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

Primary Purpose

Melanoma

Status
Active
Phase
Phase 2
Locations
Canada
Study Type
Interventional
Intervention
Vemurafenib
Cobimetinib
Sponsored by
Sunnybrook Health Sciences Centre
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Melanoma focused on measuring Melanoma stage IIIB or C with BRAF mutation, Recurrent regional lymphadenopathy not suitable for surgery, Eligible for neoadjuvant vemurafenib and cobimetinib

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 and ≥ 3 months have elapsed from the last day of adjuvant therapy to start of study treatment.
  2. Biopsy proven unresected melanoma patients with palpable regional lymph node metastases, presenting with AJCC stage IIIB-C or with recurrent regional lymphadenopathy that are not suitable or not preferred for surgical intervention.
  3. BRAF V600 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 and cobimetinib.
  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.
  9. Absence of any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

Exclusion Criteria:

  1. Cannot have received any prior therapy for the current recurrence or nodal disease. Previous adjuvant immunotherapy is allowed if prior to nodal recurrence and ≥ 3 months have elapsed from the last day of adjuvant therapy to start of study treatment.
  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 at the time of enrollment.
  8. Active autoimmune disease (e.g., systemic lupus erythematosus, autoimmune vasculitis, inflammatory bowel disease [Crohn's disease and ulcerative colitis]).
  9. Acromegaly
  10. History of malabsorption or other clinically significant metabolic dysfunction.
  11. Any other serious concomitant medical condition that would compromise safety or compromise the ability to participate in the study.
  12. Requires a concomitant medication or dietary supplement that is prohibited during the study.
  13. Unwillingness or inability to comply with study and follow-up procedures.
  14. Current, recent (within 28 days of enrolment) or planned use of any investigational product outside of this study.
  15. 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
  16. 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.
  17. Currently are known to have the following conditions:

    1. Uncontrolled glaucoma with intra-ocular pressures with > 21 mmHg
    2. Retinal venous occlusion (RVO)
    3. Hypertensive retinopathy
  18. 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 QTcF > 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.

Sites / Locations

  • The Ottawa Hospital - General Campus
  • Sunnybrook Health Sciences Centre
  • Royal Victoria Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Vemurafenib, pill, twice daily

Arm Description

Vemurafenib, 960 mg, oral, twice daily plus Cobimetinib, 60 mg, oral, four times daily

Outcomes

Primary Outcome Measures

The feasibility of treating patients with unresectable melanoma and palpable lymph node metastases that harbor the BRAF mutation with neoadjuvant vemurafenib.

Secondary Outcome Measures

Resectability rates post vemurafenib therapy
Local-regional recurrence rates after treatment with neo-adjuvant vemurafenib.
Time to distant metastases and Distant Metastatic Free Survival (DMFS).
Disease Free Survival (DFS) and Overall Survival (OS).
Immunohistochemical correlates of tumor response.
Safety and tolerability of vemurafenib in the neoadjuvant setting

Full Information

First Posted
November 28, 2013
Last Updated
October 25, 2022
Sponsor
Sunnybrook Health Sciences Centre
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1. Study Identification

Unique Protocol Identification Number
NCT02036086
Brief Title
Study of Neo-adjuvant Use of Vemurafenib Plus Cobimetinib for BRAF Mutant Melanoma With Palpable Lymph Node Metastases
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 Type
Interventional

2. Study Status

Record Verification Date
October 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
August 2015 (Actual)
Primary Completion Date
January 31, 2024 (Anticipated)
Study Completion Date
January 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Sunnybrook Health Sciences Centre

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Melanoma
Keywords
Melanoma stage IIIB or C with BRAF mutation, Recurrent regional lymphadenopathy not suitable for surgery, Eligible for neoadjuvant vemurafenib and cobimetinib

