Uptake and Biodistribution of 89Zirconium-labeled Ipilimumab in Ipilimumab Treated Patients With Metastatic Melanoma (Zirconipi)

April 14, 2021 updated by: A.J.M. van den Eertwegh, Amsterdam UMC, location VUmc

Rationale:

Ipilimumab, a monoclonal antibody targeting CTLA-4, is approved for the treatment of metastatic melanoma and significantly increases median overall survival. However, use of this drug is associated with immune related adverse events (IRAEs) like colitis, hepatitis, dermatitis, alveolitis and hypophysitis in 10-40% of the patients. In general IRAEs are manageable by cessation of ipilimumab in combination with treatment with corticosteroids or TNF-alpha blockade but they can be severe or even life-threatening. In addition, treatment with ipilimumab is expensive. Because of the high costs and the potential serious toxicity of ipilimumab, it is of great importance to identify biomarkers that correlate with clinical activity and can be used to select patients that will benefit from CTLA-4 blockade therapy.

The investigators hypothesize that differences in response to treatment with ipilimumab are due to variability in the pharmacodynamics and -kinetics of the antibody. It is hypothesized that patients who do not respond to treatment with ipilimumab have lower drug levels in tumor tissues as compared to patients with a good response to therapy. In addition, the investigators hypothesize that IRAEs are associated with high drug levels in the affected tissue.

To visualize molecular interactions a novel technique is used in which positron emission tomography (PET) is combined with labeled monoclonal antibodies. Because ipilimumab induces activation of T-lymphocytes it is hypothesized that uptake of 89Zr-ipilimumab in tumor lesions and normal tissue is different (i.e. higher) after the second administration of ipilimumab (3 weeks after first injection). Therefore immuno-PET scans will be performed after the first and after the second injection of ipilimumab.

Objective:

Part one: The primary objective is:

1. To assess uptake (visual and quantitative) of 89Zr-ipilimumab in tumor lesions and biodistribution at two timepoints (at start of ipilimumab therapy and after the second injection 3 weeks later).

The secondary objectives are:

  1. To determine the correlation between tumor targeting of ipilimumab and response to therapy.
  2. To assess uptake (visual and quantitative) of 89Zr-ipilimumab in normal tissues.
  3. To determine de correlation between organ targeting and toxicity

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

see above

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Anticipated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
29

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Locations

  • Netherlands
    • Noord-Holland
      • Amsterdam, Noord-Holland, Netherlands, 1181HV
        • Recruiting
        • VU Medical Center
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Advanced/metastatic melanoma.
  • Scheduled for treatment with ipilimumab.
  • Age ≥ 18 years.
  • Histological or cytological documentation of cancer is required.
  • WHO Performance Status of 0 or 1.
  • At least 1 measurable lesion.
  • Signed informed consent must be obtained prior to any study procedures.
  • Patients must be able to adhere to the study appointments and other protocol requirements.

Exclusion Criteria:

  • Previous exposure to ipilimumab.
  • Pregnant or breast-feeding subjects. Women of childbearing potential must have a negative pregnancy test performed within 7 days of the start treatment. Both men and women enrolled in this trial must agree to use adequate barrier birth control measures (e.g. cervical cap, condom and diaphragm) during the course of the trial. Oral birth control methods alone will not be considered adequate on this study, because of the potential pharmacokinetic interaction between study drug and oral contraceptives. Concomitant use of oral and barrier contraceptives is advised. Contraception is necessary for at least 6 months after receiving study drug.
  • Concurrent anticancer chemotherapy, immunotherapy or investigational drug therapy during the study or within 4 weeks after starting the study drug.
  • Radiotherapy of target lesions during study or within 4 weeks after starting the study drug. Palliative radiotherapy will be allowed.
  • Major surgery within 28 days of start of study drug.
  • Substance abuse, medical, psychological or social conditions that may interfere with the subject's participation in the study or evaluation of the study results.
  • Any condition that is unstable or could jeopardize the safety of the subject and their compliance in the study.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: DIAGNOSTIC
  • Allocation: NA
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
EXPERIMENTAL: Zirconium-ipilimumab
Zirconium-ipilimumab is an experimental tracer and is administered at start of ipilimumab treatment and after second infusion 3 weeks later
Biological: 89Zirconium-labeled ipilimumab
Metastatic melanoma patients, who are treated with ipilimumab (3 mg/kg), will be infused with 89Zr-labeled ipilimumab within 2 hours after injection of the first and second standard ipilimumab doses. Peripheral blood mononuclear cells (PBMCs) will be collected for immunomonitoring.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
The detection of 89Zr-ipilimumab in tumor lesions
Time Frame: 3 weeks
The detection (visual and quantitative) of 89Zr-ipilimumab in tumor lesions (the short axis diameter of a measurable tumor lesion is ≥1 cm. The five largest lesions will be used for evaluation).
3 weeks

