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Study of Neo-adjuvant Use of Vemurafenib Plus Cobimetinib for BRAF Mutant Melanoma With Palpable Lymph Node Metastases

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ClinicalTrials.gov Identifier: NCT02036086
Recruitment Status : Recruiting
First Posted : January 14, 2014
Last Update Posted : January 23, 2018
Sponsor:
Information provided by (Responsible Party):
Sunnybrook Health Sciences Centre

Brief Summary:
This study will evaluate the clinical and pathological response to vemurafenib and cobimetinib in the neoadjuvant treatment of patients with histologically confirmed, BRAF V600 mutation-positive Stage IIIB and C melanoma. 20 patients will be treated with vemurafenib and cobimetinib for 2 months. Then they will be assessed for surgery. Patients will undergo surgery and subsequently resume taking vemurafenib and cobimetinib after recovery from surgery. Patients will undergo radiation therapy if appropriate then continue vemurafenib and cobimetinib. The maximum treatment period is 12 months. After 12 months of treatment, patients will be followed for disease recurrence and survival during for a total of 5 years.

Condition or disease Intervention/treatment Phase
Melanoma Drug: Vemurafenib Drug: Cobimetinib Phase 2

Detailed Description:

At Screening: Assessments will include CT or MRI of the brain, CT of chest, abdomen and pelvis, dermatology assessment, head and neck exam, pelvic and anal exam, ophthalmology exam, electrocardiogram (ECG), echocardiogram (ECHO) or multigated acquisition (MUGA) scan, a history and physical exam. A core biopsy will be performed within 14 days of study entry.

During Treatment: The maximum treatment period is 12 months. Patients will be assessed monthly while on treatment. Assessments performed will include vital signs assessment and physical exam, dermatology exam, ophthalmology exam, echocardiogram (ECHO) or multigated acquisition (MUGA) scan, electrocardiogram (ECG), safety blood tests, pelvic and anal exam.

Follow-up after treatment: Patients will be followed for 5 years. Radiology exams will be done to assess for disease. Other assessments performed include vital signs assessment and physical exam, dermatology exam, include echogram (ECHO) or multigated acquisition (MUGA) scans.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Pilot Study of the Neo-adjuvant Use of Vemurafenib Plus Cobimetinib (GDC-0973) in Patients With BRAF Mutant Melanoma With Palpable Lymph Node Metastases.
Study Start Date : August 2015
Estimated Primary Completion Date : October 2022
Estimated Study Completion Date : October 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Melanoma

Arm Intervention/treatment
Experimental: Vemurafenib, pill, twice daily
Vemurafenib, 960 mg, oral, twice daily plus Cobimetinib, 60 mg, oral, four times daily
Drug: Vemurafenib
Drug
Other Name: Zelboraf

Drug: Cobimetinib
Drug
Other Name: GDC-0973




Primary Outcome Measures :
  1. The feasibility of treating patients with unresectable melanoma and palpable lymph node metastases that harbor the BRAF mutation with neoadjuvant vemurafenib. [ Time Frame: 24 months ]

Secondary Outcome Measures :
  1. Resectability rates post vemurafenib therapy [ Time Frame: 5 years ]
  2. Local-regional recurrence rates after treatment with neo-adjuvant vemurafenib. [ Time Frame: 5 years ]
  3. Time to distant metastases and Distant Metastatic Free Survival (DMFS). [ Time Frame: 5 years ]
  4. Disease Free Survival (DFS) and Overall Survival (OS). [ Time Frame: 5 years ]
  5. Immunohistochemical correlates of tumor response. [ Time Frame: 5 years ]
  6. Safety and tolerability of vemurafenib in the neoadjuvant setting [ Time Frame: 5 years ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Naïve to treatment for locally advanced unresectable disease (Stage IIIB and C). Prior adjuvant therapy (including immunotherapy, e.g., Ipilimumab) is allowed if prior to nodal recurrence.
  2. Biopsy proven unresected melanoma with palpable regional lymph node metastases, stage IIIB or C or with recurrent regional lymphadenopathy that are not suitable or not preferred for surgical intervention.
  3. BRAFV600 mutation positive
  4. Eastern Cooperative Oncology Group performance status of 0 or 1
  5. Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
  6. Adequate hematologic, renal and liver function within 7 days prior to the first dose of vemurafenib.
  7. Agree to always use an effective form(s) of contraception beginning from the informed consent signature date until at least 6 months after completion of study therapy
  8. Negative serum pregnancy test within 14 days prior to start of treatment in women of childbearing potential only.

