MelanomaPhase 2VECODUENCT03224208
Vemurafenib Plus Cobimetinib in Advanced or Metastatic Melanoma Patients
A Phase 2 study testing Vemurafenib and Cobimetinib in people with Melanoma and Melanoma (Skin), run by Fondazione Melanoma Onlus at 1 site in Italy.
Trial summary
In the BRIM-3 trial, which was conducted in patients with previously untreated advanced melanoma harboring the BRAF V600E mutation, vemurafenib, a potent inhibitor of mutated BRAF, was associated with prolonged overall survival (OS) and progression-free survival (PFS) compared to dacarbazine. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Melanoma, Melanoma (Skin), Melanoma Stage
- 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
- 9 participants
- Where
- 1 siteItaly
- Study dates
- 17 May 2018to 8 Jan 2021
- 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
- Patients must have histologically confirmed, unresectable stage IIIc or stage IV metastatic melanoma, as defined by the American Joint Committee on Cancer 7th edition. Unresectability of stage IIIc disease must have confirmation from a surgical oncologist;
- Patients with advanced melanoma who have received one prior immunotherapy systemic regimen for advanced disease, for whom vemurafenib/cobimetinib treatment has been scheduled by the treating physician.
- Adjuvant treatment is allowed, except for anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 agents;
- Patients must be naïve to treatment for locally advanced unresectable or metastatic with BRAF/MEK inhibitors;
- Documentation of BRAFV600 mutation-positive status in melanoma tumor tissue BRAF V600 mutation test;
- At least one measurable lesion according to disease per RECIST v1.1 criteria;
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- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0- 2;
- Male or female patient aged ≥ 18 years;
- Able to participate and willing to give written informed consent prior to performance of any study-related procedures and to comply with the study protocol;
- Life expectancy ≥ 12 weeks.
Who cannot join
- History of any prior systemic treatment for unresectable stage IIIc or stage IV melanoma (prior anti RAF or MEK agents) other than one prior first-line immunotherapy;
- 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;
- Patients with 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 BCC,resected cutaneous SCC, resected melanoma in-situ, resected carcinoma in-situ of the cervix, and resected carcinoma in-situ of the breast; Exclusion Criteria Based on Organ Function.
- Ocular:
- History of, or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment/central serouschorioretinopathy (CSCR), retinal vein occlusion (RVO) or neovascularmacular degeneration;
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- The risk factors for RVO are listed below. Patients will be excluded if they currently have the following conditions:
- Uncontrolled glaucoma with intra-ocular pressures ≥21 mmHg;
- Serum cholesterol ≥Grade 2;
- Hypertriglyceridemia ≥ Grade 2;
- Hyperglycemia (fasting) ≥Grade 2;
- Cardiac:
- 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 inserum electrolytes (sodium, potassium, calcium, magnesium, phosphorus);
- Uncontrolled hypertension≥ Grade 2 (patients with a history 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.
- Central Nervous System:
- Patients with active/symptomatic CNS lesions are excluded.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: VECODUE A Phase II Trial of Vemurafenib Plus Cobimetinib in Patients Treated With Prior First-line Systemic Immunotherapy for Inoperable Locally Advanced or Metastatic Melanoma
In the BRIM-3 trial, which was conducted in patients with previously untreated advanced melanoma harboring the BRAF V600E mutation, vemurafenib, a potent inhibitor of mutated BRAF, was associated with prolonged overall survival (OS) and progression-free survival (PFS) compared to dacarbazine. In the same setting, combined use of vemurafenib and cobimetinib, a selective inhibitor of MEK, yielded a significant improvement in PFS and response rate, compared to vemurafenib monotherapy, along with an advantage in OS, which did not cross the pre-specified significance bounderies (COBRIM trial). In treatment-naïve patients with mutated BRAF, both anti PD-1-based immunotherapy and BRAF-targeted agents are feasible therapeutic options, with the former and latter agents being associated with more durable and earlier responses, respectively.
As suggested by National Comprehensive Cancer Network (NCCN) guidelines, the use of combined BRAF and MEK inhibitors in patients with progressive disease after immunotherapy, is also feasible, but it is not supported by category 1 evidence, in view of the lack of studies conducted in this setting.
