MelanomaPhase 2CA209-322NCT02621515
Nivo/Ipi Combination Therapy in Symptomatic Brain Metastases
A Phase 2 study testing Nivolumab in people with Melanoma and Brain Metastasis, run by University Medical Center Groningen at 4 sites in Netherlands.
Trial summary
The effect of nivolumab on symptomatic brain metastases is currently unknown. This phase 2 clinical trial will be the first to evaluate this intracranial effect in humans, with the aim to give these patients the possibility to be treated with anti-PD-1. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Melanoma, Brain Metastasis
- What is being tested?
- Nivolumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 7 participants
- Where
- 4 sitesNetherlands
- Study dates
- Aug 2016to 30 May 2018
- 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
- Subjects must sign informed consent prior to inclusion in this trial.
- Subjects must be ≥18 years of age and competent to give informed consent.
- Histologically confirmed stage IV melanoma.
- At least one radiologic new lesion in the brain by MRI, which should be measurable by RANO-BM criteria (longest diameter ≥ 10 mm and perpendicular diameter ≥ 5 mm). Lesions with prior local treatment (i.e., SRT or surgical resection) can be considered measurable if there has been demonstrated progression since the time of local treatment. Leptomeningeal involvement is allowed, but could not be used as target lesion.
- BRAF status is determined. If positive, initial treatment for maximal 8 weeks with BRAF-inhibitors is allowed.
- Subjects must be treatment-naive to nivolumab. (also as adjuvant treatment)
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- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.
- Subjects must have adequate organ function as defined by the following laboratory values (determined within 28 days prior to randomization/registration):
- White blood cells (WBC) ≥ 2000 /µL
- Absolute neutrophil count (ANC) ≥ 1500 /µL
- Platelets ≥ 100 x103 /µL
- Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L
- Serum creatinine ≤ 1.5 times upper limit of normal (ULN) or creatinine clearance > 40 ml/min (using the Cockcroft-Gault formula)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 times ULN
- Bilirubin ≤ 1.5 times ULN (Except patient with Gilbert Syndrome, who can have total bilirubin ≤ 3.0 mg/dL)
- LDH < 2 times ULN
- Female subjects of childbearing potential should have a negative urine or serum pregnancy test within 24 hours prior to receiving the first administration of nivolumab. Women with non-childbearing potential may be included if they are either surgically sterile or have been postmenopausal for ≥ 1 year.
- Women of child-bearing potential (WOCBP) and men who are sexually active with WOCBP must agree to use appropriate method(s) of contraception. (see section 5.2)
Who cannot join
- Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2 antibody. (also as adjuvant treatment)
- Subjects who have not recovered to Common Terminology Criteria for Adverse Events (CTCAE) v4.0 grade 1 or better from adverse events due to previous cancer therapy.
- Evidence for an active, known or suspected autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.
- Treatment with corticosteroids in an increasing dosage in the 7 days prior to the first administration of nivolumab. (A stable or decreasing dosage of ≤ 4 mg dexamethasone or equivalent is allowed. In addition, inhaled or topical steroids and adrenal replacement doses are permitted in the absence of active autoimmune disease.)
- Previous malignancies (except non-melanoma skin cancers, in situ bladder cancer, gastric or colon cancers, cervical cancers/dysplasia or breast carcinoma in situ) unless a complete remission was achieved at least 1 years prior to study entry and no additional therapy is required or anticipated to be required during the study period.
- Previous severe hypersensitivity reaction to treatment with another monoclonal antibody, or known hypersensitivity to study drugs components.
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- A positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection.
- Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
- Any serious or uncontrolled medical disorder or active infection that, in the opinion of the investigator, may increase the risk associated with study participation, study drug administration, or would impair the ability of the patients to receive protocol therapy.
- A known psychiatric or substance abuse disorder that could interfere with cancer therapy.
- Women of childbearing potential with a positive serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of nivolumab.
- Breastfeeding women.
- Inability to comply with other requirements of the protocol.
Trial locations and contacts
4 sites in 1 country.
