Vemurafenib Plus Cobimetinib Plus PEG-interferon in Advanced Melanoma Patients Harboring the V600BRAF Mutation

Phase I-II Study of the Combination Vemurafenib Plus Cobimetinib Plus PEG-interferon in Advanced Melanoma Patients Harboring the V600BRAF Mutation

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.

Phase I A cohort of 3 consecutive patients will be treated at each dose level (first step). Patients are scheduled to receive at least two courses of therapy (cycle every 28 days) at the same dose level. Escalation of the dose to the next higher level proceeds in absence of dose-limiting toxicity (DLT). Drug-related toxicities will be evaluated during each cycle of therapy and graded according to the NCI Common Toxicity Criteria.

Adverse events (AEs) and the activity of the treatment in terms of ORR, will be assessed as primary endpoints, respectively for phase I and phase II; other variables will be compared as secondary endpoints.

The treatment scheme is Peg-Interferon 1/2/3 micrograms/Kg (lyophilized powder 296 and 444 μg vials) one time per week + Vemurafenib film-coated capsules 960 mg b.i.d. + Cobimetinib tablets 60 mg o.d. 21 days on followed by 7 days off.

Interferon treatment should start after 15 days of Vemurafenib + Cobimetinib only.

Phase I will be conducted at Istituto Nazionale per lo Studio e la Cura dei Tumori - Fondazione G. Pascale (PI Paolo Antonio Ascierto) and a minimum of 3 patients per cohort will be enrolled. Groups of 3 patients will be entered at each dose level (vemurafenib 960 mg b.i.d. + Cobimetinib 60 mg o.d. 21 days on followed by 7 days off + Peg-interferon 1/2/3 micrograms/Kg). DLT will be determined after 2 courses of therapy: 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 after the first 2 courses of therapy in each cohort, 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 the MTD.

The maximum tolerated dose (MTD) is then considered the recommended dose for further evaluation (next step).

Patients experiencing toxicities that were not dose-limiting can be retreated at the same dose level upon full recovery.

Special case is represented by patients with liver metastases for whom ALT or AST increases >3xULN (i.e., Grade 2 of the CTCAE) requires a closer monitoring of the liver tests. In such cases patients with AT up to 5xULN may be allowed to participate in the trial. Therefore, a threshold level of ALT or AST >3xBaseline value (vs. the standard >3xULN threshold) is considered to prompt closer monitoring for the whole duration of the treatment. Patients with rapidly rising or high serum ALT or AST or with ALT or AST elevations accompanied by jaundice require urgent evaluation to find treatable causes of hepatocellular necrosis.

Patients will be treated until progression if the MTD is not reached.

Phase II Phase II will be conducted in approximately 10 Investigational sites located in Italy and 42 patients will be enrolled in total (including 3 patients from the phase I).

Treatment will be continued until progression or unacceptable toxicity.

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