The main objective of this phase II trial is to evaluate the efficacy and safety of the combined use of vemurafenib plus cobimetinib in advanced melanoma patients who have received first-line systemic immunotherapy for inoperable locally advanced / metastatic disease.
Read the detailed description
In the BRIM-3 trial, which was conducted in patients with previously untreated advanced melanoma harboring the BRAF V600E mutation, vemurafenib, a potent inhibitor of mutated BRAF, was associated with prolonged OS and PFS compared to dacarbazine. In the same setting, combined use of vemurafenib and cobimetinib, a selective inhibitor of MEK, yielded a significant improvement in PFS and response rate, compared to vemurafenib monotherapy, along with an advantage in OS, which did not cross the pre-specified significance bounderies (COBRIM trial). In treatment-naïve patients with mutated BRAF, both anti PD-1-based immunotherapy and BRAF-targeted agents are feasible therapeutic options, with the former and latter agents being associated with more durable and earlier responses, respectively.
As suggested by NCCN guidelines, the use of combined BRAF and MEK inhibitors in patients with progressive disease after immunotherapy, is also feasible, but it is not supported by category 1 evidence, in view of the lack of studies conducted in this setting.
The main objective of this phase II trial is to evaluate the efficacy and safety of the combined use of vemurafenib plus cobimetinib in advanced melanoma patients who have received first-line systemic immunotherapy for inoperable locally advanced / metastatic disease.
As evidenced above, vemurafenib inhibits the BRAF V600E kinase, (this mutation is found in 50% to 60% of melanomas), and enables a remarkable clinical response rate, more than 50% and a statistically significant improvement in OS in patients with unresectable stage III and IV melanoma.
However, the clinical utility of BRAF-I treatment is limited by the development of drug resistance. Multiple mechanisms underlie the development of BRAF-I resistance in BRAF V600E melanoma cells including point mutations in MEK1, amplification of mutant BRAF V600E, elevated closely related serinethreonine kinase activity, activating NRAS mutations, increased levels of COT/Tpl2, aberrantly spliced BRAF V600E and growth factor receptor upregulation. Most of these alterations cause BRAF-I resistance by reactivating the MAPK pathway which plays a major role in the proliferation, survival, and metastatic potential of melanoma cells [Shi 2014a, Shi 2014b, Van Allen 2014].
Inhibition of MEK by the novel MEK-I, trametenib or cobimetinib, has been demonstrated to overcome the reactivation of MAPK pathway which is induced by BRAF-I resistance and to increase both OS and OvRR of melanoma patients when combined with BRAF-I [Flaherty 2012a, Flaherty 2012b, Hoeflich 2012, Ribas 2014]. The above-described phase III study, 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma has shown that the combination of vemurafenib and cobimetinib, as compared with vemurafenib alone, resulted in an improvement in PFS and objective responses, with early evidence of improved OS and a somewhat increased toxicity profile [Larkin 2014].
- Conditions
- Melanoma, Melanoma (Skin), Melanoma Stage
- Being tested
- Vemurafenib, Cobimetinib
- Keywords
- melanoma, advanced, vemurafenib, 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
Vemurafenib will be orally adminitered at 960 mg b.i.d. on Days 1-28
CobimetinibDrug
Cobimetinib will be given orally at 60 mg qd on Days 1-21 of each 28-day treatment cycle
| Study group | Role | What they receive |
|---|---|---|
| Single arm | Experimental | Vemurafenib will be orally adminitered at 960 mg b.i.d. on Days 1-28. Cobimetinib will be given orally at 60 mg qd on Days 1-21 of each 28-day treatment cycle until disease progression.
Treatments will be continued until the development of progressive disease (as per Investigator assessment), unacceptable toxicity, consent withdrawal, death, reasons deemed by the treating physician or study termination by the Sponsor. Receives: Drug: Vemurafenib; Drug: Cobimetinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Overall Survival
OS will be calculated from the first day of treatment until the date of death from any cause.Any patient not know to have died at the time of data analysis will be censored at the time of the last recorded date on which the patient was know to be alive.