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
24 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Vemurafenib, pill, twice daily
Arm Type
Experimental
Arm Description
Vemurafenib, 960 mg, oral, twice daily plus Cobimetinib, 60 mg, oral, four times daily
Intervention Type
Drug
Intervention Name(s)
Vemurafenib
Other Intervention Name(s)
Zelboraf
Intervention Description
Drug
Intervention Type
Drug
Intervention Name(s)
Cobimetinib
Other Intervention Name(s)
GDC-0973
Intervention Description
Drug
Primary Outcome Measure Information:
Title
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 Measure Information:
Title
Resectability rates post vemurafenib therapy
Time Frame
5 years
Title
Local-regional recurrence rates after treatment with neo-adjuvant vemurafenib.
Time Frame
5 years
Title
Time to distant metastases and Distant Metastatic Free Survival (DMFS).
Time Frame
5 years
Title
Disease Free Survival (DFS) and Overall Survival (OS).
Time Frame
5 years
Title
Immunohistochemical correlates of tumor response.
Time Frame
5 years
Title
Safety and tolerability of vemurafenib in the neoadjuvant setting
Time Frame
5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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 and ≥ 3 months have elapsed from the last day of adjuvant therapy to start of study treatment. Biopsy proven unresected melanoma patients with palpable regional lymph node metastases, presenting with AJCC stage IIIB-C or with recurrent regional lymphadenopathy that are not suitable or not preferred for surgical intervention. BRAF V600 mutation positive. Eastern Cooperative Oncology Group performance status of 0 or 1. Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Adequate hematologic, renal and liver function within 7 days prior to the first dose of vemurafenib and cobimetinib. 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. Negative serum pregnancy test within 14 days prior to start of treatment in women of childbearing potential only. Absence of any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule. Exclusion Criteria: Cannot have received any prior therapy for the current recurrence or nodal disease. Previous adjuvant immunotherapy is allowed if prior to nodal recurrence and ≥ 3 months have elapsed from the last day of adjuvant therapy to start of study treatment. History of prior RAF or MEK pathway inhibitor treatment. 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. Evidence of distant metastatic disease. 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. Active infection or chronic infection requiring chronic suppressive antibiotics. Pregnant or breastfeeding at the time of enrollment. Active autoimmune disease (e.g., systemic lupus erythematosus, autoimmune vasculitis, inflammatory bowel disease [Crohn's disease and ulcerative colitis]). Acromegaly History of malabsorption or other clinically significant metabolic dysfunction. Any other serious concomitant medical condition that would compromise safety or compromise the ability to participate in the study. Requires a concomitant medication or dietary supplement that is prohibited during the study. Unwillingness or inability to comply with study and follow-up procedures. Current, recent (within 28 days of enrolment) or planned use of any investigational product outside of this study. The following foods or supplements are prohibited at least 7 days prior to initiation of and during study treatment: St. John's wort or hyperforin Grapefruit juice 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. Currently are known to have the following conditions: Uncontrolled glaucoma with intra-ocular pressures with > 21 mmHg Retinal venous occlusion (RVO) Hypertensive retinopathy Clinically significant cardiac dysfunction, including the following: Current unstable angina Current symptomatic congestive heart failure of New York Heart Association class 2 or higher History of congenital long QT syndrome or QTcF > 450 msec at baseline or uncorrectable abnormalities in serum electrolytes (sodium, potassium, calcium, magnesium, phosphorus). Current uncontrolled hypertension ≥Grade 2 (patients with a history of hypertension controlled with anti-hypertensives to ≤ Grade 1 are eligible). 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Teresa Petrella, MD, BSc, MSc
Organizational Affiliation
Sunnybrook Health Sciences Centre
Official's Role
Principal Investigator
Facility Information:
Facility Name
The Ottawa Hospital - General Campus
City
Ottawa
State/Province
Ontario
ZIP/Postal Code
K1H 8L6
Country
Canada
Facility Name
Sunnybrook Health Sciences Centre
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M4N 3M5
Country
Canada
Facility Name
Royal Victoria Hospital
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H3A 1A1
Country
Canada

12. IPD Sharing Statement

Plan to Share IPD
Yes
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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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