Patients with unresectable or metastatic BRAF V600 mutant melanoma.
Conditions
Interventions
Trade Name: Zelboraf
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: vemurafenib
CAS Number: 918504-65-1
Other descriptive name: VEMURAFENIB
Concentration unit: mg milligram(s)
Concentrat
Sponsors
University Hospital Essen
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Be willing and able to provide written informed consent for the trial. 2. Male or female patient being ? 18 years of age on day of signing informed consent. 3. Histologically confirmed diagnosis of locally advanced, unresectable or metastatic melanoma AJCC (unresectable stage IIIB, IIIC, IVM1a, IVM1b, or IVM1c) without active or untreated brain metastases; all known CNS lesions must have been treated with stereotactic therapy or surgery at least 4 weeks prior to the first dose of trial treatment AND the patient must be without evidence of clinical or radiographic disease progression in the CNS for at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms must have returned to baseline, the patient must have no evidence of new or enlarging brain metastases, and the patient must not have used steroids in dosing exceeding 10 mg daily of prednisone equivalent for at least 3 weeks prior to trial treatment. 4. No previous therapy for the advanced or metastatic stage. Prior adjuvant therapy is permitted (e.g. IFN, IL-2-therapy, chemo- or radiotherapy). Prior adjuvant therapy has to be terminated (last dose) at least 28 days before enrolment. Patients who are in follow-up period of a clinical trial in adjuvant setting and progressing may be enrolled / randomized. 5. Measurable disease, i.e., present with at least one measurable lesion per RECIST, version 1.1, for the definition of a measureable lesion. 6. Presence of BRAF mutation (V600) in tumor tissue from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion prior to enrolment. 7. Have provided tissue from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion. 8. Have a performance status of 0 or 1 on the ECOG Performance Scale. 9. Demonstrate adequate organ function as defined in the study protocol. All screening labs should be performed within 28 days of treatment initiation. 10. Adequate cardiac function: ? Left ventricular ejection fraction (LVEF) = 50% as determined by multigated acquisition (MUGA) scan or echocardiogram ? QTc interval = 450 ms 11. All prior treatment-related toxicities (except alopecia) following adjuvant therapy must be = Grade 1 according to the CTCAE (version 4.03) at the time of randomization. Note: Subjects with = Grade 2 neuropathy are an exception to this criterion and may qualify for the study. 12. Able to take oral medications. 13. Patient is deemed by the investigator to have the initiative and means to be compliant with the protocol. 14. Female subject of childbearing potential should have a negative urine pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 15. Female patients of childbearing potential and male patients with partners of childbearing potential must agree to always use a highly effective form of contraception according to CTFG during the course of this study and for at least 6 months after completion of study therapy. Birth control methods which may be considered as highly effective can achieve a failure rate of less than 1% per year when used consistently and correctly. - Females of childbearing potential are defined as sexually mature women without prior oophorectomy or hysterectomy who have had menses within the last 12 months. - Females are not considered to be of childbearing potential if amenorrheic
Exclusion criteria
Exclusion criteria: 1. Use of any investigational or non-registered product within the 30 days before registration. 2. Diagnosis of immunodeficiency or receiving systemic steroid therapy in dosing exceeding 10 mg daily of prednisone equivalent or any other form of immunosuppressive therapy within 7 days prior to study Day 1. 3. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways). 4. Prior therapy with a BRAF inhibitor (including but not limited to vemurafenib, dabrafenib, encorafenib and / or MEK inhibitor (including but not limited to trametinib, AZD6244, Binimetinib, Cobimetinib) also in an adjuvant setting. 5. Prior major surgery. Note: Subjectsmay be enrolled if they have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. 6. Known additional malignancy that is progressing or requires active treatment within 3 years prior to the study. Exceptions include adequately treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy without evidence or recurrence. 7. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. 8. History of leptomeningeal metastases 9. History or current evidence of central serous retinopathy (CSR) or retinal vein occlusion (RVO) or predisposing factors to RVO or CSR (e.g. uncontrolled glaucoma or ocular hypertension, uncontrolled diabetes mellitus, history of hyperviscosity or hypercoagulability syndromes). 