Measured: Patients enrolled will receive study medication until disease progression, unaccettable toxicity, withdrawal of consent or death, whichever comes first, assested up to 24 month
Secondary outcomes (2)
PFS
PFS will be defined as the time from initiation of study treatment to the first occurrence of disease progression or death from any cause, whichever occurs first.PFS will be calculated based on disease status evaluated bythe investigator according to RECIST v1.1
Measured: Patients enrolled will receive study medication until disease progression, unaccettable toxicity, withdrawal of consent or death, whichever comes first, assested up to 24 month
ORR
ORR, defined as the proportion of patients with a best overall response of either complete response (CR) or partial response (PR), will be calculated based on disease status evaluated by the investigator accordingto RECIST v1.1
Measured: Patients enrolled will receive study medication until disease progression, unaccettable toxicity, withdrawal of consent or death, whichever comes first, assested up to 24 month
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Jul 2017
- Study start17 May 2018
- Primary completion12 Sep 2020
- Study completion8 Jan 2021
Why it stopped: low enrolment rate
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for MelanomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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
- 9 participants (actual)
Sponsor and investigators
- Lead sponsor
- Fondazione Melanoma Onlus
- Sponsor type
- University, hospital or other
- Collaborators
- Roche Pharma AG
- Responsible party
- Sponsor
- Investigators
- Paolo Antonio Ascierto, Study chair, IRCCS Fondazione Pascale Naploli
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03224208
- Sponsor's protocol ID
- VECODUE
- Acronym
- VECODUE
- Status last verified
- Apr 2021
- First submitted
- 19 Jul 2017
- Last updated
- 26 Apr 2021
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 26 Apr 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- VECODUE A Phase II Trial of Vemurafenib Plus Cobimetinib in Patients Treated With Prior First-line Systemic Immunotherapy for Inoperable Locally Advanced or Metastatic Melanoma
- ClinicalTrials.gov ID
- NCT03224208
- Acronym / sponsor ID
- VECODUE / VECODUE
- Conditions
- Melanoma, Melanoma (Skin), Melanoma Stage
- Keywords
- melanoma, advanced, vemurafenib, cobimetinib
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: low enrolment rate
- Enrolment
- 9 participants (actual)
- Lead sponsor
- Fondazione Melanoma OnlusUniversity, hospital or other
- Collaborators
- Roche Pharma AG
- Study start
- 17 May 2018 (actual)
- Primary completion
- 12 Sep 2020 (actual)
- Study completion
- 8 Jan 2021 (actual)
- First posted
- 21 Jul 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
In the BRIM-3 trial, which was conducted in patients with previously untreated advanced melanoma harboring the BRAF V600E mutation, vemurafenib, a potent inhibitor of mutated BRAF, was associated with prolonged overall survival (OS) and progression-free survival (PFS) compared to dacarbazine. In the same setting, combined use of vemurafenib and cobimetinib, a selective inhibitor of MEK, yielded a significant improvement in PFS and response rate, compared to vemurafenib monotherapy, along with an advantage in OS, which did not cross the pre-specified significance bounderies (COBRIM trial). In treatment-naïve patients with mutated BRAF, both anti PD-1-based immunotherapy and BRAF-targeted agents are feasible therapeutic options, with the former and latter agents being associated with more durable and earlier responses, respectively.
As suggested by National Comprehensive Cancer Network (NCCN) guidelines, the use of combined BRAF and MEK inhibitors in patients with progressive disease after immunotherapy, is also feasible, but it is not supported by category 1 evidence, in view of the lack of studies conducted in this setting.
The main objective of this phase II trial is to evaluate the efficacy and safety of the combined use of vemurafenib plus cobimetinib in advanced melanoma patients who have received first-line systemic immunotherapy for inoperable locally advanced / metastatic disease.
Detailed description
In the BRIM-3 trial, which was conducted in patients with previously untreated advanced melanoma harboring the BRAF V600E mutation, vemurafenib, a potent inhibitor of mutated BRAF, was associated with prolonged OS and PFS compared to dacarbazine. In the same setting, combined use of vemurafenib and cobimetinib, a selective inhibitor of MEK, yielded a significant improvement in PFS and response rate, compared to vemurafenib monotherapy, along with an advantage in OS, which did not cross the pre-specified significance bounderies (COBRIM trial). In treatment-naïve patients with mutated BRAF, both anti PD-1-based immunotherapy and BRAF-targeted agents are feasible therapeutic options, with the former and latter agents being associated with more durable and earlier responses, respectively.
As suggested by NCCN guidelines, the use of combined BRAF and MEK inhibitors in patients with progressive disease after immunotherapy, is also feasible, but it is not supported by category 1 evidence, in view of the lack of studies conducted in this setting.
