Colorectal and Ovarian Cancer Patients With Liver Metastases Clinical Trial
Official title:
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
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.
| Status | Completed |
| Enrollment | 41 |
| Est. completion date | November 2013 |
| Est. primary completion date | November 2013 |
| Accepts healthy volunteers | No |
| Gender | Both |
| Age group | 18 Years and older |
| Eligibility |
Inclusion Criteria: - Provision of signed written informed consent - Male or female subjects, aged at least 18 years - Subjects with liver metastases (3 to 10 centimeter [cm] diameter) from colorectal and ovarian cancers - Failure of standard cancer therapy - Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 at study entry and an estimated life expectancy of at least 3 months - Adequate haematological function, defined by absolute neutrophil count (ANC) greater than or equal to (>=) 1.5 x 10^9 per liter (/L), platelet count >= 100 x 10^9 / L, and haemoglobin concentration >= 9 gram per deciliter (g/dL) - As subjects with documented liver metastases are treated in this trial, liver function test values are accepted as followed: up to the upper limit of Grade 2 as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0. This includes total bilirubin level less than or equal to (=<) 3 times the upper limit of normal (ULN), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels =<5 x ULN - Adequate renal function defined by serum creatinine =<1.5 x ULN or a creatinine clearance of >=50 milliliter per minute (mL/min) calculated by Cockcroft-Gault - Effective contraception (example: double barrier method) for both male and female subjects if the risk of conception exists. These subjects must be willing to avoid pregnancy during the study (screening to end of study [EOS]) as well as for at least 3 months after the last dosing. Exclusion Criteria: - Any systemic cancer treatment within 30 days before treatment with EMD 525797 - Thrombolytics or oral or parenteral anticoagulants (except to maintain patency of preexisting, permanent indwelling intravenous catheters) within 10 days prior to study start and during treatment - Radiotherapy, chemotherapy, surgery, or any investigational drug in the 30 days before the start of treatment in this study, and/or diagnostic biopsies within 2 weeks before the start of treatment in this study - Previous treatment with anti-integrin therapy or anti angiogenic therapy within the last 6 months - Confirmed or clinically suspected brain metastases - Known hypersensitivity reactions to the study medication - History of allergic reactions to other monoclonal antibody (mAb) therapy - Uncontrolled hypertension (systolic blood pressure greater than (>) 180 millimeter of mercury (mmHg), diastolic >100 mmHg) - Current history of chronic daily aspirin therapy (doses of =< 150 mg is permitted), bleeding disorders, and/or history of thromboembolic events - Severe peripheral vascular disease or ulceration - Unstable angina pectoris, or myocardial infarction within 6 months before start of study treatment, clinical significant abnormal electrocardiogram (ECG) at screening; - In women of childbearing potential, pregnancy (absence to be confirmed by beta human chorionic gonadotropin [ß HCG] test, unless a subject has previously undergone hysterectomy or bilateral ovariectomy), or lactation period - Known alcohol or drug abuse - Participation in another clinical trial within the past 30 days before start of study treatment - All other significant diseases which, in the opinion of the principal investigator (PI), might impair the subject's tolerance of study treatment - Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent - Legal incapacity or limited legal capacity (not applicable only in rare cases) - Known human immuno deficiency (HIV) infection and/or active hepatitis B or C virus infections - Ongoing uncontrolled infections - Contraindications to magnetic resonance imaging (MRI) |
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
| Country | Name | City | State |
|---|---|---|---|
| United Kingdom | Christie Hospital | Manchester |
| Lead Sponsor | Collaborator |
|---|---|
| Merck KGaA |
United Kingdom,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Number of Subjects With Dose Limiting Toxicities (DLTs) | 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. | Up to Week 4 | Yes |
| Primary | Volume Transfer Coefficient of Contrast Agent Across the Capillary Walls | 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. | Screening 1, screening 2, Week 1 Day 2, Week 1 Day 5, and Week 2 Day 1 | No |
| Primary | Blood Plasma Volume and Extravascular/Extracellular Volume | Blood plasma volume and extracellular/extravascular volume was measured using DCE-MRI. | Screening 1, screening 2, Week 1 Day 2, Week 1 Day 5, and Week 2 Day 1 | No |
| Primary | Initial Area Under the DCE-MRI Contrast Agent Concentration Time Curve After 60 Seconds (IAUC60) | 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. | Screening 1, screening 2, Week 1 Day 2, Week 1 Day 5, and Week 2 Day 1 | No |
| Primary | Whole Tumor Volume and Enhancing Tumor Volume | 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. | Screening 1, screening 2, Week 1 Day 2, Week 1 Day 5, and Week 2 Day 1 | No |
| Secondary | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death | 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. | From the initiation of the trial treatment until 30 days after last administration of trial treatment. | Yes |
| Secondary | Number of Subjects With Best Overall Response, Tumor Response and Clinical Benefit | 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. | Up to 4 years | No |
| Secondary | Number of Subjects With Worsened Post Baseline Shift in ECOG Performance Status Score | 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. | Up to 4 weeks after last dose administration | No |
| Secondary | Number of Subjects With Positive Binding Abituzumab Antibodies | 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. | Day 1 of Weeks 1, 3, 5, 6, 7, 8, and week 11 and end of study (EOS) visit (4 weeks after last dose administration) | No |
| Secondary | Progression-Free Survival (PFS) Time | 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. | Time from first study drug intake to disease progression, death or last tumor assessment until end of trial visit (4 weeks after last dose administration) | No |