Melanoma Metastasized to the Brain and Steroids

Malignant Melanoma Clinical Trial

— MEMBRAINS  

Official title:

Efficacy of Immunotherapy in Melanoma Patients With Brain Metastases Treated With Steroids

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03563729
• Other study ID #: MM1807
• Status: Recruiting
• Phase: Phase 2
• Start date: June 6, 2018
• Est. completion date: June 6, 2028

Study information

• Verified date: July 2023
• Source: Herlev Hospital
• Contact: Inge M Svane, Professor
• Phone: 004538683868
• Email: inge.marie.svane[@]regionh.dk
• Is FDA regulated: No
• Study type: Interventional

Clinical 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. 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).

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 80
• Est. completion date: June 6, 2028
• Est. primary completion date: June 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Malignant Melanoma
• Melanoma

Intervention

Drug:
• Pembrolizumab Injection [Keytruda]
Alone
• Ipilimumab Injection [Yervoy]
In combination with nivolumab.
• Nivolumab Injection [Opdivo]
In combination with ipilimumab.
• Encorafenib
In combination with binimetinib
• Binimetinib
In combination with encorafenib
• Dabrafenib
In combination with dabrafenib
• Trametinib
In combination with trametinib

Locations

Country	Name	City	State
Denmark	Aarhus Universityhospital	Aarhus	Midt
Denmark	Herlev Universityhospital	Herlev	Hovedstaden
Denmark	Odense Universityhospital	Odense	Syd

Sponsors (1)

Lead Sponsor	Collaborator
Inge Marie Svane

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	6 months progression-free survival rate	Proportion of patients who did not progress or die within 6 months from commencing study treatment.	6 months
Primary	6 months overall survival rate	Proportion of patients who did not die within 6 months from commencing study treatment.	6 months
Secondary	Overall progression-free survival	Time from commencing study treatment to the date of progression or death.	4 years
Secondary	Overall survival	Time from commencing study treatment to the date of death from any cause.	4 years
Secondary	Overall response rate	Proportion of patients with an overall complete or partial response according to modified RECIST 1.1.	4 years
Secondary	Extracranial response rate	Proportion of patients with an overall complete or partial response in extracranial lesions according to modified RECIST 1.1.	4 years
Secondary	Intracranial response rate	Proportion of patients with an overall complete or partial response in intracranial lesions according to modified RECIST 1.1.	4 years
Secondary	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
Secondary	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

External Links

•   Homepage of Center for Cancer Immune Therapy