MelanomaPhase 2ZirconipiNCT03313323
Uptake and Biodistribution of 89Zirconium-labeled Ipilimumab in Ipilimumab Treated Patients With Metastatic Melanoma
A Phase 2 study testing 89Zirconium-labeled ipilimumab in people with Melanoma, run by Amsterdam UMC, location VUmc at 1 site in Netherlands.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Melanoma
- What is being tested?
- 89Zirconium-labeled ipilimumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 29 participants
- Where
- 1 siteNetherlands
- Study dates
- 16 Feb 2017to 15 Feb 2022
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
Netherlands1 site, 1 recruiting
- Recruiting
VU Medical Center
Amsterdam, North Holland, 1181HV
Alfonsus MJ van den Eertwegh, Dr., +31 (0)20-4444321, vandeneertwegh@vumc.nl
About this study
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.
Read more
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:
- 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:
- To determine the correlation between tumor targeting of ipilimumab and response to therapy.
- To assess uptake (visual and quantitative) of 89Zr-ipilimumab in normal tissues.
- To determine de correlation between organ targeting and toxicity
Read the detailed description
see above
- Conditions
- Melanoma
- Being tested
- 89Zirconium-labeled ipilimumab
- Keywords
- Immuno-PET, Ipilimumab, Immunotherapy
- Medical subject headings
- Melanoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
89Zirconium-labeled ipilimumabBiological
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.
| Study group | Role | What they receive |
|---|---|---|
| Zirconium-ipilimumab | Experimental | Zirconium-ipilimumab is an experimental tracer and is administered at start of ipilimumab treatment and after second infusion 3 weeks later Receives: Biological: 89Zirconium-labeled ipilimumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
The detection of 89Zr-ipilimumab in tumor lesions
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).
Measured: 3 weeks
Secondary outcomes (9)
The visual detection of 89Zr-ipilimumab in normal tissue
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.
Measured: 3 weeks
The quantitative detection of 89Zr-ipilimumab in normal tissue
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.
Measured: 3 weeks
Comparison between uptake of 89Zr-ipilimumab
Comparison between uptake (SUVmean and SUVpeak) of 89Zr-ipilimumab after the first injection of ipilimumab and after the second injection 3 weeks later.
Measured: 3 weeks
Clinical outcome (response)
Response after starting therapy with ipilimumab at 12 and 24 weeks and every 12 weeks thereafter
Measured: 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)
Overall survival
Measured: Through study completion, an average of 1 year
Side effects
- 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
Measured: Until 30 days after the last immuno-PET scan
Pharmacokinetics 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.
Measured: 144 hours after first injection of 89Zr-ipilimumab
CTLA-4+CD4+ expression of PBMCs
Measured: Before start of ipilimumab and during treatment, up to 11 weeks
Immunohistochemical analysis
Immunohistochemical analysis (% of tissue with inflammatory infiltrate and characterization of intratumoral T-lymphocytes (CD4, CD8, HLA-DR, FOX-P3, CTLA-4) of tumor biopsy
Measured: 3 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Oct 2017
- Study start16 Feb 2017
- Primary completion15 Feb 2022 (estimated)
- Study completion15 Feb 2022 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for MelanomaStudies of the same condition, open and under way.
- More trials run by Amsterdam UMC, location VUmcThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Diagnosis
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 29 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Amsterdam UMC, location VUmc
- Sponsor type
- University, hospital or other
- Collaborators
- Bristol-Myers Squibb
- Responsible party
- Principal investigator, A.J.M. van den Eertwegh, Amsterdam UMC, location VUmc
- Investigators
- Alfonsus JM van den Eertwegh, Prof.dr., Principal investigator, Amsterdam UMC, location VUmc
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03313323
- Sponsor's protocol ID
- 2015.300
- Acronym
- Zirconipi
- Status last verified
- Apr 2021
- First submitted
- 8 Aug 2017
- Last updated
- 15 Apr 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 15 Apr 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Uptake and Biodistribution of 89Zirconium-labeled Ipilimumab in Ipilimumab Treated Patients With Metastatic Melanoma
- ClinicalTrials.gov ID
- NCT03313323
- Acronym / sponsor ID
- Zirconipi / 2015.300
- Conditions
- Melanoma
- Keywords
- Immuno-PET, Ipilimumab, Immunotherapy
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 29 participants (estimated)
- Lead sponsor
- Amsterdam UMC, location VUmcUniversity, hospital or other
- Collaborators
- Bristol-Myers Squibb
- Study start
- 16 Feb 2017 (actual)
- Primary completion
- 15 Feb 2022 (estimated)
- Study completion
- 15 Feb 2022 (estimated)
- First posted
- 18 Oct 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- 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:
- To determine the correlation between tumor targeting of ipilimumab and response to therapy.
- To assess uptake (visual and quantitative) of 89Zr-ipilimumab in normal tissues.
- To determine de correlation between organ targeting and toxicity
Detailed description
see above
Study design
- Primary purpose
- Diagnosis
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Zirconium-ipilimumab | Experimental | Biological: 89Zirconium-labeled ipilimumabZirconium-ipilimumab is an experimental tracer and is administered at start of ipilimumab treatment and after second infusion 3 weeks later |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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.
Key exclusion criteria (7 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| 89Zirconium-labeled ipilimumabMetastatic 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. | Biological | Zirconium-ipilimumab |
Primary outcome
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).
9 secondary outcomes
The visual detection of 89Zr-ipilimumab in normal tissue
Time frame: 3 weeks
The quantitative detection of 89Zr-ipilimumab in normal tissue
Time frame: 3 weeks
Comparison between uptake of 89Zr-ipilimumab
Time frame: 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
Clinical outcome (survival)
Time frame: Through study completion, an average of 1 year
Side effects
Time frame: Until 30 days after the last immuno-PET scan
Pharmacokinetics of 89Zr-ipilimumab
Time frame: 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
Immunohistochemical analysis
Time frame: 3 weeks
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Apr 2021.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Alfonsus JM van den Eertwegh, Prof.dr. principal investigator
Amsterdam UMC, location VUmc
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing 89Zirconium-labeled ipilimumab in people with Melanoma, run by Amsterdam UMC, location VUmc at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 15 Apr 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Jelle Arts (+31 (0)20 4444254, trialoffice-onc@vumc.nl), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The detection of 89Zr-ipilimumab in tumor lesions (time frame: 3 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Apr 2021.