Study of Ferumoxytol Enhanced MRI for Detecting Lymph Node Metastases in Prostate, Bladder, and Kidney Cancers

Evaluation of Ferumoxytol Enhanced MRI for the Detection of Lymph Node Metastases in Genitourinary (Prostate, Bladder and Kidney) Cancers

Background:

People with prostate, bladder, or kidney cancer often have their cancer spread (metastasize) to lymph nodes. It is important for your doctor to know if this has occurred but currently it can be hard to determine if this has occurred on standard imaging studies like computed tomography (CT) or magnetic resonance imaging (MRI). This study uses an agent called Ferumoxytol to identify lymph nodes that might be involved by cancer.

Objective:

- To see how well Ferumoxytol can detect lymph node metastases in patients with prostate, bladder, or kidney cancer.

Eligibility:

-Adults over age 18 with prostate, bladder, or kidney cancer with lymph node involvement.

Design:

• Participants will be screened with a medical history.
• Participants will have blood drawn and a physical exam. Their vital signs will be measured. They will answer questions about their health and current medications.
• Participants should not have a history of iron overload or have an allergy to Ferumoxytol.
• Participants will have a magnetic resonance imaging (MRI) scan. The scanner is a metal cylinder with a strong magnetic field. Participants will lie on a table that slides in and out of the scanner. They will have a standard sensor, known as a coil, wrapped around their abdomen to improve the scan. This is like a small blanket with wiring inside. Participants will need to lie still on the scanning table for about 1 hour.
• Participants will have an ultrasound. This uses harmless sound waves to provide pictures of organs or tissues inside the body.
• Participants will receive an injection of Ferumoxytol through an intravenous line. A very thin plastic tube will be inserted into a vein in order to inject the agent.
• Participants will have another MRI and ultrasound 24 and 48 hours after injection.
• The study will follow participants medical course for at least 1 year.

Study Overview

• Status: Completed
• Conditions: Kidney Cancer; Prostate Cancer; Bladder Cancer
• Intervention / Treatment: Drug: Ferumoxytol; Diagnostic test: Magnetic Resonance Imaging (MRI)

Detailed Description

Background:

• Conventional imaging modalities (e.g. computed tomography [CT] and magnetic resonance imaging [MRI]) are currently used for the detection of lymph node metastases in many cancer types, including prostate, bladder and kidney cancers, however diagnosis is based on node enlargement which is neither sensitive nor specific (i.e. small nodes harbor metastases, large nodes can be hyperplastic).
• As a consequence, the standard of care is to remove numerous lymph nodes during surgery or to biopsy enlarged nodes to ascertain lymph node status.
• In 2003 Dextran coated ultra small superparamagnetic iron oxide particles (USPIO), also known as Ferumoxtran-10 (Combidex, AMAG Pharmaceuticals, Inc. Lexington, Massachusetts (MA), United States (US)) was shown to localize lymph node metastases with much greater accuracy than unenhanced MRI. Although a large study in prostate cancer was successful, and Food and Drug Administration (FDA) Advisory Panel did not recommend approval and the company abandoned the agent.
• In 2009 Ferumoxytol (Feraheme AMAG Pharmaceuticals, Inc. Lexington, MA, United States (US)) a semi-synthetic carbohydrate coated, magnetic iron oxide preparation similar to ferumoxtran 10 was approved for iron replacement therapy. Like ferumoxtran 10, this compound is taken up by normal lymph nodes and excluded from malignant nodal tissue.
• Results of a recent National Cancer Institute (NCI) trial (11-C-0098) in 15 patients revealed that using the dose of 7.5 mg/kg Fe is safe and yields homogenous and accurate signal changes in benign lymph nodes in comparison with the 4 and 6 mg/kg Fe doses. This dose was further tested in 5 patient's with known or suspected nodal involvement from prostate cancer and in four of five patients positive lymph nodes had a lower signal drop than the benign nodes. The one case in which there was uptake by positive nodes may have been on a vascular basis. This pilot study stimulated interest in a larger study involving a variety of cancer types.

Primary Objective:

-To compare the difference in signal between metastatic and normal nodes in prostate, kidney and bladder cancer patients.

Eligibility

• Subject must be greater than or equal to 18 years old.
• Eastern Cooperative Oncology Group Performance score of 0 to 2.
• There are 3 parallel arms in this study. All patients must have evidence of lymph node involvement (with a short axis diameter greater than or equal to 1.5 cm).
• In addition:
• Arm 1: Subject must have a documented diagnosis of prostate cancer.
• Arm 2: Subject must have a documented diagnosis of bladder cancer (transitional cell carcinoma).
• Arm 3: Subject must have a documented diagnosis of kidney cancer (all renal cell cancer types).