10. History of retinal degenerative disease. 11. History of allogenic bone marrow transplantation or organ transplantation. 12. History of Gilbert’s syndrome 13. Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following: ? History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) 450 ms at baseline or uncorrectable abnormalities in serum electrolytes (sodium, potassium, calcium, magnesium, phosphorus). 14. Uncontrolled arterial hypertension despite medical treatment. 15. Patients who have neuromuscular disorders which are associated with elevated CK (e. g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy). 16. Impairment of gastrointestinal function or gastrointestinal disease (e.g. ulcerative disease, uncontrolled nausea, vomiting, malabsorption syndrome, small bowel resection). 17. Active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids in dosing exceeding 10 mg daily of prednisone equivalent or immunosuppressive agents. 18. Evidence of interstitial lung disease or active, non-infectious pneumonitis. 19. Active infec
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The objectives of the study are to assess the best timing of treatment approaches targeting the Ras/Raf signalling pathway by BRAF and MEK inhibition and targeting immunologic checkpoint control with an antiPD-L1 antibody in patients with unresectable or metastatic BRAFV600 mutant melanoma. Furthermore the safety of the study treatment will be assessed. The following endpoints will help to address the study objectives: Primary endpoint: Time to Second Objective Disease Progression (PFS2) defined as time from start of run-in phase (date of first intake of study drug) to second objective disease progression according to RECIST v. 1.1. (PD2) following randomization or death from any cause.;Secondary Objective: Among others: -Safety -Overall Survival (OS) of a patient defined as the time from start of run-in phase (date of first intake of study drug) until documented date of death -Overall survival rate at 12 months and 24 months defined as the rate of patients alive 12 months and 24 months, respectively after start of run-in phase (date of first intake of study drug) -12-months and 24-months disease control rate (DCR). DCR is defined as the rate of patients showing complete response (CR) or partial response (PR) or stable disease (SD) at 12 months and at 24 months after start of run-in phase (date of first intake of study drug). CR, PR, and SD are defined according to RECIST v1.1 Criteria -Rate of patients with progressive disease who could not cross-over to subsequent line of therapy due to deterioration of ECOG status and/or brain metastases (...);Primary end point(s): Time to Second Objective Disease Progression (PFS2) defined as time from start of run-in phase (date of first intake of study drug) to second objective disease progression according to RECIST v. 1.1. (PD2) following randomization or death from any cause.;Timepoint(s) of evaluation of this end point: Time to Second Objective Disease Progression (PFS2) defined as time from start of run-in | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): -Safety Safety as a secondary endpoint is defined as all adverse events = Grade 3 according to CTCAE, Version 4.03 criteria and all SAEs, regardless of causal relationship to the administration of the investigational agents will be assessed. Overall Survival (OS) of a patient defined as the time from start of run-in phase (date of first intake of study drug) until documented date of death -Overall survival rate at 12 months and 24 months defined as the rate of patients alive 12 months and 24 months, respectively after the start of run-in phase (date of first intake of study drug) -12-months and 24-months disease control rate (DCR). DCR is defined as the rate of patients showing complete response (CR) or partial response (PR) of stable disease (SD) at 12 months and at 24 months after the start of run-in phase (date of first intake of study drug)). CR, PR, and SD are defined according to RECIST v1.1 Criteria -Rate of patients with progressive disease who could not cross-over to subsequent line of therapy due to deterioration of ECOG status and/or symptomatic brain metastases -From vemurafenib + cobimetinib to atezolizumab (Arm A) -From atezolizumab to vemurafenib + cobimetinib (Arm B) -PFS1 defined as time from start of run-in phase (date of first intake of study drug) until the first documented tumor progression date (PD1) or death by any cause -PFS3 defined as time from the first documented tumor progression date (PD1) until the second documented tumor progression date (PD2) after randomization or death by any cause.;Timepoint(s) of evaluation of this end point: Patients will be treated up to second disease progression after randomization, death or unacceptable toxicity. | — |
Countries
France, Germany, Greece, Russian Federation, Serbia
Contacts
Public ContactDepartment of Dermatology
University Hospital Essen
Outcome results
None listed