Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
EMD 525797 · 4 trials · 5 indications
DLT was defined as any Grade 3 or 4 haematological or non-haematological toxicity occurring at any dose level until the end of Week 4, and suspected to be reasonably related to the investigational medicinal product by the Investigator and/or Sponsor. Toxicities not considered to be DLTs are as follows- Allergic reactions or anaphylaxis; any Grade 3 or 4 out-of-range laboratory values without any clinical correlate, which were reversible within 7 days, unless the Investigator decided this event is clinically significant. For this reason Grade 3 or 4 out-of-range laboratory values must be re-assessed within 7 days. In case the Investigator provides the subject any treatment(s) due to the out-of-range laboratory values, the event was regarded as a DLT.
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).
Area under the serum concentration-time curve from time zero to the last sampling time at which the concentration is at or above LLQ.
Total body clearance of drug in serum was calculated: as CL= Dose divided by Area under the serum concentration-time curve from time zero to infinity (AUC0-inf).
Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. CL of drug in serum was calculated as : CL= Dose/ AUC0-inf. Area under the serum concentration-time curve from time zero to infinity (AUC0-inf), 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 LLQ and λz is the elimination rate constant.
Apparent volume of distribution during the terminal phase, calculated as Vz = Dose/AUC0-inf multiplied by elimination rate constant \[λz\]) following single dose. Area under the serum concentration-time curve from time zero to infinity, calculated (AUC0-inf) 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 LLQ and λz is the elimination rate constant. And the elimination rate constant obtained from linear regression of the terminal phase of the log transformed concentration-time data. A minimum of three points is required to calculate λz.
The observed serum concentration immediately before next dosing determined directly from the serum concentration-time profile of each subject (= trough concentration).
Apparent volume of distribution during the terminal phase, calculated as Vz = Dose/(Area under the serum concentration-time curve within one complete dosing interval \[AUCtau\]\* λz) following multiple dose.
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.
| Arm | Type | Description |
|---|---|---|
| EMD525797 250 milligram (mg) | EXPERIMENTAL | - |
| EMD525797 500 mg | EXPERIMENTAL | - |
| EMD525797 1000 mg | EXPERIMENTAL | - |
| EMD525797 1500 mg | EXPERIMENTAL | - |
| Safety part: EMD 525797 250 mg + Standard of Care (SoC) | EXPERIMENTAL | EMD 525797 250 mg in combination with cetuximab and irinotecan |
| Safety part: EMD 525797 500 mg + SoC | EXPERIMENTAL | EMD 525797 500 mg in combination with cetuximab and irinotecan |
| Safety part: EMD 525797 750 mg + SoC | EXPERIMENTAL | EMD 525797 750 mg in combination with cetuximab and irinotecan |
| Safety part: EMD 525797 1000 mg + SoC | EXPERIMENTAL | EMD 525797 1000 mg in combination with cetuximab and irinotecan |
| Randomized part: EMD 525797 500 mg + SoC | EXPERIMENTAL | EMD 525797 500 mg in combination with cetuximab and irinotecan |
| Randomized Part: EMD 525797 1000 mg + SoC | EXPERIMENTAL | EMD 525797 1000 mg (or dose as defined by safety monitoring committee (SMC)\] in combination with cetuximab and irinotecan. |
| Randomized Part: SoC | OTHER | Cetuximab and irinotecan |
| EMD 525797 | EXPERIMENTAL | - |
| Name | Type | Description |
|---|---|---|
| EMD525797 | BIOLOGICAL | Subjects will receive 250 milligram (mg) of EMD525797 intravenously every 2 weeks, until progressive disease (PD), unacceptable toxicity or withdrawal of consent. |
| EMD 525797 250 mg | DRUG | EMD 525797 will be administered at a target dose of 250 mg as a 1-hour intravenous infusion for every 2 week until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent . |
| EMD 525797 500 mg | DRUG | Safety part: EMD 525797 will be administered at a target dose of 500 mg as a 1-hour intravenous infusion for every 2 weeks until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent . Randomized part: EMD 525797 will be administered at a target dose of 500 mg as a 1-hour intravenous infusion for every 2 weeks until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent. |
