German Clinical Trials Register

Acronym/abbreviation of the study

SORATRAM

URL of the study

No Entry

Brief summary in lay language

The study is designed for patients with an advanced tumor disease in whom a specific genetic change, a mutation in the BRAF gene, has been identified during further testing of tumor tissue samples. The protein product of this gene is, among other things, part of a communication and signaling pathway in our cells (the so-called MAP kinase pathway), which is involved in the normal growth and survival of cells. Mutations in this gene can cause this signaling pathway to become overactive, which can accelerate tumor growth. Other mutations can lead to the signaling pathway being inactivated or restricted. In this case, the tumour cell switches on a bypass pathway (CRAF). This is done by activating another protein product (RAS), which can also accelerate the growth of the cancer cells. BRAF is mutated in approximately one in 10 tumor patients (8%). There are already drugs available that specifically inhibit the overactivation (so-called BRAF inhibitors); these are approved, for example, for patients with black skin cancer or certain forms of lung cancer. In every 4th to 5th patient with a BRAF mutation, however, there is no overactivity; the biological function of the protein molecule is either restricted or unknown here. For this case of BRAF hypofunction and activation of the alternative pathway CRAF, there are still no approved effective drugs. Studies on tumor cells suggest that patients with corresponding BRAF mutations may benefit from combined treatment with a CRAF inhibitor and an inhibitor of MEK (also part of the MAP kinase signaling pathway). The drug sorafenib inhibits CRAF and has shown some efficacy in laboratory tests alone. This effect could be further enhanced by additional MEK inhibition with the drug trametinib in laboratory trials. First case reports of so-called individualized healing trials on patients support this hypothesis. The rationale for this clinical trial for therapy with sorafenib combined with trametinib is based on the findings available to date to test the tolerability and efficacy of this combined therapeutic approach.

Brief summary in scientific language

BRAF mutations are found in 7-8% of solid tumors. In 25% of cases, these mutations impair or inactivate the BRAF kinase. In these patients, BRAF leads to paradoxical CRAF activation and BRAF inhibitors are not active. These cases constitute an unmet medical need. Our previous work demonstrates that a combination of CRAF (sorafenib) and MEK (trametinib) inhibitors suppresses downstream MEK and ERK activation in vitro in cell lines expressing BRAF variants with impaired kinase activity. Treatment of a patient with metastatic melanoma harboring an inactivating BRAFD594G mutation with sorafenib and trametinib was tolerated well and led to a clinical and radiographic response lasting for 6 months. We thus propose that the combination of CRAF and MEK inhibition might offer a promising treatment strategy in patients with advanced solid tumors carrying BRAF mutations with impaired kinase activity. This multicenter prospective project is intended to demonstrate feasibility, safety and a first proof of concept that sorafenib in combination with trametinib is clinically active in advanced malignancies with BRAF mutations with impaired kinase activity. We will initiate a prospective multicenter phase I trial at all nine DKTK partner sites to evaluate the safety of trametinib in increasing doses in combination with of sorafenib in advanced malignancies with BRAF mutations impairing BRAF kinase activity.