Melanoma Metastasized to the Brain and Steroids (MEMBRAINS)

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).

Study Overview

• Status: Recruiting
• Conditions: Malignant Melanoma
• Intervention / Treatment: Drug: Pembrolizumab Injection [Keytruda]; Drug: Ipilimumab Injection [Yervoy]; Drug: Nivolumab Injection [Opdivo]; Drug: Encorafenib; Drug: Binimetinib; Drug: Dabrafenib; Drug: Trametinib

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 Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Inge M Svane, Professor; Phone Number: 004538683868; Email: inge.marie.svane@regionh.dk
• Study Contact Backup: Name: Troels H Borch, PhD; Phone Number: 004538683868; Email: troels.holz.borch@regionh.dk

Study Locations

• Denmark
  • Hovedstaden
    • Herlev, Hovedstaden, Denmark, 2730
      • Recruiting
      • Herlev Universityhospital
      • Contact: Inge M Svane, Professor; Phone Number: 004538683868; Email: inge.marie.svane@regionh.dk
      • Contact: Troels H Borch, PhD; Phone Number: 004538683868; Email: troels.holz.borch@regionh.dk
      • Principal Investigator: Troels H Borch, PhD
      • Sub-Investigator: Marco Donia, PhD
  • Midt
    • Aarhus, Midt, Denmark, 8000
      • Not yet recruiting
      • Aarhus Universityhospital
      • Contact: Henrik Schmidt, PhD
      • Principal Investigator: Henrik Schmidt, PhD
  • Syd
    • Odense, Syd, Denmark, 5000
      • Not yet recruiting
      • Odense Universityhospital
      • Contact: Lars Bastholt
      • Principal Investigator: Lars Bastholt

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: B: Pembrolizumab (Prednisolone >10 mg); Intravenous infusion of pembrolizumab 2 mg/kg every third week for up to two years.	Drug: Pembrolizumab Injection [Keytruda]; Alone
Experimental: C: Ipilimumab/nivolumab (Prednisolone 11-25 mg); 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.	Drug: Ipilimumab Injection [Yervoy]; In combination with nivolumab.; Drug: Nivolumab Injection [Opdivo]; In combination with ipilimumab.
Experimental: D: Ipilimumab/nivolumab (Prednisolone >25 mg); 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.	Drug: Ipilimumab Injection [Yervoy]; In combination with nivolumab.; Drug: Nivolumab Injection [Opdivo]; In combination with ipilimumab.
Experimental: E: BRAF/MEK -> ipi/nivo (prednisolone >10 mg); 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.	Drug: Ipilimumab Injection [Yervoy]; In combination with nivolumab.; Drug: Nivolumab Injection [Opdivo]; In combination with ipilimumab.; Drug: Encorafenib; In combination with binimetinib; Drug: Binimetinib; In combination with encorafenib; Drug: Dabrafenib; In combination with dabrafenib; Drug: Trametinib; In combination with trametinib

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall progression-free survival	Time from commencing study treatment to the date of progression or death.	4 years
Overall survival	Time from commencing study treatment to the date of death from any cause.	4 years
Overall response rate	Proportion of patients with an overall complete or partial response according to modified RECIST 1.1.	4 years
Extracranial response rate	Proportion of patients with an overall complete or partial response in extracranial lesions according to modified RECIST 1.1.	4 years
Intracranial response rate	Proportion of patients with an overall complete or partial response in intracranial lesions according to modified RECIST 1.1.	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.	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.	5 years

Collaborators and Investigators

• Sponsor: Inge Marie Svane
• Investigators: Principal Investigator: Troels H Borch, PhD, Center for Cancer Immune Therapy, Department of Hematology and Department of Oncology

Publications and helpful links

Helpful Links

• Homepage of Center for Cancer Immune Therapy

Study record dates

Study Major Dates

• Study Start (Actual): June 6, 2018
• Primary Completion (Estimated): June 1, 2024
• Study Completion (Estimated): June 6, 2028

Study Registration Dates

• First Submitted: June 6, 2018
• First Submitted That Met QC Criteria: June 19, 2018
• First Posted (Actual): June 20, 2018

Study Record Updates

• Last Update Posted (Actual): July 13, 2023
• Last Update Submitted That Met QC Criteria: July 12, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: nivolumab; MEK inhibitor; BRAF inhibitor; pembrolizumab; brain metastasis; checkpoint inhibitor; steroid; ipilimumab; Immune therapy
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Immune Checkpoint Inhibitors; Nivolumab; Pembrolizumab; Trametinib; Dabrafenib; Ipilimumab
• Other Study ID Numbers: MM1807

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• 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