Exclusion Criteria:

  1. Cannot have received any prior therapy. Previous adjuvant immunotherapy is allowed if more than 3 months have elapsed prior to nodal recurrence.
  2. History of prior RAF or MEK pathway inhibitor treatment.
  3. Active malignancy (other than BRAF−mutated melanoma) or a previous malignancy within the past 3 years are excluded; except for patients with resected melanoma, resected basal cell carcinoma (BCC), resected cutaneous squamous cell carcinoma (SCC), resected melanoma in situ, resected carcinoma in-situ of the cervix, and resected carcinoma in-situ of the breast.
  4. Evidence of distant metastatic disease.
  5. History of clinically significant liver disease (including cirrhosis), current alcohol abuse, or known infection with Human Immunodeficiency Virus (HIV), hepatitis B virus, or hepatitis C virus.
  6. Active infection or chronic infection requiring chronic suppressive antibiotics
  7. Pregnant or breastfeeding
  8. Active autoimmune disease
  9. Acromegaly
  10. History of malabsorption or other clinically significant metabolic dysfunction
  11. Requires a concomitant medication or dietary supplement that is prohibited during the study
  12. Current, recent (within 28 days of enrolment) or planned use of any investigational product outside of this study
  13. The following foods or supplements are prohibited at least 7 days prior to initiation of and during study treatment:

    1. St. John's wort or hyperforin
    2. Grapefruit juice
  14. History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment / central serous chorioretinopathy (CSCR), retinal vein occlusion (RVO), or neovascular macular degeneration.
  15. Risk factors for retinal vein occlusion (RVO) based on the following:

    1. Uncontrolled glaucoma with intra-ocular pressures
    2. Serum cholesterol ≥Grade 2
    3. Hypertriglyceridemia ≥Grade 2
    4. Hyperglycemia (fasting) ≥Grade 2
  16. Clinically significant cardiac dysfunction, including the following:

    1. Current unstable angina
    2. Current symptomatic congestive heart failure of New York Heart Association class 2 or higher
    3. History of congenital long QT syndrome or or corrected QT interval greater than 450 msec at baseline or uncorrectable abnormalities in serum electrolytes (sodium, potassium, calcium, magnesium, phosphorus).
    4. Current uncontrolled hypertension ≥Grade 2 (patients with a history of hypertension controlled with anti-hypertensives to ≤ Grade 1 are eligible).
    5. Left ventricular ejection fraction (LVEF) below institutional lower limit of normal (LLN) or below 50%, whichever is lower
  17. Palliative radiotherapy or major surgery within 14 days prior to first dose of study treatment

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02036086


Contacts
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Contact: Teresa Petrella, MD, BSc, MSc 416 480 5248 teresa.petrella@sunnybrook.ca
Contact: Frances Wright, MD, MEd 416 480 4210 frances.wright@sunnybrook.ca

Locations
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Canada, Ontario
The Ottawa Hospital - General Campus Recruiting
Ottawa, Ontario, Canada, K1H 8L6
Contact: Carolyn Nessim, MD, MSc    613-737-8899 ext 71085    cnessim@toh.on.ca   
Principal Investigator: Carolyn Nessim, MD, MSc         
Sunnybrook Health Sciences Centre Recruiting
Toronto, Ontario, Canada, M4N 3M5
Contact: Teresa Petrella, MD, BSc, MSc    416 480 5248    teresa.petrella@sunnybrook.ca   
Principal Investigator: Teresa Petrella, MD, BSc, MSc         
Canada, Quebec
Royal Victoria Hospital Recruiting
Montreal, Quebec, Canada, H3A 1A1
Contact: Catalin Mihalcioiu, MD    514 934 1934 ext 35800    catalin.mihalcioiu@muhc.mcgill.ca   
Principal Investigator: Catalin Mihalcioiu, MD         
Sponsors and Collaborators
Sunnybrook Health Sciences Centre
Investigators
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Principal Investigator: Teresa Petrella, MD, BSc, MSc Sunnybrook Health Sciences Centre

Publications:

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Responsible Party: Sunnybrook Health Sciences Centre
ClinicalTrials.gov Identifier: NCT02036086     History of Changes
Other Study ID Numbers: ML28606
First Posted: January 14, 2014    Key Record Dates
Last Update Posted: January 23, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes

Keywords provided by Sunnybrook Health Sciences Centre:
Melanoma stage IIIB or C with BRAF mutation
Recurrent regional lymphadenopathy not suitable for surgery
Eligible for neoadjuvant vemurafenib and cobimetinib

Additional relevant MeSH terms:
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Melanoma
Nevi and Melanomas
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Vemurafenib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action