S0933: Taking a Notch out of melanoma
The Notch receptor takes its name from where its effects were first observed -- the notched wings that flies developed (shown here) when researchers interfered with the gene that encodes the receptor. The Notch receptor is now seen as part of an evolutionarily ancient signaling pathway important in cell differentiation, proliferation, and apoptosis and is a site of intense focus in oncology research.
Credit: J. Cell. Biol. (CC)
"Phase II study of RO4929097 (NSC-749225) in advanced melanoma"
SWOG's newest trial, S0933, is a phase II study testing the effect of an investigational drug known as RO4929097 on survival in stage IV melanoma patients. The drug, a selective gamma-secretase inhibitor, interferes with the Notch receptor signaling pathway, which is thought to promote cell proliferation in melanoma.
The Notch receptor is a key piece of the system cells use to communicate to their neighbors and is believed to be important in cell development and differentiation.
Recent work by study coordinator Thomas Gajewski, M.D., Ph.D., of the University of Chicago and others has shown that by interfering with the control of Notch-based function on gene expression in the melanoma cell, gamma-secretase inhibitors can limit proliferation and increase apoptosis, or programmed cell death, among melanoma cells grown in the lab.
"After 48 hours of drug exposure, no viable cells were detected, indicating a very powerful anti-tumor activity in vitro," says S0933 lead study coordinator Kim A. Margolin, M.D., of the Seattle Cancer Care Alliance.
Gajewski's lab worked with melanoma cell lines that have high levels of Notch activation, thus making them particularly sensitive to treatments that interfere with Notch function.
In the clinic, a recently-completed phase I study treated patients with advanced solid tumors using RO4929097, the same gamma-secretase inhibitor to be used in S0933. A 2009 report by that phase I study's investigator stated that of 71 treated patients, 15 had shown clinical benefit from the treatment.
The phase II S0933 uses the dose of study drug determined in this phase I trial to be most likely to inhibit Notch signaling while still maintaining an acceptable safety profile. S0933 patients will take 20 mg of RO4929097 daily for 3 consecutive days each week until the cancer grows or until side effects or laboratory toxicities are not tolerable at the same or a reduced drug dose.
The primary objective is to assess the six-month progression-free survival and one-year overall survival probability in stage IV melanoma patients who have had no prior chemotherapy and who undergo this treatment with RO4929097.
Secondary objectives include investigating how Notch activation status and gene expression profile as well as immune system parameters relate to clinical outcomes, including tumor regression and toxicities.
Eligibility for study participation
Patients must have Stage IV, histologically confirmed, measurable melanoma, a Zubrod performance status of 0-1, and adequate bone marrow, liver, and renal function.
Patients may not have a history of, or current evidence of, brain metastases. They may have received cytotoxic drugs as part of adjuvant therapy if completed at least 180 days prior to registration, and they may have received prior radiation therapy if completed at least 28 days prior to registration and if there remains measurable tumor outside of radiation ports.
The study has an accrual target of 72 eligible patients. The first local IRB approval of the trial took place in mid November, 2010, at the Columbus (OH) CCOP.
Please review the detailed eligibility criteria. Eligible patients can find the nearest participating institution online or by contacting the Southwest Oncology Group at (210) 614-8808 or at firstname.lastname@example.org.