Design:

• This is a single site 3-arm (arm 1=prostate cancer, arm 2=bladder cancer, arm 3=kidney cancer) study enrolling 50 evaluable patients (30 evaluable in each arm 1, 10 evaluable in arms 2 and 3) with documented prostate, bladder or kidney cancer with evidence of lymph node involvement [with a size of greater than or equal to 1.5 cm measured on conventional imaging (e.g. CT, MRI)].
• All subjects will undergo pre-infusion, 24, 48 hours post-Ferumoxytol infusion (dose of 7.5mg/kg Fe) MRI consisting of T1 weighted (W), T2W and T2*W 3 Tesla MRI.
• Imaging will be correlated with histology of resected or biopsied lymph nodes when available. Occasionally, patients may not undergo biopsy or surgical excision of their lymph nodes. This may occur if their lymph nodes are overtly large and therefore highly likely to represent lymph node involvement. In such cases, patients will be evaluated with clinical follow up which typically occurs every three months in most NCI protocols. If the lesion demonstrates growth or regression based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria on these follow up studies' then the lesion will be considered positive for tumor. If it is stable for at least one year, then it will be considered non-malignant. The MR imaging analysis will be intra-patient.
• Patients will also undergo ultrasound examination of imageable lymph nodes (e.g. inguinal nodes) at pre-infusion and 24, 48 hours post-Ferumoxytol infusion time points. The signal changes at post-infusion ultrasound will be visually evaluated to determine if the uptake of ferumoxytol alters sonographic features.

• Study Type: Interventional
• Enrollment (Actual): 43
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

• INCLUSION CRITERIA

2.1.1.1 Subject must be greater than or equal to 18 years old.

2.1.1.2 Diagnosis

• Arm 1: Subject must have a documented diagnosis of prostate cancer with evidence of lymph node involvement (with a short axis diameter of greater than or equal to 1.5 cm on a conventional computed tomography (CT) or magnetic resonance (MRI) obtained within 8 weeks of the Ferumoxytol imaging procedure)
• Arm 2: Subject must have a documented diagnosis of bladder cancer (transitional cell carcinoma) with evidence of lymph node involvement (with a short axis diameter of greater than or equal to 1.5cm on a conventional CT or MRI obtained within 8 weeks of the Ferumoxytol imaging procedure)
• Arm 3: Subject must have a documented diagnosis of kidney cancer (all renal cell cancer types) with evidence of lymph node involvement (with a short axis diameter of greater than or equal to 1.5 cm on a conventional CT or MRI obtained within 8 weeks of the Ferumoxytol imaging procedure)

2.1.1.3 Subject must have Eastern Cooperative Oncology Group Performance score greater than or equal to 2.

2.1.1.4 Ability to provide informed consent. All subjects must sign an informed consent form indicating their understanding of the investigational nature and risks of the study before any protocol-related studies are performed.

2.1.EXCLUSION CRITERIA

2.1.2.1 Subjects with known hypersensitivity and allergy to iron.

2.1.2.2 Subjects with evidence of iron overload with a pre-study ferritin level greater than 370 ng/ml and percent saturation of transferrin level greater than 40%. Patients with lab values above these limits may be included in the study if documented hematology consultation rules out hemochromatosis, idiopathic or iatrogenic iron overload.

2.1.2.3 Subjects with any coexisting medical or psychiatric condition that is likely to interfere with study procedures and/or results.

2.1.2.4 Subjects with severe claustrophobia unresponsive to oral anxiolytics.

2.1.2.5 Subjects with contraindications to MRI.

2.1.2.6 Subjects weighing >136 kg (weight limit for scanner table).

2.1.2.7 Subjects with any type of pacemaker, cerebral aneurysm clips, shrapnel injury, or other implanted electronic devices or metal not compatible with MRI.

2.1.2.8 Subjects with abnormal liver function tests suggesting liver dysfunction (aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) greater than or equal to 3 x of the upper limits of normal; total bilirubin greater than or equal to 2 x the upper limits of normal or >3.0 mg/dl in patients with Gilbert's syndrome).

2.1.2.9 Subjects with other medical conditions deemed by the principal investigator (or associates) to make the subject ineligible for protocol procedures.

