Melanoma Metastasized to the Brain and Steroids

Official title

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

Overview

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.

Interventions

• Drug Pembrolizumab Injection [Keytruda]
  Alone
• 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

Primary outcome measures

• 6 months progression-free survival rate [Time frame: 6 months]
• 6 months overall survival rate [Time frame: 6 months]

Secondary outcome measures (7)

• 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]

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Denmark · 3 centers

• Herlev Universityhospital — Herlev
• Aarhus Universityhospital — Aarhus
• Odense Universityhospital — Odense

Identifiers

NCT: NCT03563729 · MM1807

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