Netherlands4 sites
Dutch Cancer Institute/ A v. Leeuwenhoek Hospital
Amsterdam, 1066 CX
VU Medical Center
Amsterdam, 1081 HZ
University Medical Center Groningen
Groningen, 9713 GZ
Erasmus Medical Center
Rotterdam, 3075 EA
About this study
Official title: An Open-label, Single-arm, Phase II, Multicenter Study to Evaluate the Efficacy of Nivolumab/Ipilimumab Combination Therapy in Metastatic Melanoma Patients With Symptomatic Brain Metastases.
The effect of nivolumab on symptomatic brain metastases is currently unknown. This phase 2 clinical trial will be the first to evaluate this intracranial effect in humans, with the aim to give these patients the possibility to be treated with anti-PD-1. Besides the objective response rate, long term benefits in this patient category will be evaluated by measuring survival in terms of progression free survival and overall survival. Furthermore safety and tolerability of administration of this drug in patients with symptomatic brain metastases will be studied, as this is the first study for nivolumab in this specific patient category.
Read the detailed description
This study is an open label, single arm, phase II clinical trial of prospectively collected data evaluating efficacy and safety of nivolumab in metastatic melanoma patients with symptomatic brain metastases. It will be conducted in several study centers in the Netherlands.
Patients with radiologic evidence of brain metastases and who are eligible for treatment with nivolumab will be screened for inclusion.
All patients in this trial will receive treatment with nivolumab for 24 months. Treatment will be discontinued if confirmed disease progression has been demonstrated, if unacceptable toxicity or intercurrent illness prevents further treatment, and when informed consent is withdrawn. After discontinuation of treatment, follow-up will start. Duration of follow-up depends on survival of patients, with a maximum of 24 months. Therefore the end of this study is determined as 24 months after the last patient in this trial has started follow-up, has died, withdraws consent or is lost to follow-up for a different reason.
- Conditions
- Melanoma, Brain Metastasis
- Being tested
- Nivolumab
- Keywords
- Nivolumab, Brain metastasis, Melanoma
- Medical subject headings
- Melanoma, Brain Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
NivolumabDrug
Also called Opdivo
All patients in this phase 2 trial will receive treatment with nivolumab, a monoclonal antibody against the PD1-receptor on T cells. Dosing will be based on patients' weight (3 mg/kg). It will be administered in an intravenous infusion every 2 weeks and for a maximum of 2 years.
| Study group | Role | What they receive |
|---|---|---|
| Nivolumab | Experimental | All patients in this trial will receive treatment with nivolumab for 24 months. Treatment will be discontinued if confirmed disease progression has been demonstrated, if unacceptable toxicity or intercurrent illness prevents further treatment, and when informed consent is withdrawn. After discontinuation of treatment, follow-up will start. Duration of follow-up depends on survival of patients, with a maximum of 24 months. Therefore the end of this study is determined as 24 months after the last patient in this trial has started follow-up, has died, withdraws consent or is lost to follow-up for a different reason Receives: Drug: Nivolumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
The best overall response rate (BORR) of brain metastases to nivolumab will be assessed on Magnetic Resonance Imaging (MRI) using the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria.
Per patient, the BORR of brain metastases to nivolumab will be assessed in terms of complete response, partial response, stable disease and progressive disease. An MRI of the brain will be used for radiologic response evaluation. Response evaluation will be performed according to the RANO-BM criteria.
Measured: 2 years
Secondary outcomes (7)
The difference in BORR will be assessed between previously treated and previously untreated brain metastases using the RANO-BM criteria.
Measured: 2 years
The difference in BORR will be assessed between intracranial metastases on and extra-cranial metastases within the same patient, using the RANO-BM criteria and the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria respectively.
Evaluation of intracranial metastases will be performed using MRI. Evaluation of extracranial metastases will be performed using CT.
Measured: 2 years
Duration of response (DOR)
DOR is defined as the time between the date of first documented response (CR or PR) to the date of the first documented progression as determined by the RANO-BM criteria, or death due to any cause, whichever occurs first.
