Malignant MelanomaPhase 2MEMBRAINSNCT03563729
Melanoma Metastasized to the Brain and Steroids
A Phase 2 study testing Pembrolizumab Injection [Keytruda], Ipilimumab Injection [Yervoy] and Nivolumab Injection [Opdivo] in people with Malignant Melanoma, run by Inge Marie Svane at 3 sites in Denmark.
Trial summary
This clinical trial is to clarify whether treatment with a checkpoint inhibitor alone (pembrolizumab) or two in combination (ipilimumab and nivolumab), results in clinical benefit for MM patients with brain metastases and in need of steroid treatment. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Malignant Melanoma
- What is being tested?
- Pembrolizumab Injection [Keytruda], Ipilimumab Injection [Yervoy] and Nivolumab Injection [Opdivo]
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 80 participants
- Where
- 3 sitesDenmark
- Study dates
- 6 Jun 2018to 6 Jun 2028
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
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
- Histologically confirmed metastatic melanoma with radiologically verified brain metastasis
- Need for systemic steroid treatment (prednisolone > 10 mg daily; dexamethasone > 1.6 mg daily, hydrocortisone > 40 mg daily or equivalent) due to brain metastasis
- At least one measurable lesion according to RECIST version 1.1 guidelines
- Evaluable intracranial disease
- 18 years of age or older
- Performance status 0-2
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- Able to undergo MRI with gadolinium contrast agent
- Adequate hematological and organ function
- No significant toxicity from previous cancer treatments (CTC<1)
- Women of childbearing potential: Negative serum pregnancy test and must use effective contraception. This applies from screening and until 6 months after treatment. Birth control pills, spiral, depot injection with gestagen, subdermal implantation, hormonal vaginal ring and transdermal depot patch are all considered effective contraceptives
- Men with female partner of childbearing potential must use effective contraception from screening and until 6 months after treatment. Effective contraceptives are as described above for the female partner. In addition documented vasectomy and sterility or double barrier contraception are considered effective contraceptives
- Signed statement of consent after receiving oral and written study information.
- Willingness to participate in the planned treatment and follow-up and capable of handling toxicities.
- For arm E specifically: Tumor cells must harbor BRAF mutation.
Who cannot join
- Another malignancy or concurrent malignancy unless disease-free for 3 years
- Ocular melanoma
- Neurological symptoms from brain metastases present at baseline despite steroid treatment, unless symptoms are related to prior surgery
- Known hypersensitivity to one of the active drugs or excipients
- Acute or chronic infections with HIV or hepatitis
- Any medical condition that will interfere with patient compliance or safety
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- Prior treatment with anti-PD-1/PD-L1/PD-L2/CTLA-4 antibodies in the metastatic setting
- Prior systemic treatment with anti-PD-1/PD-L1/PD-L2/CTLA-4 antibodies in the adjuvant setting, unless completed more than 6 months before enrolment in this study
- Simultaneous treatment with other experimental drugs or other anti-cancer drugs
- Pregnant or breastfeeding females.
- For arm E specifically: Prior treatment with BRAF/MEK inhibitors.
Trial locations and contacts
3 sites in 1 country. Contact the study team or a site near you to ask about taking part.
Denmark3 sites, 3 recruiting
- Not yet recruiting
Aarhus Universityhospital
Aarhus, Midt, 8000
Henrik Schmidt, PhD
Henrik Schmidt, PhD
- Recruiting
Herlev Universityhospital
Herlev, Capital Region, 2730
Inge M Svane, Professor, 004538683868, inge.marie.svane@regionh.dk
Troels H Borch, PhD, 004538683868, troels.holz.borch@regionh.dk
- Not yet recruiting
Odense Universityhospital
Odense, Syd, 5000
Lars Bastholt
Lars Bastholt
About this study
Official title: Efficacy of Immunotherapy in Melanoma Patients With Brain Metastases Treated With Steroids
This clinical trial is to clarify whether treatment with a checkpoint inhibitor alone (pembrolizumab) or two in combination (ipilimumab and nivolumab), results in clinical benefit for MM patients with brain metastases and in need of steroid treatment. Patients will be treated in four arms depending on steroid dose level at inclusion (> 10 < 25 mg prednisolone or > 25 mg prednisolone) and treatment (pembrolizumab alone or the combination of ipilimumab and nivolumab).
Read the detailed description
Cancer immunotherapy with checkpoint inhibitors (CPI) has demonstrated significant response rates, with clinical responses of exceptional duration observed in pivotal clinical trials for multiple types of solid tumors. Results from clinical trials demonstrate a considerable survival benefit of CPI over standard treatments, leading to registration of CPI for lung-, head and neck-, bladder-, renal cancer, lymphomas and metastatic melanoma (MM). To date, CPI appear to hold the key for longterm survival - at least for patients treated in clinical trials.
