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MelanomaPhase 2NCT02583516

Clinical Trial to Evaluate the Efficacy of Vemurafenib in Combination With Cobimetinib (Continuous and Intermittent) in BRAFV600-mutation Positive Patients With Unresectable Locally Advanced or Metastatic Melanoma

A Phase 2 study testing vemurafenib and cobimetinib in people with Melanoma, run by Grupo Español Multidisciplinar de Melanoma at 18 sites in Spain.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

The purpose of this study is to evaluate the efficacy and safety of two different schedules of administration of vemurafenib in combination with cobimetinib (continuous and intermittent) in previously untreated BRAFV600- mutation positive patients with unresectable locally advanced or metastatic melanoma. 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
Could I receive a placebo?
No, everyone receives an active treatment
How many people
70 participants
Where
18 sitesSpain
Study dates
30 Jun 2015to 30 Sep 2019
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

  • Disease-Specific Inclusion Criteria:
  • Patients with histologically confirmed melanoma, either unresectable stage IIIc or stage IV metastatic melanoma.
  • Patients must be naïve to treatment for locally advanced unresectable or metastatic disease.
  • Documentation of BRAFV600 mutation-positive status in melanoma tumor tissue.
  • Measurable disease per RECIST v1.1.
  • ECOG performance status of 0 or 1.
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  • Additionally, patients to be included in the biomarker sub- study should meet the following criteria:
  • Consent to provide archival tissue for biomarker analyses.
  • Consent to undergo tumor biopsies.
  • General Inclusion Criteria:
  • Male or female patient aged major or equal 18 years.
  • Able to participate and willing to give written informed.
  • Life expectancy mayor o igual 12 weeks.
  • Adequate hematologic and end organ function, within 14 days prior to first dose of study drug treatment:
  • ANC major or equal 1.5 × 109/L.
  • Platelet count major or equal 100 × 109/L.
  • Hemoglobin major or equal 9 g/dL.
  • Albumin major or equal 2.5 g/dL.
  • Bilirubin minor or equal 1.5 × the upper limit of normal (ULN).
  • AST, ALT, and alkaline phosphatase minor or equal 3 × ULN, with the following exceptions:
  • Patients with documented liver metastases: AST and/or ALT minor or equal 5 × ULN.
  • Patients with documented liver or bone metastases alkaline phosphatase minor o equal 5 × ULN.
  • Serum creatinine minor o equal 1.5 × ULN or CrCl major or equal 40 mL/min on the basis of measured CrCl from a 24- hour urine collection.
  • Female patients of childbearing potential and male patients with partners of childbearing potential must agree to always use 2 effective forms of contraception during the course of this study and for at least 6 months after completion of study therapy.
  • Negative serum pregnancy test within 10 days prior to commencement of dosing in women of childbearing potential.
  • Absence of any psychological, familial, sociological, or geographical condition that potentially hampers compliance with the study protocol and follow-up after treatment discontinuation schedule.

Who cannot join

  • Cancer-Related Exclusion Criteria:
  • History of prior RAF or MEK pathway inhibitor treatment.
  • Palliative radiotherapy within 14 days prior to the first dose of study treatment.
  • Major surgery or traumatic injury within 14 days prior to first dose of study treatment.
  • Active malignancy other than melanoma that could potentially interfere with the interpretation of efficacy measures. Patients with a previous malignancy within the past 3 years are excluded except for patients with resected BCC or SCC of the skin, melanoma in-situ, carcinoma in-situ of the cervix, and carcinoma in-situ of the breast. History of isolated elevation in prostate-specific antigen in the absence of radiographic evidence of metastatic prostate cancer is allowed.
  • History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, retinal vein occlusion (RVO), or neovascular macular degeneration.
Show all 30Show fewer
  • The risk factors for RVO are listed below. Patients will be excluded if they have the following conditions:
  • Uncontrolled glaucoma with intra-ocular pressures > 21 mmHg.
  • Serum cholesterol major or equal Grade 2.
  • Hypertriglyceridemia major or equal Grade 2.
  • Hyperglycemia (fasting) major or equal Grade 2.
  • History of clinically significant cardiac dysfunction, including the following:
  • Current unstable angina.
  • Symptomatic congestive heart failure of New York Heart Association class 2 or higher.
  • History of congenital long QT syndrome or mean (average of triplicate measurements) QTcF > 450 msec at baseline or uncorrectable abnormalities in serum electrolytes (sodium, potassium, calcium, magnesium, phosphorus). If not automated, calculation of QTcF must be done through the following formula: QTcF = (QT interval in ms) / [(60 / heart rate in bpm) )^(1/3)]
  • Uncontrolled hypertension major or equal Grade 2 (patients with a history hypertension controlled with anti-hypertensives to minor or equal Grade 1 are eligible).
  • Left ventricular ejection fraction (LVEF) below institutional lower limit of normal (LLN) or below 50%.
  • Exclusion Criteria Based on Central Nervous System Function:
  • Patients with active CNS lesions (including melanomatous meningitis) are excluded. However, patients are eligible if:
  • All known CNS lesions have been treated with stereotactic therapy or surgery, AND
  • There has been no evidence of clinical and radiographic disease progression in the CNS for major or equal 3 weeks after radiotherapy or surgery.
  • Whole brain radiotherapy is not allowed, with the exception of patients who have had definitive resection or stereotactic therapy of all radiologically detectable parenchymal brain lesions.
  • General Exclusion Criteria:
  • Current severe, uncontrolled systemic disease.
  • History of malabsorption or other condition that would interfere with absorption of study drugs.
  • Pregnant or lactating.
  • Unwillingness or inability to comply with study and follow- up procedures.
  • The following foods/supplements are prohibited at least 7 days prior to initiation of and during study treatment:
  • St. Johns wort or hyperforin (potent cytochrome P450 CYP3A4 enzyme inducer).
  • Grapefruit juice (potent cytochrome P450 CYP3A4 enzyme inhibitor).

