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Genital Diseases

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Female Urogenital Diseases and Pregnancy Complications

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Hematinics

All Drugs and Chemicals

Liver Extracts

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.

EMD 525797

Medical Responsible

This study is intended to test an experimental drug called EMD 525797 (Abituzumab). This drug is not yet approved for sale and has only been tested in a small number of people to date (prior to this study starting another research study was carried out involving 37 healthy volunteers receiving the study drug). Until more is known about this study drug, it can only be used in research studies.

This research study is planned to answer important questions about how the study drug is tolerated and how it may work in subjects with ovarian and colorectal cancer which has spread to the liver (i.e. metastatic cancer). The Sponsor (Merck KGaA) of this study is developing the study drug.

EMD 525797 in Colorectal and Ovarian Cancer Patients With Liver Metastases

A Phase I, Open-label, Dose-escalation Study to Investigate the Safety, Tolerability, PD and PK of EMD 525797 Using DCE-MRI as a PK Measure of Response in Colorectal and Ovarian Cancer Patients With Liver Metastases After Failure of Standard Therapy

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.

An adverse event (AE) was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. 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. TEAEs were the AEs that occurred between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state.

Tumor response was assessed by the Investigator, based on Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0 criteria. Tumor response was defined as the presence of a "best overall response" of complete response (CR) or partial response (PR). CR: Disappearance of all target and non-target lesions and/or normalization of serum levels of tumor markers. PR: At least a 30 percent decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum of the LD of target lesions. The qualification of a CR or of a PR needed a confirmation by a second computed tomography (CT) scan at least 4 weeks after the first scan. Best overall response was derived programmatically as the best response recorded from the first investigation medicinal product administration until disease progression. Clinical benefit was defined as the presence of a "best overall response" of complete response or partial response or stable disease lasting at least 6 weeks.

The number of subjects who experienced worse post baseline shift were assessed as per ECOG performance status score recorded during the treatment. The ECOG score is categorized as Grade 0, 1, 2, 3 and 4 where Grade 0=fully active, Grade 1=restricted in physically strenuous activity, Grade 2=unable to carry out any work activities, Grade 3=capable of only limited self-care and Grade 4=completely disabled.

Subjects were defined as abituzumab positive if at least one positive result of antibodies against abituzumab was observed. In all other cases, subjects were defined as abituzumab negative.

PFS was defined as the time from first study drug intake until radiological progression (based on RECIST Version 1.0) or death due to any cause. Only deaths within 84 days of last tumor assessment are considered. Subjects without event were censored on the date of last tumor assessment. Investigator read was the assessment of all imaging by the treating physician at the local trial site.

Merck KGaA, Darmstadt, Germany

Abituzumab was administered as an intravenous infusion for an hour at a dose of 250 mg at Weeks 1, 3 and 5. In case of clinical benefit (SD, CR, or PR) as assessed by the RECIST Version 1.0 during initial 6 Weeks, subjects were allowed to continue treatment at the start of Week 7 at the given dose every second week until intolerance to treatment, withdrawal of consent, or the subject was no longer benefiting from treatment in the opinion of the Investigator.

Abituzumab 250 mg

Abituzumab was administered as an intravenous infusion for an hour at a dose of 500 mg at Weeks 1, 3 and 5. In case of clinical benefit (SD, CR, or PR) as assessed by the RECIST Version 1.0 during initial 6 Weeks, subjects were allowed to continue treatment at the start of Week 7 at the given dose every second week until intolerance to treatment, withdrawal of consent, or the subject was no longer benefiting from treatment in the opinion of the Investigator.

Abituzumab 500 mg

Abituzumab was administered as an intravenous infusion for an hour at a dose of 1000 mg at Weeks 1, 3 and 5. In case of clinical benefit (SD, CR, or PR) as assessed by the RECIST Version 1.0 during initial 6 Weeks, subjects were allowed to continue treatment at the start of Week 7 at the given dose every second week until intolerance to treatment, withdrawal of consent, or the subject was no longer benefiting from treatment in the opinion of the Investigator.

Abituzumab 1000 mg

Abituzumab was administered as an intravenous infusion for an hour at a dose of 1500 mg at Weeks 1, 3 and 5. In case of clinical benefit (SD, CR, or PR) as assessed by the RECIST Version 1.0 during initial 6 Weeks, subjects were allowed to continue treatment at the start of Week 7 at the given dose every second week until intolerance to treatment, withdrawal of consent, or the subject was no longer benefiting from treatment in the opinion of the Investigator.

