Patients with stage IV melanoma and four or more symptomatic brain metastases, who are not eligible for surgery or radiosurgery MedDRA version: 21.1 Level: LLT Classification code 10025655 Term: Malignant melanoma of skin System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.1 Level: PT Classification co
Conditions
Interventions
Trade Name: Yervoy
Product Name: Ipilimumab
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: IPILIMUMAB
C
Sponsors
University Hospital Tübingen
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Signed Informed Consent (ICF) prior to any screening procedures being performed 2. Ability to comply with protocol requirements 3. Metastatic histologically confirmed melanoma (per AJCC staging system) that is unresectable 4. Presence of four or more active brain metastasis confirmed/evaluated by MRI Patients with symptomatic brain metastases will be defined as subjects with brain metastases and any of the following: focal neurological deficits, seizures, headache or any other neurological and/or psychiatric alteration with temporal relation to the diagnosis of CNS disease 5. Measurable disease by MRI per iRANO and RECIST 1.1 criteria 6. The time between the baseline MRI and the date of registration should not exceed 28 days. Steroid treatment is permissible before brain MRI evaluation but the dose should have been stable for at least 7 days and should be carefully documented 7. Patient must agree to the cerebro-spinal fluid (CSF) collections which are planned according to the study protocol. 8. Patients naïve for systemic treatment are eligible 9. Patients pre-treated with systemic immunotherapy, targeted therapy or chemotherapy are eligible, with the exception of previous treatment with the combination of CTLA-4 and PD-1 antibodies (see exclusion criterion 2) 10. Patients must have recovered completely from any treatment-related acute toxicity associated with prior therapy 11. At least two weeks must have passed since the last systemic anti-cancer treatment 12. Patients with prior local therapy of brain metastases are eligible 13. Patients may have received irradiation therapies: a. A) None b. B) Whole brain irradiation only c. C) Stereotactic irradiation of single or few metastases. Such lesions cannot be selected as target lesions and must therefore be excluded for the evaluation of the IC-DCR d. D) Combined B+C) 14. Screening laboratory values must meet the following criteria (using CTCAE v4.0) and should be obtained within 14 days prior to registration: • WBC = 2,000/µL • Neutrophils = 1,500/µL • Platelets = 100 x103/µL • Hemoglobin > 9.0 g/dL • Serum creatinine = 1.5 x ULN or creatinine clearance (CrCl) = 40 mL/min (if using the Cockcroft-Gault formula below): o Female CrCl = (140 - age in years) x weight in kg x 0.85 / (72 x serum creatinine in mg/dL) o Male CrCl = (140 - age in years) x weight in kg x 1.00 / (72 x serum creatinine in mg/dL) • AST/ALT = 3 x ULN • Total bilirubin = 1.5 x ULN (except patients with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL) • INR = 1.5 15. ECOG Performance Status 0, 1 or 2 16. Expected life expectancy of =three months 17. Males and females = 18 years old 18. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug 19. Women must not be breastfeeding 20. Women of childbearing potentia
Exclusion criteria
Exclusion criteria: 1. Diagnosed ocular melanoma 2. Previous systemic therapy with the combination of CTLA-4 and PD-1 antibodies 3. Use of any investigational or non-registered product within the 30 days before registration in the study 4. Prior active malignancy within the previous 3 years except locally curable cancers that have been apparently cured, such as: basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the prostate, cervix, or breast 5. History of organ transplantation 6. Active infection requiring systemic therapy 7. Active, known or suspected autoimmune disease. Exceptions: Patients with controlled Type I diabetes mellitus (patients who keep their preprandial blood glucose within the target range of 4 to 7 mmol/L), hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, can be enrolled. 8. Interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity 9. Any serious or uncontrolled medical disorders thatmay increase the risk associated with study participation or study drug administration, impair the ability of the patient to receive protocol therapy, or interfere with the interpretation of study results in the opinion of the investigator. 10. Known substance abuse or psychiatric disorders that would preclude cooperation with tany requirements of the trial. 11. Legal incapacity or limited legal capacity 12. Administration of live, attenuated vaccine within 4 weeks prior to the start of study drug 13. Positive test for hepatitis B virus surface antigen (HBs Ag) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection. 14. Known history of a positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). 15. Patients with known allergy or hypersensitivity to any of the study drugs or excipients Patients with results of imaging or radiological examinations indicating increased cerebral pressure which would prevent lumbar puncture
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of the study is to assess the intracranial disease control rate (IC-DCR) at six months of treatment, defined as the proportion of patients with confirmed complete intracranial responses (CR), partial intracranial responses (PR) or stable in-tracranial disease (SD) assessed by investigators and secondary by an independent neuroradiology reference review in patients with melanoma-derived brain metastases treated with ipilimumab and nivolumab combination therapy.; Secondary Objective: The secondary objectives of the study are to assess: • Overall and progression-free survival • Percentage of patients in whom stereotactic irradiation or surgery of all brain metastases becomes applicable after par-tial tumor remission • Tolerability according to NCI-CTCAE-Criteria (version 4.0) • Best Overall Response Rate (BORR) according to RECIST v1.1 at six months of treatment • Cognitive function assessed by standardized diagnostic pro-cedures • Quality of life ;Primary end point(s): The primary endpoint for this study is Disease Control Rate at 6 months (week 24) according RECIST 1.1 and iRANO [30] as assessed by the treating physicians. The analysis of the primary endpoint will be done when all patients, who are still on-treatment, have had, at least, 2 evaluations after baseline.;Timepoint(s) of evaluation of this end point: The primary endpoint for this study is Disease Control Rate at 6 months (week 24) according RECIST 1.1 and iRANO [30] as assessed by the treating physicians. The analysis of the primary endpoint will be done when all patients, who are still on-treatment, have had, at least, 2 evaluations after baseline. | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: At 6 months (week 24): For consistency, the secondary endpoints will use the same analysis population as the primary endpoint ; Secondary end point(s): The following secondary endpoints should be evaluated • Overall and progression-free survival • Percentage of patients in whom stereotactic irradiation or surgery of all metasta-ses becomes applicable after partial tumor remission • Tolerability according to NCI-CTCAE-Criteria (version 4.0) • Best Overall Response Rate (BORR) according to RECIST v1.1 and iRANO at six months of treatment • Cognitive function • Quality of life | — |
Countries
Germany
Contacts
Public ContactDepartment of Dermatology, Dermatoo
University Hospital Tübingen
Outcome results
None listed