Measured: 4 years
Time to development of new brain metastases in responding patients
For all responding patients, the time between response to study treatment, as assessed on MRI using the RANO-BM criteria, occurence of new brain metastases will be measured.
Measured: 4 years
Progression free survival
Progression free survival is defined as the time from first administration of nivolumab to the date of the first documented progression, as determined by the RANO-BM criteria, or death due to any cause, whichever occurs first.
Measured: 4 years
Overall survival
Overall survival is defined as the time between the date of first administration of nivolumab and the date of death.
Measured: 4 years
The number of patients with treatment related adverse events as assessed by CTCAE v4.0.
Measured: 4 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Dec 2015 (estimated)
- Study startAug 2016
- Primary completion30 May 2018
- Study completion30 May 2018
Why it stopped: In the Netherlands we wanted to add pilimumab to nivolumab. This resulted in a very long METC procedure which resulted in a to slow inclusion rate.
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 University Medical Center GroningenThe 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
- 7 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Medical Center Groningen
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Geke AP Hospers, Md PhD, Principal investigator, University Medical Center Groningen
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02621515
- Sponsor's protocol ID
- 201500776
- Acronym
- CA209-322
- Status last verified
- May 2024
- First submitted
- 9 Sep 2015
- Last updated
- 6 May 2024
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 6 May 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Open-label, Single-arm, Phase II, Multicenter Study to Evaluate the Efficacy of Nivolumab/Ipilimumab Combination Therapy in Metastatic Melanoma Patients With Symptomatic Brain Metastases.
- ClinicalTrials.gov ID
- NCT02621515
- Acronym / sponsor ID
- CA209-322 / 201500776
- Conditions
- Melanoma, Brain Metastasis
- Keywords
- Nivolumab, Brain metastasis, Melanoma
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: In the Netherlands we wanted to add pilimumab to nivolumab. This resulted in a very long METC procedure which resulted in a to slow inclusion rate.
- Enrolment
- 7 participants (actual)
- Lead sponsor
- University Medical Center GroningenUniversity, hospital or other
- Study start
- Aug 2016 (actual)
- Primary completion
- 30 May 2018 (actual)
- Study completion
- 30 May 2018 (actual)
- First posted
- 3 Dec 2015 (estimated)
- 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.
The effect of nivolumab on symptomatic brain metastases is currently unknown. This phase 2 clinical trial will be the first to evaluate this intracranial effect in humans, with the aim to give these patients the possibility to be treated with anti-PD-1. Besides the objective response rate, long term benefits in this patient category will be evaluated by measuring survival in terms of progression free survival and overall survival. Furthermore safety and tolerability of administration of this drug in patients with symptomatic brain metastases will be studied, as this is the first study for nivolumab in this specific patient category.
Detailed description
This study is an open label, single arm, phase II clinical trial of prospectively collected data evaluating efficacy and safety of nivolumab in metastatic melanoma patients with symptomatic brain metastases. It will be conducted in several study centers in the Netherlands.
Patients with radiologic evidence of brain metastases and who are eligible for treatment with nivolumab will be screened for inclusion.
All patients in this trial will receive treatment with nivolumab for 24 months. Treatment will be discontinued if confirmed disease progression has been demonstrated, if unacceptable toxicity or intercurrent illness prevents further treatment, and when informed consent is withdrawn. After discontinuation of treatment, follow-up will start. Duration of follow-up depends on survival of patients, with a maximum of 24 months. Therefore the end of this study is determined as 24 months after the last patient in this trial has started follow-up, has died, withdraws consent or is lost to follow-up for a different reason.
Study design
- Primary purpose
- Diagnosis
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Nivolumab | Experimental | Drug: NivolumabAll patients in this trial will receive treatment with nivolumab for 24 months. Treatment will be discontinued if confirmed disease progression has been demonstrated, if unacceptable toxicity or intercurrent illness prevents further treatment, and when informed consent is withdrawn. After discontinuation of treatment, follow-up will start. Duration of follow-up depends on survival of patients, with a maximum of 24 months. Therefore the end of this study is determined as 24 months after the last patient in this trial has started follow-up, has died, withdraws consent or is lost to follow-up for a different reason |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (18 listed)
- Subjects must sign informed consent prior to inclusion in this trial.
