Description:
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.
Title
- 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.
Clinical Trial IDs
- ORG STUDY ID:
ML28606
- NCT ID:
NCT02036086
Conditions
Interventions
Drug | Synonyms | Arms |
---|
Vemurafenib | Zelboraf | Vemurafenib, pill, twice daily |
Cobimetinib | GDC-0973 | Vemurafenib, pill, twice daily |
Purpose
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.
Trial Arms
Name | Type | Description | Interventions |
---|
Vemurafenib, pill, twice daily | Experimental | Vemurafenib, 960 mg, oral, twice daily plus Cobimetinib, 60 mg, oral, four times daily | |
Eligibility 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 and ≥ 3 months have elapsed from the last day of adjuvant therapy to
start of study treatment2. Biopsy proven unresected melanoma with palpable regional
lymph node.
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 prefered for surgcal 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.
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | 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 |
Safety Issue: | |
Description: | |
Secondary Outcome Measures
Measure: | Resectability rates post vemurafenib therapy |
Time Frame: | 5 years |
Safety Issue: | |
Description: | |
Measure: | Local-regional recurrence rates after treatment with neo-adjuvant vemurafenib. |
Time Frame: | 5 years |
Safety Issue: | |
Description: | |
Measure: | Time to distant metastases and Distant Metastatic Free Survival (DMFS). |
Time Frame: | 5 years |
Safety Issue: | |
Description: | |
Measure: | Disease Free Survival (DFS) and Overall Survival (OS). |
Time Frame: | 5 years |
Safety Issue: | |
Description: | |
Measure: | Immunohistochemical correlates of tumor response. |
Time Frame: | 5 years |
Safety Issue: | |
Description: | |
Measure: | Safety and tolerability of vemurafenib in the neoadjuvant setting |
Time Frame: | 5 years |
Safety Issue: | |
Description: | |
Details
Phase: | Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Active, not recruiting |
Lead Sponsor: | Sunnybrook Health Sciences Centre |
Trial Keywords
- Melanoma stage IIIB or C with BRAF mutation
- Recurrent regional lymphadenopathy not suitable for surgery
- Eligible for neoadjuvant vemurafenib and cobimetinib
Last Updated
October 22, 2020