Patients enrolled in pivotal clinical trials for immunotherapy of MM are highly selected and does not include patients with brain metastases. Small phase II studies lend support to CPI to yield responses in melanoma that has metastasized to the brain. However, a large proportion of patients that develop brain metastasis will require continued systemic treatment with steroids to alleviate symptoms from the central nervous system (CNS). This group of patients are not offered treatment with CPI, as it is generally assumed that steroid treatment hamper their clinical efficacy. Thus, this group of patients face a large unmet need.
Due to the immune inhibiting effects, steroids are used to manage immune-related adverse events (irAEs) induced by CPI treatment. However, patients receiving steroids in this context are still able to achieve and maintain clinical benefit even after stopping treatment.
It is not known whether steroid treatment at the time of initiation of CPI treatment diminishes the treatment effect, as patients in need of steroid treatment are generally excluded from clinical trials.
- Conditions
- Malignant Melanoma
- Being tested
- Pembrolizumab Injection [Keytruda], Ipilimumab Injection [Yervoy], Nivolumab Injection [Opdivo], Encorafenib, Binimetinib
- Keywords
- Immune therapy, checkpoint inhibitor, pembrolizumab, ipilimumab, nivolumab, steroid, brain metastasis, BRAF inhibitor, MEK inhibitor
- 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.
Pembrolizumab Injection [Keytruda]Drug
Alone
Ipilimumab Injection [Yervoy]Drug
In combination with nivolumab.
Nivolumab Injection [Opdivo]Drug
In combination with ipilimumab.
EncorafenibDrug
In combination with binimetinib
BinimetinibDrug
In combination with encorafenib
DabrafenibDrug
In combination with dabrafenib
TrametinibDrug
In combination with trametinib
| Study group | Role | What they receive |
|---|---|---|
| B: Pembrolizumab (Prednisolone >10 mg) | Experimental | Intravenous infusion of pembrolizumab 2 mg/kg every third week for up to two years. Receives: Drug: Pembrolizumab Injection [Keytruda] |
| C: Ipilimumab/nivolumab (Prednisolone 11-25 mg) | Experimental | Intravenous infusion of ipilimumab 3 mg/kg and nivolumab 1 mg/kg four times every three weeks in the induction phase and nivolumab 480 mg every four weeks in the maintenance phase for up to two years. Receives: Drug: Ipilimumab Injection [Yervoy]; Drug: Nivolumab Injection [Opdivo] |
| D: Ipilimumab/nivolumab (Prednisolone >25 mg) | Experimental | Intravenous infusion of ipilimumab 3 mg/kg and nivolumab 1 mg/kg four times every three weeks in the induction phase and nivolumab 480 mg every four weeks in the maintenance phase for up to two years. Receives: Drug: Ipilimumab Injection [Yervoy]; Drug: Nivolumab Injection [Opdivo] |
| E: BRAF/MEK -> ipi/nivo (prednisolone >10 mg) | Experimental | Induction treatment with BRAF/MEK inhibitors (either the combination of encorafenib/binimetinib or dabrafenib/trametinib) orally for 28 days followed by intravenous infusion of ipilimumab 3 mg/kg and nivolumab 1 mg/kg four times every three weeks in the induction phase and nivolumab 480 mg every four weeks in the maintenance phase for up to two years. Receives: Drug: Ipilimumab Injection [Yervoy]; Drug: Nivolumab Injection [Opdivo]; Drug: Encorafenib; Drug: Binimetinib; Drug: Dabrafenib; Drug: Trametinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
6 months progression-free survival rate
Proportion of patients who did not progress or die within 6 months from commencing study treatment.
Measured: 6 months
6 months overall survival rate
Proportion of patients who did not die within 6 months from commencing study treatment.
Measured: 6 months
Secondary outcomes (7)
Overall progression-free survival
Time from commencing study treatment to the date of progression or death.
Measured: 4 years
Overall survival
Time from commencing study treatment to the date of death from any cause.
Measured: 4 years
Overall response rate
Proportion of patients with an overall complete or partial response according to modified RECIST 1.1.
Measured: 4 years
Extracranial response rate
Proportion of patients with an overall complete or partial response in extracranial lesions according to modified RECIST 1.1.
Measured: 4 years
Intracranial response rate
Proportion of patients with an overall complete or partial response in intracranial lesions according to modified RECIST 1.1.
Measured: 4 years
Intracranial clinical benefit rate
Proportion of patients with an overall complete, partial response or stable disease > 6 months according to modified RECIST 1.1.
