EMD 525797

DLT was defined as any Grade 4 hematologic toxicity or Grade 3/4 non-hematologic toxicity assessed as related to trial treatment by the Investigator and/or Sponsor and confirmed by the safety monitoring committee (SMC) to be relevant to the combination treatment within the first cycle of therapy. Any Grade 3 or 4 non haematological toxicity, any Grade 4 hematological toxicity, treatment related deaths within the first 2 weeks of therapy. Toxicities excluded from DLT: alopecia, rash, nausea, vomiting and hypomagnesemia of Grade 3 or 4 severity, Grade 4 neutropenia or leukopenia lasting for =\< 5 days and not associated with fever; Single laboratory values out of normal range without any clinical correlation and resolve within 7 days; Grade 3 or 4 diarrhoea without adequate supportive care. Adequate supportive care has been administered and Grade 4 diarrhea persists (investigator decision); isolated Grade 4 lymphocytopenia and thrombocytopenia without clinical correlation.

PFS was defined as the time from the randomization date to first documented sign of objective radio-graphic disease progression (PD) as per Response Evaluation Criteria In Solid Tumors version 1. (RECIST 1.0) or death from any cause if reported within 12 weeks from the last tumor assessment. PD per RECIST v 1.0 was defined as at least 20% increase in the sum of the longest diameter of target lesions, taking as the reference the smallest sum of longest diameters recorded since treatment started, or unequivocal progression of existing non-target lesion or appearance of new lesions. Subjects who did not progress or died at the time of analyses, or subjects who died without previously radio-graphically documented PD and death was observed after more than 12 weeks of last tumor assessment without progression, these subjects were censored at their last tumor assessment date or date of randomization, whichever occurred last.

Toxicity was graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. A DLT was defined as any Grade 3 or 4 haematological or non-haematological toxicity occurring during the first 4 weeks of treatment (that is, until the beginning of Week 5, with the exception of Grade 3 asymptomatic increase in liver function tests (aspartate aminotransferase \[AST\], alanine aminotransferase \[ALT\], and alkaline phosphatase \[ALP\]) returning to Baseline within 7 days.), at any dose level, for which a causal relationship to the investigative medicinal product could not be ruled out by the Investigator and/or the Sponsor.

Volume transfer coefficient was defined as the volume transfer coefficient of contrast agent across the capillary wall, reflecting endothelial permeability and blood flow. Volumetric transfer coefficient was measured by dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). DCE-MRI is a noninvasive quantitative method of investigating microvascular structure and function by tracking the pharmacokinetics of injected low molecular weight contrast agents as they pass through tumor vasculature.

Blood plasma volume and extracellular/extravascular volume was measured using DCE-MRI.

IAUC 60 was used to give a gross indication of the delivery and uptake of contrast agent within the tumor (indicating the degree of perfusion and endothelial permeability. IAUC60 was measured using DCE-MRI.

Tumor volume (three-dimensional measurement) and the enhancing fraction of the tumor, which provides a gross measure of the proportion of the tumor that has a measurable level of perfusion, were assessed using DCE-MRI.

DLT was defined using National Cancer Institute Common Toxicity Criteria for Adverse Events Version 3.0 as any Grade 3 or 4 hematological or non-hematological toxicity occurring at any dose level until the end of Week 6, and suspected to be reasonably related to the investigational product by the Investigator and/or Sponsor except for allergic/ hypersensitivity reactions and any Grade 3/4 out-of-range laboratory values without any clinical correlate, which were reversible within 7 days.

An AE was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Treatment-emergent are events between first dose of study drug that were absent before treatment or that worsened relative to pre-treatment state. TEAEs include both Serious TEAEs and non-serious TEAEs.Treatment-related are events which had causal relationship to study drug as assessed by the Investigator and were suspected to be reasonably related to the study drug.

Area under the serum concentration-time curve from time zero to the last sampling time at which the concentration is at or above lower limit of quantification (LLQ). AUC0-t was calculated according to the mixed log linear trapezoidal rule.

Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Total body clearance of drug from serum, calculated as CL = dose/AUC0-inf. Where AUC0-inf is area under the serum concentration time curve from time zero to infinity, calculated as AUC0 t + AUCextra. AUCextra represents an extrapolated value obtained by Clast/λz, where Clast is the calculated serum concentration at the last sampling time point at which the measured serum concentration is at or above lower limit of quantification (LLQ) and λz is elimination rate constant.

Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. Apparent volume of distribution during the terminal phase, calculated as = Dose/(AUC0-inf \*λz) after first infusion. Where 'λz' is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Where AUC0-inf is area under the serum concentration time curve from time zero to infinity, calculated as AUC0 t + AUCextra. AUCextra represents an extrapolated value obtained by Clast/λz, where Clast is the calculated serum concentration at the last sampling time point at which the measured serum concentration is at or above lower limit of quantification (LLQ) and λz is elimination rate constant.

Ctrough is the concentration prior to study drug administration.

Ctrough is the concentration prior to study drug administration.

Ctrough is the concentration prior to study drug administration.