sorafenib appear safe at 200 mg daily dose with clinical activity. CNS response was favorable compared to historical controls. This combination should be considered for further efficacy evaluation. FLT-PET may be useful as an early response imaging tool for brain metastases. TRIAL AND CLINICAL REGISTRY: Trial registration numbers and dates: NCT01724606 (November 12, 2012) and NCT01621906 (June 18, 2012).
Entities:
Keywords:
Brain metastasis; Breast cancer; FLT-PET; Sorafenib; Whole brain radiotherapy
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