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Melanoma Metastasized to the Brain and Steroids (MEMBRAINS)

Primary Purpose

Malignant Melanoma

Status
Recruiting
Phase
Phase 2
Locations
Denmark
Study Type
Interventional
Intervention
Pembrolizumab Injection [Keytruda]
Ipilimumab Injection [Yervoy]
Nivolumab Injection [Opdivo]
Encorafenib
Binimetinib
Dabrafenib
Trametinib
Sponsored by
Inge Marie Svane
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Malignant Melanoma focused on measuring Immune therapy, checkpoint inhibitor, pembrolizumab, ipilimumab, nivolumab, steroid, brain metastasis, BRAF inhibitor, MEK inhibitor

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • 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
  • 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.

Exclusion Criteria:

  • 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
  • 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.

Sites / Locations

  • Herlev UniversityhospitalRecruiting
  • Aarhus Universityhospital
  • Odense Universityhospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

B: Pembrolizumab (Prednisolone >10 mg)

C: Ipilimumab/nivolumab (Prednisolone 11-25 mg)

D: Ipilimumab/nivolumab (Prednisolone >25 mg)

E: BRAF/MEK -> ipi/nivo (prednisolone >10 mg)

Arm Description

Intravenous infusion of pembrolizumab 2 mg/kg every third week for up to two years.

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.

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.

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.

Outcomes

Primary Outcome Measures

6 months progression-free survival rate
Proportion of patients who did not progress or die within 6 months from commencing study treatment.
6 months overall survival rate
Proportion of patients who did not die within 6 months from commencing study treatment.

Secondary Outcome Measures

Overall progression-free survival
Time from commencing study treatment to the date of progression or death.
Overall survival
Time from commencing study treatment to the date of death from any cause.
Overall response rate
Proportion of patients with an overall complete or partial response according to modified RECIST 1.1.
Extracranial response rate
Proportion of patients with an overall complete or partial response in extracranial lesions according to modified RECIST 1.1.
Intracranial response rate
Proportion of patients with an overall complete or partial response in intracranial lesions according to modified RECIST 1.1.
Intracranial clinical benefit rate
Proportion of patients with an overall complete, partial response or stable disease > 6 months according to modified RECIST 1.1.
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.

Full Information

First Posted
June 6, 2018
Last Updated
July 12, 2023
Sponsor
Inge Marie Svane
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1. Study Identification

Unique Protocol Identification Number
NCT03563729
Brief Title
Melanoma Metastasized to the Brain and Steroids
Acronym
MEMBRAINS
Official Title
Efficacy of Immunotherapy in Melanoma Patients With Brain Metastases Treated With Steroids
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Recruiting
Study Start Date
June 6, 2018 (Actual)
Primary Completion Date
June 1, 2024 (Anticipated)
Study Completion Date
June 6, 2028 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Inge Marie Svane

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No

5. Study Description

Brief 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. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malignant Melanoma
Keywords
Immune therapy, checkpoint inhibitor, pembrolizumab, ipilimumab, nivolumab, steroid, brain metastasis, BRAF inhibitor, MEK inhibitor

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
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)
Allocation
Non-Randomized
Enrollment
80 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
B: Pembrolizumab (Prednisolone >10 mg)
Arm Type
Experimental
Arm Description
Intravenous infusion of pembrolizumab 2 mg/kg every third week for up to two years.
Arm Title
C: Ipilimumab/nivolumab (Prednisolone 11-25 mg)
Arm Type
Experimental
Arm Description
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.
Arm Title
D: Ipilimumab/nivolumab (Prednisolone >25 mg)
Arm Type
Experimental
Arm Description
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.
Arm Title
E: BRAF/MEK -> ipi/nivo (prednisolone >10 mg)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Pembrolizumab Injection [Keytruda]
Intervention Description
Alone
Intervention Type
Drug
Intervention Name(s)
Ipilimumab Injection [Yervoy]
Intervention Description
In combination with nivolumab.
Intervention Type
Drug
Intervention Name(s)
Nivolumab Injection [Opdivo]
Intervention Description
In combination with ipilimumab.
Intervention Type
Drug
Intervention Name(s)
Encorafenib
Intervention Description
In combination with binimetinib
Intervention Type
Drug
Intervention Name(s)
Binimetinib
Intervention Description
In combination with encorafenib
Intervention Type
Drug
Intervention Name(s)
Dabrafenib
Intervention Description
In combination with dabrafenib
Intervention Type
Drug
Intervention Name(s)
Trametinib
Intervention Description
In combination with trametinib
Primary Outcome Measure Information:
Title
6 months progression-free survival rate
Description
Proportion of patients who did not progress or die within 6 months from commencing study treatment.
Time Frame
6 months
Title
6 months overall survival rate
Description
Proportion of patients who did not die within 6 months from commencing study treatment.
Time Frame
6 months
Secondary Outcome Measure Information:
Title
Overall progression-free survival
Description
Time from commencing study treatment to the date of progression or death.
Time Frame
4 years
Title
Overall survival
Description
Time from commencing study treatment to the date of death from any cause.
Time Frame
4 years
Title
Overall response rate
Description
Proportion of patients with an overall complete or partial response according to modified RECIST 1.1.
Time Frame
4 years
Title
Extracranial response rate
Description
Proportion of patients with an overall complete or partial response in extracranial lesions according to modified RECIST 1.1.
Time Frame
4 years
Title
Intracranial response rate
Description
Proportion of patients with an overall complete or partial response in intracranial lesions according to modified RECIST 1.1.
Time Frame
4 years
Title
Intracranial clinical benefit rate
Description
Proportion of patients with an overall complete, partial response or stable disease > 6 months according to modified RECIST 1.1.
Time Frame
4 years
Title
Blood and tissue biomarkers of response and progression
Description
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.
Time Frame
5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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 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. Exclusion Criteria: 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 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Inge M Svane, Professor
Phone
004538683868
Email
inge.marie.svane@regionh.dk
First Name & Middle Initial & Last Name or Official Title & Degree
Troels H Borch, PhD
Phone
004538683868
Email
troels.holz.borch@regionh.dk
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Troels H Borch, PhD
Organizational Affiliation
Center for Cancer Immune Therapy, Department of Hematology and Department of Oncology
Official's Role
Principal Investigator
Facility Information:
Facility Name
Herlev Universityhospital
City
Herlev
State/Province
Hovedstaden
ZIP/Postal Code
2730
Country
Denmark
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Inge M Svane, Professor
Phone
004538683868
Email
inge.marie.svane@regionh.dk
First Name & Middle Initial & Last Name & Degree
Troels H Borch, PhD
Phone
004538683868
Email
troels.holz.borch@regionh.dk
First Name & Middle Initial & Last Name & Degree
Troels H Borch, PhD
First Name & Middle Initial & Last Name & Degree
Marco Donia, PhD
Facility Name
Aarhus Universityhospital
City
Aarhus
State/Province
Midt
ZIP/Postal Code
8000
Country
Denmark
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Henrik Schmidt, PhD
First Name & Middle Initial & Last Name & Degree
Henrik Schmidt, PhD
Facility Name
Odense Universityhospital
City
Odense
State/Province
Syd
ZIP/Postal Code
5000
Country
Denmark
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lars Bastholt
First Name & Middle Initial & Last Name & Degree
Lars Bastholt

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Links:
URL
https://www.herlevhospital.dk/ccit-denmark/Sider/default.aspx
Description
Homepage of Center for Cancer Immune Therapy

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Melanoma Metastasized to the Brain and Steroids

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