Measured: 4 years
Blood and tissue biomarkers of response and progression
Correlation of the baseline PD-L1 status, immune markers, genomics and other biomarkers in tumour tissue and blood with complete or partial response and at subsequent disease progressionanalyses of potential specific biomarkers predictive of response or progression.
Measured: 5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Jun 2018
- Study start6 Jun 2018
- Primary completion1 Jun 2024 (estimated)
- Study completion6 Jun 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Malignant MelanomaStudies of the same condition, open and under way.
- 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
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Model description
- Six patients are enrolled in each arm. If clinical benefit is observed, each arm will be expanded to enroll a total of 20 patients.
- Masking
- None (open label)
- Enrolment
- 80 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Inge Marie Svane
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Inge Marie Svane, Herlev Hospital
- Investigators
- Troels H Borch, PhD, Principal investigator, Center for Cancer Immune Therapy, Department of Hematology and Department of Oncology
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03563729
- Sponsor's protocol ID
- MM1807
- Acronym
- MEMBRAINS
- Status last verified
- Jul 2023
- First submitted
- 6 Jun 2018
- Last updated
- 13 Jul 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 13 Jul 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Efficacy of Immunotherapy in Melanoma Patients With Brain Metastases Treated With Steroids
- ClinicalTrials.gov ID
- NCT03563729
- Acronym / sponsor ID
- MEMBRAINS / MM1807
- Conditions
- Malignant Melanoma
- Keywords
- Immune therapy, checkpoint inhibitor, pembrolizumab, ipilimumab, nivolumab, steroid, brain metastasis, BRAF inhibitor
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 80 participants (estimated)
- Lead sponsor
- Inge Marie SvaneUniversity, hospital or other
- Study start
- 6 Jun 2018 (actual)
- Primary completion
- 1 Jun 2024 (estimated)
- Study completion
- 6 Jun 2028 (estimated)
- First posted
- 20 Jun 2018 (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.
This clinical trial is to clarify whether treatment with a checkpoint inhibitor alone (pembrolizumab) or two in combination (ipilimumab and nivolumab), results in clinical benefit for MM patients with brain metastases and in need of steroid treatment. Patients will be treated in four arms depending on steroid dose level at inclusion (> 10 < 25 mg prednisolone or > 25 mg prednisolone) and treatment (pembrolizumab alone or the combination of ipilimumab and nivolumab).
Detailed description
Cancer immunotherapy with checkpoint inhibitors (CPI) has demonstrated significant response rates, with clinical responses of exceptional duration observed in pivotal clinical trials for multiple types of solid tumors. Results from clinical trials demonstrate a considerable survival benefit of CPI over standard treatments, leading to registration of CPI for lung-, head and neck-, bladder-, renal cancer, lymphomas and metastatic melanoma (MM). To date, CPI appear to hold the key for longterm survival - at least for patients treated in clinical trials.
Patients enrolled in pivotal clinical trials for immunotherapy of MM are highly selected and does not include patients with brain metastases. Small phase II studies lend support to CPI to yield responses in melanoma that has metastasized to the brain. However, a large proportion of patients that develop brain metastasis will require continued systemic treatment with steroids to alleviate symptoms from the central nervous system (CNS). This group of patients are not offered treatment with CPI, as it is generally assumed that steroid treatment hamper their clinical efficacy. Thus, this group of patients face a large unmet need.
Due to the immune inhibiting effects, steroids are used to manage immune-related adverse events (irAEs) induced by CPI treatment. However, patients receiving steroids in this context are still able to achieve and maintain clinical benefit even after stopping treatment.
It is not known whether steroid treatment at the time of initiation of CPI treatment diminishes the treatment effect, as patients in need of steroid treatment are generally excluded from clinical trials.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 4
- Model description
- Six patients are enrolled in each arm. If clinical benefit is observed, each arm will be expanded to enroll a total of 20 patients.
