Clinical trial NCT03563729: Melanoma Metastasized to the Brain and Steroids
Official title: Efficacy of Immunotherapy in Melanoma Patients With Brain Metastases Treated With Steroids
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Malignant Melanoma
Keywords: Immune therapy
checkpoint inhibitor
pembrolizumab
ipilimumab
nivolumab
steroid
brain metastasis
BRAF inhibitor
MEK inhibitor
Lead sponsor: Herlev Hospital
Sponsor class: OTHER
First posted: 2018-06-20
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: 6 months progression-free survival rate
timeFrame: 6 months
measure: 6 months overall survival rate
timeFrame: 6 months
Secondary outcomes:
measure: Overall progression-free survival
timeFrame: 4 years
measure: Overall survival
timeFrame: 4 years
measure: Overall response rate
timeFrame: 4 years
measure: Extracranial response rate
timeFrame: 4 years
measure: Intracranial response rate
timeFrame: 4 years
measure: Intracranial clinical benefit rate
timeFrame: 4 years
measure: Blood and tissue biomarkers of response and progression
timeFrame: 5 years
Other outcomes:
Locations:
city: Herlev
country: Denmark
facility: Herlev Universityhospital
state: Hovedstaden
city: Aarhus
country: Denmark
facility: Aarhus Universityhospital
state: Midt
city: Odense
country: Denmark
facility: Odense Universityhospital
state: Syd
Study officials:
affiliation: Center for Cancer Immune Therapy, Department of Hematology and Department of Oncology
name: Troels H Borch, PhD
role: PRINCIPAL_INVESTIGATOR
References: