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MelanomaPhase 2NCT02036086

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

A Phase 2 study testing Vemurafenib and Cobimetinib in people with Melanoma, run by Sunnybrook Health Sciences Centre at 3 sites in Canada.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Melanoma
What is being tested?
Vemurafenib and Cobimetinib
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
24 participants
Where
3 sitesCanada
Study dates
Aug 2015to 31 Jan 2024
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • 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.

Who cannot join

  • 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.
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  • 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.

Trial locations and contacts

3 sites in 1 country.

Canada3 sites

  • Royal Victoria Hospital

    Montreal, Quebec, H3A 1A1

  • The Ottawa Hospital - General Campus

    Ottawa, Ontario, K1H 8L6

  • Sunnybrook Health Sciences Centre

    Toronto, Ontario, M4N 3M5

Other trials in Canada

About this study

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.

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.

Read the 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.

Conditions
Melanoma
Being tested
Vemurafenib, Cobimetinib
Keywords
Melanoma stage IIIB or C with BRAF mutation, Recurrent regional lymphadenopathy not suitable for surgery, Eligible for neoadjuvant vemurafenib and cobimetinib
Medical subject headings
Melanoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • VemurafenibDrug

    Also called Zelboraf

    Drug

  • CobimetinibDrug

    Also called GDC-0973

    Drug

Study groups in NCT02036086
Study groupRoleWhat they receive
Vemurafenib, pill, twice dailyExperimentalVemurafenib, 960 mg, oral, twice daily plus Cobimetinib, 60 mg, oral, four times daily
Receives: Drug: Vemurafenib; Drug: Cobimetinib

What is being measured

The primary outcome is the main question the study is designed to answer.

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

    Measured: 24 months

Secondary outcomes (6)

  1. Resectability rates post vemurafenib therapy

    Measured: 5 years

  2. Local-regional recurrence rates after treatment with neo-adjuvant vemurafenib.

    Measured: 5 years

  3. Time to distant metastases and Distant Metastatic Free Survival (DMFS).

    Measured: 5 years

  4. Disease Free Survival (DFS) and Overall Survival (OS).

    Measured: 5 years

  5. Immunohistochemical correlates of tumor response.

    Measured: 5 years

  6. Safety and tolerability of vemurafenib in the neoadjuvant setting

    Measured: 5 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted14 Jan 2014 (estimated)
  2. Study startAug 2015
  3. Primary completion31 Jan 2024 (estimated)
  4. Study completion31 Jan 2024 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
24 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02036086
Sponsor's protocol ID
ML28606
Status last verified
Oct 2022
First submitted
28 Nov 2013
Last updated
27 Oct 2022
Results posted
No
Data monitoring committee
No
Individual data sharing
Yes

Publications

  • Balch CM, Soong SJ, Gershenwald JE, Thompson JF, Reintgen DS, Cascinelli N, Urist M, McMasters KM, Ross MI, Kirkwood JM, Atkins MB, Thompson JA, Coit DG, Byrd D, Desmond R, Zhang Y, Liu PY, Lyman GH, Morabito A. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol. 2001 Aug 15;19(16):3622-34. doi: 10.1200/JCO.2001.19.16.3622.

    PubMed 11504744

  • Bevilacqua RG, Coit DG, Rogatko A, Younes RN, Brennan MF. Axillary dissection in melanoma. Prognostic variables in node-positive patients. Ann Surg. 1990 Aug;212(2):125-31. doi: 10.1097/00000658-199008000-00002.

    PubMed 2375645

  • Mocellin S, Pasquali S, Rossi CR, Nitti D. Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis. J Natl Cancer Inst. 2010 Apr 7;102(7):493-501. doi: 10.1093/jnci/djq009. Epub 2010 Feb 23.

    PubMed 20179267

  • Hauschild A, Gogas H, Tarhini A, Middleton MR, Testori A, Dreno B, Kirkwood JM. Practical guidelines for the management of interferon-alpha-2b side effects in patients receiving adjuvant treatment for melanoma: expert opinion. Cancer. 2008 Mar 1;112(5):982-94. doi: 10.1002/cncr.23251.

    PubMed 18236459

  • Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR, Buzaid AC, Cochran AJ, Coit DG, Ding S, Eggermont AM, Flaherty KT, Gimotty PA, Kirkwood JM, McMasters KM, Mihm MC Jr, Morton DL, Ross MI, Sober AJ, Sondak VK. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009 Dec 20;27(36):6199-206. doi: 10.1200/JCO.2009.23.4799. Epub 2009 Nov 16.

    PubMed 19917835

  • Shah GD, Socci ND, Gold JS, Wolchok JD, Carvajal RD, Panageas KS, Viale A, Brady MS, Coit DG, Chapman PB. Phase II trial of neoadjuvant temozolomide in resectable melanoma patients. Ann Oncol. 2010 Aug;21(8):1718-1722. doi: 10.1093/annonc/mdp593. Epub 2010 Jan 15.

    PubMed 20080829

  • Moschos SJ, Edington HD, Land SR, Rao UN, Jukic D, Shipe-Spotloe J, Kirkwood JM. Neoadjuvant treatment of regional stage IIIB melanoma with high-dose interferon alfa-2b induces objective tumor regression in association with modulation of tumor infiltrating host cellular immune responses. J Clin Oncol. 2006 Jul 1;24(19):3164-71. doi: 10.1200/JCO.2005.05.2498.

    PubMed 16809739

  • Gibbs P, Anderson C, Pearlman N, LaClaire S, Becker M, Gatlin K, O'Driscoll M, Stephens J, Gonzalez R. A phase II study of neoadjuvant biochemotherapy for stage III melanoma. Cancer. 2002 Jan 15;94(2):470-6. doi: 10.1002/cncr.10186.

    PubMed 11900232

  • Young K, Minchom A, Larkin J. BRIM-1, -2 and -3 trials: improved survival with vemurafenib in metastatic melanoma patients with a BRAF(V600E) mutation. Future Oncol. 2012 May;8(5):499-507. doi: 10.2217/fon.12.43.

    PubMed 22646765

  • Long GV, Menzies AM, Nagrial AM, Haydu LE, Hamilton AL, Mann GJ, Hughes TM, Thompson JF, Scolyer RA, Kefford RF. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol. 2011 Apr 1;29(10):1239-46. doi: 10.1200/JCO.2010.32.4327. Epub 2011 Feb 22.

    PubMed 21343559

  • Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, McArthur GA, Hutson TE, Moschos SJ, Flaherty KT, Hersey P, Kefford R, Lawrence D, Puzanov I, Lewis KD, Amaravadi RK, Chmielowski B, Lawrence HJ, Shyr Y, Ye F, Li J, Nolop KB, Lee RJ, Joe AK, Ribas A. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012 Feb 23;366(8):707-14. doi: 10.1056/NEJMoa1112302.

    PubMed 22356324

  • Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, Ribas A, O'Day SJ, Sosman JA, Kirkwood JM, Eggermont AM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT, McArthur GA; BRIM-3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011 Jun 30;364(26):2507-16. doi: 10.1056/NEJMoa1103782. Epub 2011 Jun 5.

    PubMed 21639808

  • Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, Chen Z, Lee MK, Attar N, Sazegar H, Chodon T, Nelson SF, McArthur G, Sosman JA, Ribas A, Lo RS. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010 Dec 16;468(7326):973-7. doi: 10.1038/nature09626. Epub 2010 Nov 24.

    PubMed 21107323

  • Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, Demidov LV, Hassel JC, Rutkowski P, Mohr P, Dummer R, Trefzer U, Larkin JM, Utikal J, Dreno B, Nyakas M, Middleton MR, Becker JC, Casey M, Sherman LJ, Wu FS, Ouellet D, Martin AM, Patel K, Schadendorf D; METRIC Study Group. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012 Jul 12;367(2):107-14. doi: 10.1056/NEJMoa1203421. Epub 2012 Jun 4.

    PubMed 22663011

  • Larkin J, Ascierto PA, Dreno B, Atkinson V, Liszkay G, Maio M, Mandala M, Demidov L, Stroyakovskiy D, Thomas L, de la Cruz-Merino L, Dutriaux C, Garbe C, Sovak MA, Chang I, Choong N, Hack SP, McArthur GA, Ribas A. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014 Nov 13;371(20):1867-76. doi: 10.1056/NEJMoa1408868. Epub 2014 Sep 29.

    PubMed 25265494

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Vemurafenib and Cobimetinib in people with Melanoma, run by Sunnybrook Health Sciences Centre at 3 sites in Canada.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 9 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 27 Oct 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome 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). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02036086, which also lists 16 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Oct 2022.

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