| EMD 525797 750 mg | DRUG | EMD 525797 will be administered at a target dose of 750 mg as a 1-hour intravenous infusion for every 2 weeks until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent . |
| EMD 525797 1000 mg | DRUG | Safety part: EMD 525797 will be administered at a target dose of 1000 mg as a 1-hour intravenous infusion for every 2 weeks until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent . Randomized part: EMD 525797 will be administered at a target dose of 1000 mg as a 1-hour intravenous infusion for every 2 weeks until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent. |
| Cetuximab | DRUG | Safety part: Cetuximab will be administered at a dose of 400 milligram per square meter (mg/m\^2) on Day 1 Cycle 1 (Week 1) as IV infusion for 2 hours, and then at a dose of 250 mg/m\^2 on Day 8 (Week 2) once weekly until DLT. Randomized part: Cetuximab will be administered at a dose of 400 milligram per square meter (mg/m\^2) on Day 1 Cycle 1 (Week 1) as IV infusion for 2 hours, and then at a dose of 250 mg/m\^2 on Day 8 (Week 2) once weekly until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent. |
| Irinotecan | DRUG | Safety part: Irinotecan will be administered at a dose of 180 mg/m\^2 as IV infusion for 30-90 minutes for every 2 weeks until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent . Randomized part: Irinotecan will be administered at a dose of 180 mg/m\^2 as IV infusion for 30-90 minutes for every 2 weeks until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent. |
| EMD 525797 | BIOLOGICAL | Abituzumab will be administered as an intravenous infusion for an hour at a dose of 250 milligram (mg) to 1500 mg at Weeks 1, 3 and 5. In case of clinical benefit (stable disease \[SD\], complete response \[CR\], or partial response \[PR\]) that will be assessed by the Response Evaluation Criteria in Solid Tumors (RECIST Version 1.0) during initial 6 Weeks, subjects will be allowed to continue treatment at the start of Week 7 at the given dose (250 mg or 500 mg or 1000 mg or 1500 mg) every second week until intolerance to treatment, withdrawal of consent, or the subject is no longer benefiting from treatment in the opinion of the Investigator. |
Inclusion Criteria: * Age greater than or equal to (\>=) 20 years * Histologically or cytologically proven advanced or metastatic solid tumor * Evidence of progressive disease after standard chemotherapy or no standard chemotherapy * Confirmation of availability of formalin-fixed paraffin-embedded ...
EMD 525797 is an investigational monoclonal antibody developed by Merck KGaA for the treatment of solid tumors. It has been studied in colorectal and ovarian cancer patients with liver metastases, metastatic colorectal cancer, prostate cancer, and other solid tumors. It remains in Phase 1 clinical development and is not approved for any indication.
EMD 525797 is developed by Merck KGaA, which trades over the counter in the United States under the ticker MKGAF. The company sponsored the Phase 1 clinical program evaluating the monoclonal antibody across several solid tumor types, including metastatic colorectal cancer and prostate cancer.
EMD 525797 is in Phase 1 clinical development. All four of its recorded trials were Phase 1 studies, and all have been completed. The drug is investigational and has not been approved by the FDA or any other regulatory agency for commercial use.
EMD 525797 has been evaluated in four completed Phase 1 trials: NCT01327313 in Japanese solid tumor patients, NCT01008475 in K-ras wild type metastatic colorectal cancer combined with cetuximab and irinotecan, NCT00958477 in prostate cancer with bone metastases, and NCT00848510 in colorectal and ovarian cancer patients with liver metastases.
Yes. EMD 525797, EMD525797, and EMD 525797 250 mg all refer to the same investigational monoclonal antibody from Merck KGaA. The variations are formatting differences in how the compound code is written, and the 250 mg label refers to a dose strength used in study documentation.
EMD 525797 was studied in metastatic colorectal cancer in a Phase 1 trial combining it with cetuximab and irinotecan in patients with K-ras wild type tumors. That study, NCT01008475, enrolled 232 patients across Europe and Israel and has been completed. The drug is not approved for this or any other use.