2.1.2.10 Women who are pregnant or breast-feeding. The effects of ferumoxytol on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for 1 day after study related imaging is completed. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

2.1.3 Inclusion of Women and Minorities.

Members of all races and ethnic groups are eligible for this trial. Women are excluded from arm 1 of this trial as prostate cancer does not occur in females.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ferumoxytol + Magnetic Resonance Imaging (MRI); Ferumoxytol +MRI	Drug: Ferumoxytol; 7.5mg/kg intravenous (IV) infusion; Other Names: Feraheme; Diagnostic test: Magnetic Resonance Imaging (MRI); 3 MRIs: pre-infusion, 24 and 48 hours post-infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage Change (From Baseline to 24 Hours) Between Metastatic and Benign Nodes	Visible nodes were quantified with manually contoured regions of interest on axial T2*W MRI to obtain the mean signal intensity (SInode). The SI of the visible lymph node was normalized using the mean SI of the adjacent muscle tissue on the same slice (SImuscle). The following equation was used to obtain the normalized SI from the lymph node (SInormal): SInormal=SInode/SImuscle. The calculation formula was 100% * ((SInormal(24hrs)- SInormal(baseline))/ SInormal(baseline)).This image processing method was performed at baseline, 24-hours post-injection MRI studies to define the SI change differences between benign and malignant lymph nodes from baseline to 24 hours post injection.	Baseline and 24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage Change for Imaging (From Baseline to 48 Hours) Between Metastatic and Benign Nodes	Visible nodes were quantified with manually contoured regions of interest on axial T2*W MRI to obtain the mean signal intensity (SInode). The SI of the visible lymph node was normalized using the mean SI of the adjacent muscle tissue on the same slice (SImuscle). The following equation was used to obtain the normalized SI from the lymph node (SInormal): SInormal=SInode/SImuscle. The calculation formula was 100% * ((SInormal(48hrs)- SInormal(baseline))/ SInormal(baseline))). This image processing method was performed at baseline, 48-hours post-injection MRI studies to define the SI change differences between benign and malignant lymph nodes from baseline to 48 hours post-injection.	Baseline to 48 hours post injection
Percent Change in Signal Difference Within Metastatic Nodes in Prostate, Kidney, Bladder Cancer Patients at Ultrasonography	Patients will undergo ultrasound examination of imageable lymph nodes at pre-infusion, 24 hours and 48 hours. The signal changes at post-infusion ultrasound will be visually evaluated to determine if the uptake of ferumoxytol alters sonographic features.	pre-infusion, 24 hours and 48 hours
Number of Participants With Serious and Non-Serious Adverse Events	Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.	Adverse events were assessed from the date treatment consent signed to date off study, approximately 3 years, 3 months, and 11 days on the Prostate Cancer Arm/Group; 2 years, 5 months, and 19 days on the Bladder Cancer Arm/Group, and 1 year, 6 months, and

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Ismail B Turkbey, M.D., National Cancer Institute (NCI)

Publications and helpful links

General Publications

• Blom JH, van Poppel H, Marechal JM, Jacqmin D, Schroder FH, de Prijck L, Sylvester R; EORTC Genitourinary Tract Cancer Group. Radical nephrectomy with and without lymph-node dissection: final results of European Organization for Research and Treatment of Cancer (EORTC) randomized phase 3 trial 30881. Eur Urol. 2009 Jan;55(1):28-34. doi: 10.1016/j.eururo.2008.09.052. Epub 2008 Oct 1.
• Birkhauser FD, Studer UE, Froehlich JM, Triantafyllou M, Bains LJ, Petralia G, Vermathen P, Fleischmann A, Thoeny HC. Combined ultrasmall superparamagnetic particles of iron oxide-enhanced and diffusion-weighted magnetic resonance imaging facilitates detection of metastases in normal-sized pelvic lymph nodes of patients with bladder and prostate cancer. Eur Urol. 2013 Dec;64(6):953-60. doi: 10.1016/j.eururo.2013.07.032. Epub 2013 Jul 30.
• Crispen PL, Breau RH, Allmer C, Lohse CM, Cheville JC, Leibovich BC, Blute ML. Lymph node dissection at the time of radical nephrectomy for high-risk clear cell renal cell carcinoma: indications and recommendations for surgical templates. Eur Urol. 2011 Jan;59(1):18-23. doi: 10.1016/j.eururo.2010.08.042. Epub 2010 Sep 15.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): May 15, 2014
• Primary Completion (Actual): November 20, 2018
• Study Completion (Actual): November 20, 2018

Study Registration Dates

• First Submitted: May 15, 2014
• First Submitted That Met QC Criteria: May 15, 2014
• First Posted (Estimate): May 19, 2014

Study Record Updates

• Last Update Posted (Actual): September 6, 2019
• Last Update Submitted That Met QC Criteria: September 5, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: Biopsy; Lymph Node; Metastatic Nodes; Imaging Agent
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplastic Processes; Neoplasm Metastasis; Kidney Neoplasms; Carcinoma, Renal Cell; Lymphatic Metastasis; Hematinics; Pharmaceutical Solutions; Parenteral Nutrition Solutions; Ferrosoferric Oxide
• Other Study ID Numbers: 140107; 14-C-0107

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No