Trial locations and contacts

18 sites in 1 country.

18 sites in 1 country

Spain18 sites

  • Hospital Clínic de Barcelona

    Barcelona

  • Hospital del Mar

    Barcelona

  • Hospital Universitario Vall d'Hebron

    Barcelona

  • Hospital General Universitario Santa Lucía

    Cartagena, Murcia

  • Hospital Universitario Donostia

    Donostia / San Sebastian, Guipuzcoa

  • Hospital Insular de Gran Canaria

    Las Palmas de Gran Canaria

  • Hospital Universitario Lucus Augusti

    Lugo

  • Hospital Universitario 12 de Octubre

    Madrid

  • Hospital Universitario La Paz

    Madrid

  • Hospital Regional Universitario de Málaga

    Málaga

  • Hospital Clínico Universitario de Salamanca

    Salamanca

  • Hospital Universitario de Canarias

    Santa Cruz de Tenerife

  • Hospital Universitario Virgen Macarena

    Seville

  • Hospital General Universitario de Valencia

    Valencia

  • Hospital Universitario Doctor Peset

    Valencia

  • Hospital Universitario y Politécnico La Fe

    Valencia

  • Hospital Álvaro Cunqueiro (Complejo Hospitalario Universitario de Vigo)

    Vigo

  • Hospital Universitario Miguel Servet

    Zaragoza

Other trials in Spain

About this study

Official title: A Randomized Phase II Study of Vemurafenib Plus Cobimetinib Continuous Versus Intermittent, in Previously Untreated BRAFV600- Mutation Positive Patients With Unresectable Locally Advanced or Metastatic Melanoma

The purpose of this study is to evaluate the efficacy and safety of two different schedules of administration of vemurafenib in combination with cobimetinib (continuous and intermittent) in previously untreated BRAFV600- mutation positive patients with unresectable locally advanced or metastatic melanoma.

Conditions
Melanoma
Being tested
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.

  • vemurafenib and cobimetinibDrug

    Comparison between different treatment regimens

Study groups in NCT02583516
Study groupRoleWhat they receive
A - Continuous AdministrationExperimental960 mg of vemurafenib po, bid, days 1 to 28 and 60 mg of cobimetinib po, od, days 1 to 21, for each 28-days' cycle.
Receives: Drug: vemurafenib and cobimetinib
B - Intermittent AdministrationExperimental960 mg of vemurafenib po, bid, days 1 to 28 and 60 mg of cobimetinib po, od, days 1 to 21, for each 28-days' cycle, during 12 weeks. After that period, patients will be treated with both drugs at the same doses indicated previously, but with an intermittent pattern: vemurafenib days 1 to 28 followed by 14 days off (4 weeks on and 2 weeks off) and cobimetinib days 1 to 21 followed by 21 days off (3 weeks on and 3 weeks off)
Receives: Drug: vemurafenib and cobimetinib

What is being measured

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

  1. Progression Free Survival (PFS)

    Measured: Through study completion, up to 42 months

Secondary outcomes (6)

  1. Overall Response Rate (ORR)

    Measured: Through study completion, up to 42 months

  2. Progression Free Survival (PFS) at one and two years

    Measured: At one and two years

  3. Overall Survival (OS) at one and two years

    Measured: At one and two years

  4. Adverse Events (AE) occurrence

    Measured: Through study completion, up to 42 months

  5. Serious Adverse Events (SAE) occurrence

    Measured: Through study completion, up to 42 months

  6. Adverse Events of Special Interest (AESI) occurrence

    Measured: Through study completion, up to 42 months

Timeline

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

  1. First posted22 Oct 2015 (estimated)
  2. Study start30 Jun 2015
  3. Primary completion30 Sep 2019
  4. Study completion30 Sep 2019

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
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
70 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02583516
Sponsor's protocol ID
GEM-01-15
Other IDs
2014-005277-36, 2014
Status last verified
Jul 2019
First submitted
8 Oct 2015
Last updated
17 Feb 2020
Results posted
No
Data monitoring committee
No
Individual data sharing
No

Publications

  • Garbe C, Peris K, Hauschild A, Saiag P, Middleton M, Spatz A, Grob JJ, Malvehy J, Newton-Bishop J, Stratigos A, Pehamberger H, Eggermont A. Diagnosis and treatment of melanoma: European consensus-based interdisciplinary guideline. Eur J Cancer. 2010 Jan;46(2):270-83. doi: 10.1016/j.ejca.2009.10.032. Epub 2009 Dec 1.

