Carlson, Robert H.
WASHINGTON—Blocking the MAP kinase pathway continues to yield anticancer benefits. In a Phase I trial reported here at the American Association for Cancer Research Annual Meeting that combined the broad-spectrum MAP kinase inhibitor dasatinib with the antiangiogenic agent bevacizumab in patients with advanced solid tumors, 59 percent of evaluable patients (10 of 17) had either a partial response (one patient with HER2+ breast cancer, for five months) or stable disease (nine patients, for a median of 10 months) (Abstract 35).
JUNG-MIN LEE, MD
The first author of the poster study, Jung-Min Lee, MD, Assistant Clinical Investigator in the Women's Cancer Clinic of the NCI's Medical Oncology Branch, noted that although previous Phase I and II trials combining the MAP kinase inhibitor sorafenib with bevacizumab showed activity, interactive side effects consistent with their overlapping molecular targets, including hand and foot syndrome and hypertension, caused sorafenib dose reductions in almost two thirds of patients.
The study's senior author was Elise Kohn, MD, Head of the Molecular Signaling Section in the Medical Oncology Branch of the NIH's Center for Cancer Research.
Since dasatinib's targets are overlapping or upstream to most of the sorafenib targets, including MAPK and SRC family kinases, she and her colleagues had hypothesized that dasatinib and bevacizumab would synergize and maintain activity with less interactive toxicity.
Dasatinib is currently approved for treatment of chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), and bevacizumab is used in combination regimens for several solid malignancies.
In her presentation here, Lee said that in the first portion of the trial dasatinib doses were escalated from 50 mg at a continuous daily dose up to 100 mg, and bevacizumab from 5 mg/kg up to 10 mg/kg once every two weeks. Fourteen of the 19 patients had metastatic gynecologic cancers; the others had breast, thyroid, and pancreatic cancers and melanoma. Patients had a median of four prior treatments, and a median age was 64.
No dose-limiting toxicities were observed, Lee said. Grade 3 toxicities included two cases of hypertension and two of pleural effusions, which are both known side effects of dasatinib, and one patient had Grade 3 thrombocytopenia. Grade 1/2 toxicities included anemia, lymphopenia, and neutropenia. There were no Grade 4 toxicities.
“Since the regimen is very active without really significant side effects, dasatinib 100 mg daily and bevacizumab 10 mg/kg once every two weeks are the doses we will use for the translational portion of the trial,” Lee said.
She added that the expansion cohort is now accruing, and will include functional imaging, tumor biopsies, and blood sampling for measurement of biochemical changes in SRC and VEGF signaling pathways.