Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

Melanoma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

All Drugs and Chemicals

Antineoplastic Agents

Immunomodulating Agents

Vemurafenib

Protein Kinase Inhibitors

Enzyme Inhibitors

Vemurafenib will be orally adminitered at 960 mg b.i.d. on Days 1-28. Cobimetinib will be given orally at 60 mg qd on Days 1-21 of each 28-day treatment cycle until disease progression.

Treatments will be continued until the development of progressive disease (as per Investigator assessment), unacceptable toxicity, consent withdrawal, death, reasons deemed by the treating physician or study termination by the Sponsor.

Vemurafenib will be orally adminitered at 960 mg b.i.d. on Days 1-28

Cobimetinib will be given orally at 60 mg qd on Days 1-21 of each 28-day treatment cycle

Cobimetinib

Paolo Antonio Ascierto

In the BRIM-3 trial, which was conducted in patients with previously untreated advanced melanoma harboring the BRAF V600E mutation, vemurafenib, a potent inhibitor of mutated BRAF, was associated with prolonged overall survival (OS) and progression-free survival (PFS) compared to dacarbazine. In the same setting, combined use of vemurafenib and cobimetinib, a selective inhibitor of MEK, yielded a significant improvement in PFS and response rate, compared to vemurafenib monotherapy, along with an advantage in OS, which did not cross the pre-specified significance bounderies (COBRIM trial). In treatment-naïve patients with mutated BRAF, both anti PD-1-based immunotherapy and BRAF-targeted agents are feasible therapeutic options, with the former and latter agents being associated with more durable and earlier responses, respectively.

As suggested by National Comprehensive Cancer Network (NCCN) guidelines, the use of combined BRAF and MEK inhibitors in patients with progressive disease after immunotherapy, is also feasible, but it is not supported by category 1 evidence, in view of the lack of studies conducted in this setting.

The main objective of this phase II trial is to evaluate the efficacy and safety of the combined use of vemurafenib plus cobimetinib in advanced melanoma patients who have received first-line systemic immunotherapy for inoperable locally advanced / metastatic disease.

In the BRIM-3 trial, which was conducted in patients with previously untreated advanced melanoma harboring the BRAF V600E mutation, vemurafenib, a potent inhibitor of mutated BRAF, was associated with prolonged OS and PFS compared to dacarbazine. In the same setting, combined use of vemurafenib and cobimetinib, a selective inhibitor of MEK, yielded a significant improvement in PFS and response rate, compared to vemurafenib monotherapy, along with an advantage in OS, which did not cross the pre-specified significance bounderies (COBRIM trial). In treatment-naïve patients with mutated BRAF, both anti PD-1-based immunotherapy and BRAF-targeted agents are feasible therapeutic options, with the former and latter agents being associated with more durable and earlier responses, respectively.

As suggested by NCCN guidelines, the use of combined BRAF and MEK inhibitors in patients with progressive disease after immunotherapy, is also feasible, but it is not supported by category 1 evidence, in view of the lack of studies conducted in this setting.

The main objective of this phase II trial is to evaluate the efficacy and safety of the combined use of vemurafenib plus cobimetinib in advanced melanoma patients who have received first-line systemic immunotherapy for inoperable locally advanced / metastatic disease.

As evidenced above, vemurafenib inhibits the BRAF V600E kinase, (this mutation is found in 50% to 60% of melanomas), and enables a remarkable clinical response rate, more than 50% and a statistically significant improvement in OS in patients with unresectable stage III and IV melanoma.

However, the clinical utility of BRAF-I treatment is limited by the development of drug resistance. Multiple mechanisms underlie the development of BRAF-I resistance in BRAF V600E melanoma cells including point mutations in MEK1, amplification of mutant BRAF V600E, elevated closely related serinethreonine kinase activity, activating NRAS mutations, increased levels of COT/Tpl2, aberrantly spliced BRAF V600E and growth factor receptor upregulation. Most of these alterations cause BRAF-I resistance by reactivating the MAPK pathway which plays a major role in the proliferation, survival, and metastatic potential of melanoma cells \[Shi 2014a, Shi 2014b, Van Allen 2014\].

Inhibition of MEK by the novel MEK-I, trametenib or cobimetinib, has been demonstrated to overcome the reactivation of MAPK pathway which is induced by BRAF-I resistance and to increase both OS and OvRR of melanoma patients when combined with BRAF-I \[Flaherty 2012a, Flaherty 2012b, Hoeflich 2012, Ribas 2014\]. The above-described phase III study, 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma has shown that the combination of vemurafenib and cobimetinib, as compared with vemurafenib alone, resulted in an improvement in PFS and objective responses, with early evidence of improved OS and a somewhat increased toxicity profile \[Larkin 2014\].

Vemurafenib Plus Cobimetinib in Advanced or Metastatic Melanoma Patients

VECODUE A Phase II Trial of Vemurafenib Plus Cobimetinib in Patients Treated With Prior First-line Systemic Immunotherapy for Inoperable Locally Advanced or Metastatic Melanoma

OS will be calculated from the first day of treatment until the date of death from any cause.Any patient not know to have died at the time of data analysis will be censored at the time of the last recorded date on which the patient was know to be alive.

PFS will be defined as the time from initiation of study treatment to the first occurrence of disease progression or death from any cause, whichever occurs first.PFS will be calculated based on disease status evaluated bythe investigator according to RECIST v1.1

ORR, defined as the proportion of patients with a best overall response of either complete response (CR) or partial response (PR), will be calculated based on disease status evaluated by the investigator accordingto RECIST v1.1

Roche Pharma AG

Fondazione Melanoma Onlus

Melanoma, Cutaneous Malignant

Antonio Piñero Madrona, MD PhD

Jacobo Cabañas, MD PhD

Antonio R Rull, MD PhD

Roberto Rodriguez, MD PhD

Jesús Hernández Gil, MD PhD

This study has been designed to validate a non-radioactive method to identify the sentinel lymph node using a superparamagnetic iron-oxide (SPIO) tracer respect to the traditional isotopic method. Both methods are used in every included patient and each patient is its own control.

* Injection of the isotopic tracer in standard form and in the usual preoperative period (hours-day).
* Identical injection in three-four punctures of 2 mL of Sienna+ ® and local massage of 5-10 minutes.
* Optional: colorant injection in standard form. Local massage of 5-10 minutes.
* After 20 minutes: transcutaneous measurement with SentiMag®
* Valuing territories (lymphoscintigraphy information?)
* Surgical identification measures:

  1. st with SentiMag®
  2. nd with gamma detection probe
* Ex vivo check and HRD record

Validation of Ferromagnetic Tracer in Melanoma Sentinel Node

Isotopic Versus Magnetic Intraoperative Node Evaluation in Cutaneous Malignant Melanoma

Detection of potential sentinel nodes using both methods (isotopic and ferromagnetic tracers). Máximum register of isotopic and ferromagnetic measurement will be the main criteria.

Agreement in isotopic and ferromagnetic sentinel node identification. Measurement criteria will be coincidence in the same node (or nodes).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Vemurafenib Plus Cobimetinib in Advanced or Metastatic Melanoma Patients	NCT03224208	Melanoma Melanoma (Skin) Melanoma Stage	Vemurafenib Cobimetinib	18 Years -	Fondazione Melanoma Onlus
Validation of Ferromagnetic Tracer in Melanoma Sentinel Node	NCT03449615	Melanoma Stage Sentinel Lymph ...		18 Years -	Sociedad Española de Oncología Quirúrgica

Spots Global Cancer Trial Database for melanoma stage