    PubMed 19959353

  • 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

  • Avril MF, Aamdal S, Grob JJ, Hauschild A, Mohr P, Bonerandi JJ, Weichenthal M, Neuber K, Bieber T, Gilde K, Guillem Porta V, Fra J, Bonneterre J, Saiag P, Kamanabrou D, Pehamberger H, Sufliarsky J, Gonzalez Larriba JL, Scherrer A, Menu Y. Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol. 2004 Mar 15;22(6):1118-25. doi: 10.1200/JCO.2004.04.165.

    PubMed 15020614

  • Bedikian AY, Millward M, Pehamberger H, Conry R, Gore M, Trefzer U, Pavlick AC, DeConti R, Hersh EM, Hersey P, Kirkwood JM, Haluska FG; Oblimersen Melanoma Study Group. Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group. J Clin Oncol. 2006 Oct 10;24(29):4738-45. doi: 10.1200/JCO.2006.06.0483. Epub 2006 Sep 11.

    PubMed 16966688

  • Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, Gore M, Aamdal S, Cebon J, Coates A, Dreno B, Henz M, Schadendorf D, Kapp A, Weiss J, Fraass U, Statkevich P, Muller M, Thatcher N. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000 Jan;18(1):158-66. doi: 10.1200/JCO.2000.18.1.158.

    PubMed 10623706

  • Eggermont AM, Schadendorf D. Melanoma and immunotherapy. Hematol Oncol Clin North Am. 2009 Jun;23(3):547-64, ix-x. doi: 10.1016/j.hoc.2009.03.009.

    PubMed 19464602

  • Hauschild A, Agarwala SS, Trefzer U, Hogg D, Robert C, Hersey P, Eggermont A, Grabbe S, Gonzalez R, Gille J, Peschel C, Schadendorf D, Garbe C, O'Day S, Daud A, White JM, Xia C, Patel K, Kirkwood JM, Keilholz U. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol. 2009 Jun 10;27(17):2823-30. doi: 10.1200/JCO.2007.15.7636. Epub 2009 Apr 6.

    PubMed 19349552

  • Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010 Aug 19;363(8):711-23. doi: 10.1056/NEJMoa1003466. Epub 2010 Jun 5.

    PubMed 20525992

  • Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011 Jun 30;364(26):2517-26. doi: 10.1056/NEJMoa1104621. Epub 2011 Jun 5.

    PubMed 21639810

  • Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ, Kutzner H, Cho KH, Aiba S, Brocker EB, LeBoit PE, Pinkel D, Bastian BC. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005 Nov 17;353(20):2135-47. doi: 10.1056/NEJMoa050092.

    PubMed 16291983

  • Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA. Mutations of the BRAF gene in human cancer. Nature. 2002 Jun 27;417(6892):949-54. doi: 10.1038/nature00766. Epub 2002 Jun 9.

    PubMed 12068308

  • Gray-Schopfer V, Wellbrock C, Marais R. Melanoma biology and new targeted therapy. Nature. 2007 Feb 22;445(7130):851-7. doi: 10.1038/nature05661.

    PubMed 17314971

  • Bollag G, Hirth P, Tsai J, Zhang J, Ibrahim PN, Cho H, Spevak W, Zhang C, Zhang Y, Habets G, Burton EA, Wong B, Tsang G, West BL, Powell B, Shellooe R, Marimuthu A, Nguyen H, Zhang KY, Artis DR, Schlessinger J, Su F, Higgins B, Iyer R, D'Andrea K, Koehler A, Stumm M, Lin PS, Lee RJ, Grippo J, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, Chapman PB, Flaherty KT, Xu X, Nathanson KL, Nolop K. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature. 2010 Sep 30;467(7315):596-9. doi: 10.1038/nature09454.

    PubMed 20823850

  • Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O'Dwyer PJ, Lee RJ, Grippo JF, Nolop K, Chapman PB. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010 Aug 26;363(9):809-19. doi: 10.1056/NEJMoa1002011.

    PubMed 20818844

  • Joseph EW, Pratilas CA, Poulikakos PI, Tadi M, Wang W, Taylor BS, Halilovic E, Persaud Y, Xing F, Viale A, Tsai J, Chapman PB, Bollag G, Solit DB, Rosen N. The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner. Proc Natl Acad Sci U S A. 2010 Aug 17;107(33):14903-8. doi: 10.1073/pnas.1008990107. Epub 2010 Jul 28.

    PubMed 20668238

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing vemurafenib and cobimetinib in people with Melanoma, run by Grupo Español Multidisciplinar de Melanoma at 18 sites in Spain.

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 26 inclusion and 30 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: finished, as of the sponsor's last update on 17 Feb 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 18 sites in Spain. 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?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

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?

Progression Free Survival (PFS) (time frame: Through study completion, up to 42 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 NCT02583516, which also lists 32 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 17 Feb 2020; AzTrials last refreshed its copy on 8 Nov 2026.

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