Of these 70 positive patients, 19 matched all the eligibility criteria and were included in the DE phase. In the SE, a total of 428 patients were prescreened for amplification by FISH, of which 15 (3.5%) matched the Omtriptolide positivity criteria for the SE (ratio 2). (FcRn) at acidic pH, stimulating transcytosis across FcRn-expressing cells and radiolabeled ARGX-111 accumulated in lymphoid tissues, bone and liver, organs expressing FcRn at high levels in a biodistribution study using human FcRn transgenic mice. In line with this, we observed, in a patient with MET-amplified ( 10 copies) gastric cancer, diminished metabolic activity in multiple metastatic lesions in lymphoid and bone tissues by 18F-FDG-PET/CT after two infusions with 0.3 mg/kg ARGX-111. When escalated to 1 1 mg/kg, a partial response was reached. Furthermore, decreased numbers of CTC (75%) possibly by the enhanced tumor cell killing witnessed the modes of action of the drug, warranting further clinical investigation of ARGX-111. amplification, defined as a ratio 2, were further screened for eligibility. For both phases of the study, all eligible Omtriptolide patients had to meet the following criteria: be 18 years old; have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; be relapsing and/or refractory to prior cancer therapy. Eligibility criteria also included: serum albumin 35 g/L; absolute neutrophil count 1.0 109/L; hemoglobin 90 g/L; platelet count 75 109/L; activated partial thromboplastin time 1.5 ULN; total bilirubin 1.5 ULN; creatine phosphokinase 2.5 ULN; serum creatinine 1.5 ULN. Patients were excluded if they had a history or clinical evidence of CNS involvement (however, irradiated brain metastases that had been stable for 1 month and did not require systemic glucocorticoid administration were allowed), major surgery or biological therapy (monoclonal antibodies) 4 weeks prior to ARGX-111 first dose administration. Patients were also excluded if they had 3 weeks prior to ARGX-111 first dose administration: systemic glucocorticoids at doses greater than physiological replacement (prednisone 20 mg equivalent); cytotoxic chemotherapy; or radiation therapy with curative intent. Further criteria for exclusion included: biological therapy other than monoclonal antibodies within 5 half-lives of ARGX-111 first dose administration; unresolved Grade 3 or 4 4 toxicity from prior therapy, including experimental therapy; history of recurrent Grade 3 or 4 4 toxicity from anti-MET therapy; uncontrolled diabetes, defined as fasting glycemia 150 mg/dL; active, untreated viral, bacterial or systemic fungal infection; any clinical finding, including psychiatric and behavioral problems; childbearing potential (unless an adequate measure of contraception was used); pregnancy or lactation; history of severe (Grade 3 or 4 4) hypersensitivity to recombinant proteins. 2.6. Rationale for Dose Selection and Treatment The highest ARGX-111 dose used in the DE was calculated based on a NOAEL of 30 mg/kg observed in cynomolgus monkeys (= 0.0174; ** = 0.0005. To explore the tissue targeting potential as a consequence of the FcRn-induced transport into the tissues, a biodistribution study in the hemizygous human FcRn transgenic mouse strain Tg32 [15] was performed. To this end, ARGX-111 and G52-WT were modified with the chelator Fe-TFP-2+/3+ intensity). Gastric, esophagus and kidney cancers displayed the highest positivity (63%) for MET expression (Figure S1A). Of these 70 positive patients, 19 matched all the eligibility criteria and were included in the DE phase. In the SE, a total of 428 patients were prescreened for amplification by FISH, of which 15 (3.5%) matched the positivity criteria for the SE (ratio Omtriptolide 2). Lung and gastric cancers displayed the highest frequency of amplifications (Figure S1B). Of these 15 positive patients, 5 were eligible and were enrolled in the SE phase. The archived biopsies of the SE patients were further analyzed by IHC. This analysis revealed that the tumors bearing high copy number (5) also displayed a high Rabbit Polyclonal to CBR1 percentage of cells expressing MET (80%) and high MET expression levels (intensity 2; Table S1). No clinically relevant difference regarding demographic characteristics.