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
The visual detection of 89Zr-ipilimumab in normal tissue
Time Frame: 3 weeks
The visual detection of 89Zr-ipilimumab in normal tissue after the first injection of ipilimumab and after the second injection 3 weeks later. Visual: Description of the biodistribution.
3 weeks
The quantitative detection of 89Zr-ipilimumab in normal tissue
Time Frame: 3 weeks
The quantitative detection of 89Zr-ipilimumab in normal tissue after the first injection of ipilimumab and after the second injection 3 weeks later. Quantitative: The % uptake (of total injected) 89Zr-ipilimumab in normal tissue, measured in VOI's.
3 weeks
Comparison between uptake of 89Zr-ipilimumab
Time Frame: 3 weeks
Comparison between uptake (SUVmean and SUVpeak) of 89Zr-ipilimumab after the first injection of ipilimumab and after the second injection 3 weeks later.
3 weeks
Clinical outcome (response)
Time Frame: Every 12 weeks, from date of starting therapy until the date of first documented progression or date of death from any cause, whichever came first. Assessed through study completion, an average of 1 year
Response after starting therapy with ipilimumab at 12 and 24 weeks and every 12 weeks thereafter
Every 12 weeks, from date of starting therapy until the date of first documented progression or date of death from any cause, whichever came first. Assessed through study completion, an average of 1 year
Clinical outcome (survival)
Time Frame: Through study completion, an average of 1 year
Overall survival
Through study completion, an average of 1 year
Side effects
Time Frame: Until 30 days after the last immuno-PET scan
  • Adverse events using Common Terminology Criteria Adverse Events, version 4.0 (CTCAE 4.0)
  • Correlation between side effects of ipilimumab and uptake of 89Zr-ipilimumab in normal tissue
Until 30 days after the last immuno-PET scan
Pharmacokinetics of 89Zr-ipilimumab
Time Frame: 144 hours after first injection of 89Zr-ipilimumab
Pharmacokinetics of 89Zr-ipilimumab. The concentration of ipilimumab in blood samples will be measured at t = 5, 30, 60, 120 minutes and 72, 144 hours after injection of 89Zr-ipilimumab in the first three patients.
144 hours after first injection of 89Zr-ipilimumab
CTLA-4+CD4+ expression of PBMCs
Time Frame: Before start of ipilimumab and during treatment, up to 11 weeks
Before start of ipilimumab and during treatment, up to 11 weeks
Immunohistochemical analysis
Time Frame: 3 weeks
Immunohistochemical analysis (% of tissue with inflammatory infiltrate and characterization of intratumoral T-lymphocytes (CD4, CD8, HLA-DR, FOX-P3, CTLA-4) of tumor biopsy
3 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Amsterdam UMC, location VUmc

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Bristol-Myers Squibb

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Alfonsus JM van den Eertwegh, Prof.dr., Amsterdam Umc, Location Vumc

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
February 16, 2017

Primary Completion (ANTICIPATED)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
February 15, 2022

Study Completion (ANTICIPATED)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
February 15, 2022

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
August 8, 2017

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
October 17, 2017

First Posted (ACTUAL)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
October 18, 2017

Study Record Updates

Last Update Posted (ACTUAL)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
April 15, 2021

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 14, 2021

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
April 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 2015.300

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.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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