- Subjects must be ≥18 years of age and competent to give informed consent.
- Histologically confirmed stage IV melanoma.
- At least one radiologic new lesion in the brain by MRI, which should be measurable by RANO-BM criteria (longest diameter ≥ 10 mm and perpendicular diameter ≥ 5 mm). Lesions with prior local treatment (i.e., SRT or surgical resection) can be considered measurable if there has been demonstrated progression since the time of local treatment. Leptomeningeal involvement is allowed, but could not be used as target lesion.
- BRAF status is determined. If positive, initial treatment for maximal 8 weeks with BRAF-inhibitors is allowed.
Key exclusion criteria (13 listed)
- Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2 antibody. (also as adjuvant treatment)
- Subjects who have not recovered to Common Terminology Criteria for Adverse Events (CTCAE) v4.0 grade 1 or better from adverse events due to previous cancer therapy.
- Evidence for an active, known or suspected autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.
- Treatment with corticosteroids in an increasing dosage in the 7 days prior to the first administration of nivolumab. (A stable or decreasing dosage of ≤ 4 mg dexamethasone or equivalent is allowed. In addition, inhaled or topical steroids and adrenal replacement doses are permitted in the absence of active autoimmune disease.)
- Previous malignancies (except non-melanoma skin cancers, in situ bladder cancer, gastric or colon cancers, cervical cancers/dysplasia or breast carcinoma in situ) unless a complete remission was achieved at least 1 years prior to study entry and no additional therapy is required or anticipated to be required during the study period.
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 |
|---|---|---|
| NivolumabAlso: OpdivoAll patients in this phase 2 trial will receive treatment with nivolumab, a monoclonal antibody against the PD1-receptor on T cells. Dosing will be based on patients' weight (3 mg/kg). It will be administered in an intravenous infusion every 2 weeks and for a maximum of 2 years. | Drug | Nivolumab |
Primary outcome
The best overall response rate (BORR) of brain metastases to nivolumab will be assessed on Magnetic Resonance Imaging (MRI) using the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria.
Time frame: 2 years
Per patient, the BORR of brain metastases to nivolumab will be assessed in terms of complete response, partial response, stable disease and progressive disease. An MRI of the brain will be used for radiologic response evaluation. Response evaluation will be performed according to the RANO-BM criteria.
7 secondary outcomes
The difference in BORR will be assessed between previously treated and previously untreated brain metastases using the RANO-BM criteria.
Time frame: 2 years
The difference in BORR will be assessed between intracranial metastases on and extra-cranial metastases within the same patient, using the RANO-BM criteria and the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria respectively.
Time frame: 2 years
Duration of response (DOR)
Time frame: 4 years
Time to development of new brain metastases in responding patients
Time frame: 4 years
Progression free survival
Time frame: 4 years
Overall survival
Time frame: 4 years
The number of patients with treatment related adverse events as assessed by CTCAE v4.0.
Time frame: 4 years
Results and safety
The study was stopped early (reason given: In the Netherlands we wanted to add pilimumab to nivolumab. This resulted in a very long METC procedure which resulted in a to slow inclusion rate.). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 May 2024.
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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.
Geke AP Hospers, Md PhD principal investigator
University Medical Center Groningen
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Nivolumab in people with Melanoma and Brain Metastasis, run by University Medical Center Groningen at 4 sites 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 18 inclusion and 13 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: stopped early, as of the sponsor's last update on 6 May 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites 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?
The study was stopped early (reason given: In the Netherlands we wanted to add pilimumab to nivolumab. This resulted in a very long METC procedure which resulted in a to slow inclusion rate.). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The best overall response rate (BORR) of brain metastases to nivolumab will be assessed on Magnetic Resonance Imaging (MRI) using the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. (time frame: 2 years). 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 6 May 2024; AzTrials last refreshed its copy on 6 Nov 2026.