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Melanoma Metastasized to the Brain and Steroids (MEMBRAINS)

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ClinicalTrials.gov Identifier: NCT03563729
Recruitment Status : Recruiting
First Posted : June 20, 2018
Last Update Posted : June 20, 2018
Sponsor:
Information provided by (Responsible Party):
Inge Marie Svane, Herlev Hospital

Tracking Information
First Submitted Date  ICMJE June 6, 2018
First Posted Date  ICMJE June 20, 2018
Last Update Posted Date June 20, 2018
Actual Study Start Date  ICMJE June 6, 2018
Estimated Primary Completion Date June 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 19, 2018)
  • 6 months progression-free survival rate [ Time Frame: 6 months ]
    Proportion of patients who did not progress or die within 6 months from commencing study treatment.
  • 6 months overall survival rate [ Time Frame: 6 months ]
    Proportion of patients who did not die within 6 months from commencing study treatment.
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: June 19, 2018)
  • Overall progression-free survival [ Time Frame: 4 years ]
    Time from commencing study treatment to the date of progression or death.
  • Overall survival [ Time Frame: 4 years ]
    Time from commencing study treatment to the date of death from any cause.
  • Overall response rate [ Time Frame: 4 years ]
    Proportion of patients with an overall complete or partial response according to modified RECIST 1.1.
  • Extracranial response rate [ Time Frame: 4 years ]
    Proportion of patients with an overall complete or partial response in extracranial lesions according to modified RECIST 1.1.
  • Intracranial response rate [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Melanoma Metastasized to the Brain and Steroids
Official Title  ICMJE Efficacy of Immunotherapy in Melanoma Patients With Brain Metastases Treated With Steroids
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE 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.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Malignant Melanoma
Intervention  ICMJE
  • Drug: Pembrolizumab Injection [Keytruda]
    Alone
  • Drug: Ipilimumab Injection [Yervoy]
    In combination with nivolumab.
  • Drug: Nivolumab Injection [Opdivo]
    In combination with ipilimumab.
Study Arms  ICMJE
  • Experimental: A: Pembrolizumab (Prednisolone 11-25 mg)
    Intravenous infusion of pembrolizumab 2 mg/kg every third week for up to two years.
    Intervention: Drug: Pembrolizumab Injection [Keytruda]
  • Experimental: B: Pembrolizumab (Prednisolone >25 mg)
    Intravenous infusion of pembrolizumab 2 mg/kg every third week for up to two years.
    Intervention: Drug: Pembrolizumab Injection [Keytruda]
  • 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.
    Interventions:
    • Drug: Ipilimumab Injection [Yervoy]
    • Drug: Nivolumab Injection [Opdivo]
  • 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.
    Interventions:
    • Drug: Ipilimumab Injection [Yervoy]
    • Drug: Nivolumab Injection [Opdivo]
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 19, 2018)
80
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 6, 2025
Estimated Primary Completion Date June 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Inge M Svane, Professor 004538683868 inge.marie.svane@regionh.dk
Contact: Troels H Borch, PhD 004538683868 troels.holz.borch@regionh.dk
Listed Location Countries  ICMJE Denmark
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03563729
Other Study ID Numbers  ICMJE MM1807
Has Data Monitoring Committee No
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Inge Marie Svane, Herlev Hospital
Study Sponsor  ICMJE Inge Marie Svane
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Troels H Borch, PhD Center for Cancer Immune Therapy, Department of Hematology and Department of Oncology
PRS Account Herlev Hospital
Verification Date June 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP