Phase 2 study of RO 4929097, a gamma‐secretase inhibitor, in metastatic melanoma: SWOG 0933
Year: 2014
Type: article
Study design: Clinical Trial
Abstract: BACKGROUND: Aberrant Notch activation confers a proliferative advantage to many human tumors, including melanoma. This phase 2 trial assessed the antitumor activity of RO4929097, a gamma-secretase inhibitor of Notch signaling, with respect to the progression-free and overall survival of patients with advanced melanoma. METHODS: Chemotherapy-naive patients with metastatic melanoma of cutaneous or unknown origin were treated orally with RO4929097 at a dose of 20 mg daily 3 consecutive days per week. A 2-step accrual design was used with an interim analysis of the first 32 patients and with continuation of enrollment if 4 or more of the 32 patients responded. RESULTS: Thirty-six patients from 23 institutions were enrolled; 32 patients were evaluable. RO4929097 was well tolerated, and most toxicities were grade 1 or 2. The most common toxicities were nausea (53%), fatigue (41%), and anemia (22%). There was 1 confirmed partial response lasting 7 months, and there were 8 patients with stable disease lasting at least through week 12, with 1 of these continuing for 31 months. The 6-month progression-free survival rate was 9% (95% confidence interval [CI], 2%-22%), and the 1-year overall survival rate was 50% (95% CI, 32%-66%). Peripheral blood T-cell assays showed no significant inhibition of the production of interleukin-2, a surrogate pharmacodynamic marker of Notch inhibition, and this suggested that the drug levels were insufficient to achieve Notch target inhibition. CONCLUSIONS: RO4929097 showed minimal clinical activity against metastatic melanoma in this phase 2 trial, possibly because of inadequate exposure to therapeutic drug levels. Although Notch inhibition remains a compelling target in melanoma, the results do not support further investigation of RO4929097 with this dose and schedule.
Source: Cancer
DOI: 10.1002/cncr.29055
Institutions: Seattle Cancer Care Alliance, University of Washington, SWOG Cancer Research Network, University of Michigan, Columbus Community Clinical Oncology Program, Wayne State University, The Barbara Ann Karmanos Cancer Institute, University of Chicago, University of California, Los Angeles, Los Angeles Medical Center, Moffitt Cancer Center
Language: English
Topic: Melanoma and MAPK Pathways
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
Awards: G117886320, G1205502904, G1257575315, G1268312386, G1331445602, G1343089328, G1391839138, Columbus Community Clinical Oncology Program (Columbus CCOP), G1545560008, G1548551769, G1646027999, G1790576020, G1938688226, G1958973285, G2043432835, G2064543036, G2201816905, G2237949143, G2276667821, G2345882982, G2397742718, G2435896781, G2750730928, COLUMBIA UNIVERSITY SOUTHWEST ONCOLOGY GROUP PROGRAM, GRAND RAPIDS CLINICAL ONCOLOGY PROGRAM, G3041257426, SOUTHWEST ONCOLOGY GROUP STATISTICAL CENTER, Southeast Cancer Control Consortium, Inc, G3295642875, G3334379738, G3484997517, G36541222, G3710026009, G3737421695, SWOG Network Group Operations Center of the NCTN, G379387698, G3939550896, G4094841028, G413878341, G4152208120, G4271794948, Southwest Oncology Group, Southwest Oncology Group, G4499432180, G5125348268, G5566132837, G6109875642, SOUTHWEST ONCOLOGY GROUP, Gulf Coast MBCCOP, G6723594983, G6943608702, G712978930, G7222907299, G763325562, Nevada Cancer Research foundation-Community Clinical Oncology Program, G7926913928, G8006406963, G8740717309, G8777682367, Integrative Molecular Epidemiology Workshop, G971274320
OpenAlex ID: W1574545886