Patient case: 54-year-old male with melanoma; genetic feature: BRAF (V600K)

Clinical trial: Study of the Combination Vemurafenib Plus PEG-interferon in Advanced Melanoma Patients Harboring the V600BRAF Mutation

Summary: The hypothesis of this study is to evaluate the safety and the efficacy of Vemurafenib/PEG-interferon combination and the IFNAR1 upregulation lead by this treatment.

Detailed description: Phase I will include 9 patients with the common design 3+3+3. This phase will last until MTD is reached and patients who were part of the cohort selected due to MTD will be extended at phase II. In the phase II, 42 patients will be enrolled.
  Vemurafenib 960 mg b.i.d. + Peg-interferon 1/2/3 micrograms/Kg one time per week (until MTD reached) Interferon treatment should start after 15 days of Vemurafenib only. In the Phase I groups of 3 patients will be entered at each dose level (vemurafenib 960 mg b.i.d. + Peg-interferon 1/2/3 micrograms/Kg). If all 3 patients treated at a dose level have been observed for 2 courses of therapy without DLT, then the dose will be escalated.
  If at least 2/3 patients have DLT, then the previous dose level will be considered as the MTD. If 1/3 patients have DLT, then 3 more patients will be treated at this dose level. If none of these patients has DLT, then the dose will be escalated. If at least one of the 3 additional patients has DLT, then the previous dose will be considered as MTD.
  This phase II is aimed:
  - to verify if the combination Vemurafenib plus PEG-interferon in advanced melanoma patients harboring the V600BRAF mutation is more active than the standard therapy (Vemurafenib) as reported in literature.
  Therefore, the lowest response probability of interest at 32 weeks is set to .40, and the combination treatment will be developed further only if the response at that time is at least .60.
  - to verify the upregulation of IFNAR1 expression in patients treated with the combination Vemurafenib plus PEG-interferon Therefore, the lowest expression probability of interest at 7 days is set to .10, and the combination treatment will be developed further only if the expression is at least .90.
  Taking in account a 10% drop-out rate, a total of 48 patients will be enrolled to ensure a minimum of 42 evaluable patients.

Eligibility: Inclusion Criteria:
  1. Patients over 18
  2. Untreated and pretreated (no more than 1 treatment) patients with metastatic melanoma at stage unreseactable IIIb-IV, histologically confirmed, that show V600 type BRAF mutations. Patients eligible for Phase I may have been pretreated with the investigational study treatments.
  3. Patient with measurable disease by RECIST v 1.1
  4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 - 1
  5. Patients who have successfully completed all the secondary side effects to previous systemic therapy
  6. Patients with an appropriate hematologic, hepatic and renal functionality, assessed in the 7 days preceding the start of therapy, as well as:
  -  Absolute neutrophil count (ANC)> 1.5 X 109 / L
  -  Absolute platelet count > 100 X 109 / L
  -  Hemoglobin > 9 g/dl
  -  Serum creatinine < 1.5 times the normal maximum values or Creatinine Clearance > 50 mL/hr (Cockroft-Gault formula)
  -  Transaminase level (AST and ALT) < 2.5 times the normal maximum values
  -  Serum bilirubin < 1.5 times the normal maximum values
  7. Negative pregnancy test performed within 7 days before beginning therapy (premenopausal women)
  8. Patients of childbearing age (or with partners of childbearing age) must use effective contraception during therapy and for at least 6 months after the effective treatment
  9. Absence of any psychological, familiar or social condition that may affect compliance with study protocol and scheduled follow-up
  10. Dated and signed informed consent before any study procedure
  Exclusion Criteria:
  1. Presence of symptomatic brain metastases
  2. Previous malignant cancer during the 2 years preceding the signing of informed consent
  3. Investigational study treatment within 28 days or 5 half-lives, whichever is longer, preceding the first dose of study treatments in this study
  4. Pregnancy and/or breast feeding;
  5. Nausea and vomit refractory to therapy, malabsorption, external biliary shunt, previous bowel resection, which could impair an adequate absorption
  6. Any of these conditions occurring in the 6 months before the start of Vemurafenib therapy: heart attack, unstable angina and/or severe degree, congestive heart failure, cerebrovascular accident or transient ischemic attack, pulmonary embolism, arterial hypertension not adequately controlled
  7. History of atrial or ventricular arrhythmia, symptomatic> grade 2 (NCI CTCAE)
  8. Hystory of retinopathy
  9. Correct QT interval > 450msec to baseline history of congenital long QT syndrome
  10. Uncontrolled medical condition among which endocrine disorders (such as hypothyroidism, hyperthyroidism and diabetes mellitus)
  11. Other severe medical or psychiatric conditions or abnormalities of laboratory tests that may increase the risk associated with study participation or the assumption of Vemurafenib, or that may interfere with the interpretation of study results, which in the judgment of the Investigator can make the patient not eligible for the study
  12. Unwillingness to practice adequate contraception
  13. Prior systemic treatment with BRAFi or MEKi, or interferon alpha

Relevance to patient case: possibly relevant