| Arm | Type | Receives |
|---|---|---|
| B: Pembrolizumab (Prednisolone >10 mg) | Experimental | Drug: Pembrolizumab Injection [Keytruda]Intravenous infusion of pembrolizumab 2 mg/kg every third week for up to two years. |
| C: Ipilimumab/nivolumab (Prednisolone 11-25 mg) | Experimental | Drug: Ipilimumab Injection [Yervoy], Drug: Nivolumab Injection [Opdivo]Intravenous infusion of ipilimumab 3 mg/kg and nivolumab 1 mg/kg four times every three weeks in the induction phase and nivolumab 480 mg every four weeks in the maintenance phase for up to two years. |
| D: Ipilimumab/nivolumab (Prednisolone >25 mg) | Experimental | Drug: Ipilimumab Injection [Yervoy], Drug: Nivolumab Injection [Opdivo]Intravenous infusion of ipilimumab 3 mg/kg and nivolumab 1 mg/kg four times every three weeks in the induction phase and nivolumab 480 mg every four weeks in the maintenance phase for up to two years. |
| E: BRAF/MEK -> ipi/nivo (prednisolone >10 mg) | Experimental | Drug: Ipilimumab Injection [Yervoy], Drug: Nivolumab Injection [Opdivo], Drug: Encorafenib, Drug: Binimetinib, Drug: Dabrafenib, Drug: TrametinibInduction treatment with BRAF/MEK inhibitors (either the combination of encorafenib/binimetinib or dabrafenib/trametinib) orally for 28 days followed by intravenous infusion of ipilimumab 3 mg/kg and nivolumab 1 mg/kg four times every three weeks in the induction phase and nivolumab 480 mg every four weeks in the maintenance phase for up to two years. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (14 listed)
- Histologically confirmed metastatic melanoma with radiologically verified brain metastasis
- Need for systemic steroid treatment (prednisolone > 10 mg daily; dexamethasone > 1.6 mg daily, hydrocortisone > 40 mg daily or equivalent) due to brain metastasis
- At least one measurable lesion according to RECIST version 1.1 guidelines
- Evaluable intracranial disease
- 18 years of age or older
Key exclusion criteria (11 listed)
- Another malignancy or concurrent malignancy unless disease-free for 3 years
- Ocular melanoma
- Neurological symptoms from brain metastases present at baseline despite steroid treatment, unless symptoms are related to prior surgery
- Known hypersensitivity to one of the active drugs or excipients
- Acute or chronic infections with HIV or hepatitis
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 |
|---|---|---|
| Pembrolizumab Injection [Keytruda]Alone | Drug | B: Pembrolizumab (Prednisolone >10 mg) |
| Ipilimumab Injection [Yervoy]In combination with nivolumab. | Drug | C: Ipilimumab/nivolumab (Prednisolone 11-25 mg), D: Ipilimumab/nivolumab (Prednisolone >25 mg), E: BRAF/MEK -> ipi/nivo (prednisolone >10 mg) |
| Nivolumab Injection [Opdivo]In combination with ipilimumab. | Drug | C: Ipilimumab/nivolumab (Prednisolone 11-25 mg), D: Ipilimumab/nivolumab (Prednisolone >25 mg), E: BRAF/MEK -> ipi/nivo (prednisolone >10 mg) |
| EncorafenibIn combination with binimetinib | Drug | E: BRAF/MEK -> ipi/nivo (prednisolone >10 mg) |
| BinimetinibIn combination with encorafenib | Drug | E: BRAF/MEK -> ipi/nivo (prednisolone >10 mg) |
| DabrafenibIn combination with dabrafenib | Drug | E: BRAF/MEK -> ipi/nivo (prednisolone >10 mg) |
| TrametinibIn combination with trametinib | Drug | E: BRAF/MEK -> ipi/nivo (prednisolone >10 mg) |
Primary outcome
6 months progression-free survival rate
Time frame: 6 months
Proportion of patients who did not progress or die within 6 months from commencing study treatment.
6 months overall survival rate
Time frame: 6 months
Proportion of patients who did not die within 6 months from commencing study treatment.
7 secondary outcomes
Overall progression-free survival
Time frame: 4 years
Overall survival
Time frame: 4 years
Overall response rate
Time frame: 4 years
Extracranial response rate
Time frame: 4 years
Intracranial response rate
Time frame: 4 years
Intracranial clinical benefit rate
Time frame: 4 years
Blood and tissue biomarkers of response and progression
Time frame: 5 years
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Jul 2023.
- Homepage of Center for Cancer Immune TherapyLink provided by the sponsor.
- Individual participant dataSharing planned: Undecided
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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.
Troels H Borch, PhD principal investigator
Center for Cancer Immune Therapy, Department of Hematology and Department of Oncology
3 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 Pembrolizumab Injection [Keytruda], Ipilimumab Injection [Yervoy] and Nivolumab Injection [Opdivo] in people with Malignant Melanoma, run by Inge Marie Svane at 3 sites in Denmark.
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 14 inclusion and 11 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: looking for participants now, as of the sponsor's last update on 13 Jul 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Denmark. 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?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Inge M Svane, Professor (004538683868, inge.marie.svane@regionh.dk), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
6 months progression-free survival rate (time frame: 6 months). The study lists 2 primary outcomes in all. 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 13 Jul 2023.