Abituzumab 1500 mg

Total

Age, Continuous

Sex: Female, Male

All subjects analysis set included all subjects who entered the trial (that is, all subjects who signed informed consent).

Merck KGaA Communication Center

Dose escalation analysis set included all subjects in the safety analysis set who experienced any DLT during the DLT observation period, regardless of the number of investigational medicinal product (IMP) administrations and subjects who received the IMP at Weeks 1, 3, and 5 for Cohort 1 and at Weeks 1 and 3 for all other cohorts.

Number of Subjects With Dose Limiting Toxicities (DLTs)

Screening 1

Screening 2

Week 1 Day 2

Week 1 Day 5

Week 2 Day 1

The DCE-MRI analysis set included all subjects who had at least one valid predose scan and at least one valid postdose (that is, after the infusion) scan.

Volume Transfer Coefficient of Contrast Agent Across the Capillary Walls

TEAEs

Serious TEAEs

TEAEs leading to Discontinuation

TEAEs Leading to Death

The safety analysis set included all subjects who received at least one dose of IMP administration.

Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death

Progressive Disease

Not Assessable

Tumor Response

Clinical Benefit

The full analysis set included all subjects who received at least one dose of IMP administration. "N" signifies the total number of participants evaluable for this outcome measure. Same subjects may be reported in more than one category.

Number of Subjects With Best Overall Response, Tumor Response and Clinical Benefit

Number of Subjects With Worsened Post Baseline Shift in ECOG Performance Status Score

Week 1 Day 1 (n=9,11,7,7)

Week 3 Day 1 (n=9,11,7,7)

Week 5 Day 1 (n=6,9,6,2)

Week 6 Day 1 (n=0,6,5,2)

Week 7 Day 1 (n=0,5,5,2)

Week 8 Day 1 (n=4,0,0,0)

Week 11 (n=0,1,3,0)

EOS Visit (n=6,3,2,1)

The immunogenicity analysis set included all subjects who received at least one dose of study drug administration and provided sufficient data from the antibodies samples. 'N' (number of subjects analyzed) signifies the subjects evaluable for this outcome measure. "n" signifies the number of subjects evaluable for each time point, respectively.

Number of Subjects With Positive Binding Abituzumab Antibodies

Blood Plasma Volume: Screening 1

Blood Plasma Volume: Screening 2

Blood Plasma Volume: Week 1 Day 2

Blood Plasma Volume: Week 1 Day 5

Blood Plasma Volume: Week 2 Day 1

Extravascular Volume: Screening 1

Extravascular Volume: Screening 2

Extravascular Volume: Week 1 Day 2

Extravascular Volume: Week 1 Day 5

Extravascular Volume: Week 2 Day 1

Blood Plasma Volume and Extravascular/Extracellular Volume

Initial Area Under the DCE-MRI Contrast Agent Concentration Time Curve After 60 Seconds (IAUC60)

Whole Tumor Volume: Screening 1

Whole tumor volume: Screening 2

Whole tumor volume: Week 1 Day 2

Whole tumor volume: Week 1 Day 5

Whole tumor volume: Week 2 Day 1

EnhancingTumor Volume: Screening 1

Enhancing tumor volume: Screening 2

Enhancing tumor volume: Week 1 Day 2

Enhancing tumor volume: Week 1 Day 5

Enhancing tumor volume: Week 2 Day 1

Whole Tumor Volume and Enhancing Tumor Volume

Progression-Free Survival (PFS) Time

Abituzumab was administered as an intravenous infusion for an hour at a dose of 250 milligram (mg) at Weeks 1, 3 and 5. In case of clinical benefit (stable disease \[SD\], complete response \[CR\], or partial response \[PR\]) as assessed by the Response Evaluation Criteria in Solid Tumors version (RECIST) Version 1.0 during initial 6 Weeks, subjects were allowed to continue treatment at the start of Week 7 at the given dose every second week until intolerance to treatment, withdrawal of consent, or the subject was no longer benefiting from treatment in the opinion of the Investigator.

Overall Study

Spots Global Cancer Trial Database for colorectal and ovarian cancer patients with liver metastases