Data access will be granted to anonymized patient\level data, protocols and clinical study reports after authorization by an independent scientific review panel. self-employed scientific review panel. Bayer is not involved in the decisions made by the self-employed review panel. Bayer will take all necessary actions to ensure that patient privacy is definitely safeguarded. Abstract Regorafenib 160?mg orally once daily (QD) 3 weeks about/1 week off is approved in colorectal malignancy, gastrointestinal stromal tumors and hepatocellular carcinoma. We founded the security and pharmacokinetics (PK) of regorafenib combined with cetuximab in advanced refractory solid tumors. This was a phase 1, open\label, dose\escalation study (“type”:”clinical-trial”,”attrs”:”text”:”NCT01973868″,”term_id”:”NCT01973868″NCT01973868) in individuals with advanced/metastatic solid tumors who progressed after standard therapy. Regorafenib was given at various dose levels QD continually or intermittently (3?weeks on/1?week off) combined with intravenous cetuximab 250?mg/m2 weekly. The primary objectives were security, PK and maximum tolerated dose (MTD). The secondary objective was tumor response. Dose\limiting toxicities (DLTs) were evaluated in Cycle 1. Of 42 treated individuals, 31 received regorafenib intermittently (120?mg, crazy\type mCRC and those with squamous cell carcinoma of the head and neck.12, 13 The most common adverse reactions associated with cetuximab include cutaneous adverse reactions (including rash, pruritus and toenail changes), headache, diarrhea and infection. Preclinical models possess demonstrated the combination of regorafenib and cetuximab may conquer intrinsic and acquired resistance 3AC in EGFR\sensitive and EGFR\resistant tumors, and may provide an improved medical benefit over either drug alone in certain tumor types.14 Furthermore, preclinical data have demonstrated decreased angiogenesis and increased tumor and endothelial cell apoptosis with combined inhibition of VEGF and EGFR.15 Inside a recently published phase 1 study of regorafenib plus cetuximab in individuals with metastatic cancer refractory to standard therapies, regorafenib 80?mg QD in addition cetuximab 200?mg/m2 loading dose, followed by cetuximab 150?mg/m2 every week, was determined as the MTD and demonstrated initial activity in mCRC.16 3AC With this phase 1, dose\finding study, we aimed to establish the safety and pharmacokinetics (PK) of regorafenib (continuous and intermittent dosing) in combination with the standard dose of cetuximab in individuals with advanced stable tumors. Materials and Methods Patient human population Individuals 18? years of age having a histologically or cytologically confirmed locally advanced or metastatic solid tumors who have been unsuitable for, or no longer responding to standard therapy, or for whom regorafenib or cetuximab was considered as a standard treatment, were eligible for inclusion. Other key inclusion criteria included an Eastern Cooperative Oncology Group overall performance status of 0 or 1, no mutation in individuals with mCRC, a life expectancy of 3 months and adequate bone marrow (platelet 100,000/mm3, complete neutrophil count 1,000/mm3), liver (aspartate aminotransferase 2.5??top limit of normal) and renal function (creatinine clearance 30?ml/min). Individuals were excluded if they experienced received previous treatment with regorafenib; previously discontinued cetuximab due to toxicity or intolerance; experienced known metastatic mind or meningeal tumors; a history of organ allograft or cardiac disease; or were diagnosed with human immunodeficiency disease or active hepatitis B/C. Further exclusion criteria included major surgery treatment within 4 weeks of start of study treatment; a nonhealing Rabbit Polyclonal to ERD23 wound, ulcer, or bone fracture; uncontrolled hypertension or significant acute gastrointestinal disorders with diarrhea as a major sign; arterial or venous thrombotic or embolic events; and pregnancy or breastfeeding. In addition, additional anticancer treatments were not permitted during the study. Study design and treatment This was an open\label, dose\escalation, phase 1b study of regorafenib in combination with cetuximab carried out at four sites in the USA (“type”:”clinical-trial”,”attrs”:”text”:”NCT01973868″,”term_id”:”NCT01973868″NCT01973868; Supporting Info Fig. S1). The primary objectives were to determine the safety, tolerability and MTD of regorafenib in combination with cetuximab, and to characterize the PK of this combination. The secondary objective was 3AC the initial evaluation of tumor response for this combination. All individuals offered written educated consent before any study process. The trial was authorized by each center’s ethics committee or institutional evaluate table and complied with Good Clinical Practice recommendations, the Declaration of Helsinki and relevant local laws. Before the start of combination treatment (run\in period), individuals received a 3AC single dose of regorafenib in the assigned dose level on Day time ?14 (2 days) for PK evaluation only, followed by.