MEMBRAINS: Melanoma Metastasized to the Brain and Steroids

Sponsor

Inge Marie Svane (Other)

Overall Status

Recruiting

CT.gov ID

NCT03563729

Collaborator

(none)

Enrollment

Locations

Arms

Anticipated Duration (Months)

26.7

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

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).

Condition or Disease	Intervention/Treatment	Phase
Malignant Melanoma	Drug: Pembrolizumab Injection [Keytruda] Drug: Ipilimumab Injection [Yervoy] Drug: Nivolumab Injection [Opdivo] Drug: Encorafenib Drug: Binimetinib Drug: Dabrafenib Drug: Trametinib	Phase 2

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

Study Type:

Interventional

Anticipated Enrollment :

80 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Intervention 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.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)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jun 6, 2018

Anticipated Primary Completion Date :

Jun 1, 2021

Anticipated Study Completion Date :

Jun 6, 2025

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts 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.