The main objective of this phase II trial is to evaluate the efficacy and safety of the combined use of vemurafenib plus cobimetinib in advanced melanoma patients who have received first-line systemic immunotherapy for inoperable locally advanced / metastatic disease.
As evidenced above, vemurafenib inhibits the BRAF V600E kinase, (this mutation is found in 50% to 60% of melanomas), and enables a remarkable clinical response rate, more than 50% and a statistically significant improvement in OS in patients with unresectable stage III and IV melanoma.
However, the clinical utility of BRAF-I treatment is limited by the development of drug resistance. Multiple mechanisms underlie the development of BRAF-I resistance in BRAF V600E melanoma cells including point mutations in MEK1, amplification of mutant BRAF V600E, elevated closely related serinethreonine kinase activity, activating NRAS mutations, increased levels of COT/Tpl2, aberrantly spliced BRAF V600E and growth factor receptor upregulation. Most of these alterations cause BRAF-I resistance by reactivating the MAPK pathway which plays a major role in the proliferation, survival, and metastatic potential of melanoma cells [Shi 2014a, Shi 2014b, Van Allen 2014].
Inhibition of MEK by the novel MEK-I, trametenib or cobimetinib, has been demonstrated to overcome the reactivation of MAPK pathway which is induced by BRAF-I resistance and to increase both OS and OvRR of melanoma patients when combined with BRAF-I [Flaherty 2012a, Flaherty 2012b, Hoeflich 2012, Ribas 2014]. The above-described phase III study, 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma has shown that the combination of vemurafenib and cobimetinib, as compared with vemurafenib alone, resulted in an improvement in PFS and objective responses, with early evidence of improved OS and a somewhat increased toxicity profile [Larkin 2014].
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Single arm | Experimental | Drug: Vemurafenib, Drug: CobimetinibVemurafenib will be orally adminitered at 960 mg b.i.d. on Days 1-28. Cobimetinib will be given orally at 60 mg qd on Days 1-21 of each 28-day treatment cycle until disease progression. Treatments will be continued until the development of progressive disease (as per Investigator assessment), unacceptable toxicity, consent withdrawal, death, reasons deemed by the treating physician or study termination by the Sponsor. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- Patients must have histologically confirmed, unresectable stage IIIc or stage IV metastatic melanoma, as defined by the American Joint Committee on Cancer 7th edition. Unresectability of stage IIIc disease must have confirmation from a surgical oncologist;
- Patients with advanced melanoma who have received one prior immunotherapy systemic regimen for advanced disease, for whom vemurafenib/cobimetinib treatment has been scheduled by the treating physician.
- Adjuvant treatment is allowed, except for anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 agents;
- Patients must be naïve to treatment for locally advanced unresectable or metastatic with BRAF/MEK inhibitors;
- Documentation of BRAFV600 mutation-positive status in melanoma tumor tissue BRAF V600 mutation test;
Key exclusion criteria (20 listed)
- History of any prior systemic treatment for unresectable stage IIIc or stage IV melanoma (prior anti RAF or MEK agents) other than one prior first-line immunotherapy;
- 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;
- Patients with 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 BCC,resected cutaneous SCC, resected melanoma in-situ, resected carcinoma in-situ of the cervix, and resected carcinoma in-situ of the breast; Exclusion Criteria Based on Organ Function.
- History of, or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment/central serouschorioretinopathy (CSCR), retinal vein occlusion (RVO) or neovascularmacular degeneration;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| VemurafenibVemurafenib will be orally adminitered at 960 mg b.i.d. on Days 1-28 | Drug | Single arm |
| CobimetinibCobimetinib will be given orally at 60 mg qd on Days 1-21 of each 28-day treatment cycle | Drug | Single arm |
Primary outcome
Overall Survival
Time frame: Patients enrolled will receive study medication until disease progression, unaccettable toxicity, withdrawal of consent or death, whichever comes first, assested up to 24 month
OS will be calculated from the first day of treatment until the date of death from any cause.Any patient not know to have died at the time of data analysis will be censored at the time of the last recorded date on which the patient was know to be alive.
2 secondary outcomes
PFS
Time frame: Patients enrolled will receive study medication until disease progression, unaccettable toxicity, withdrawal of consent or death, whichever comes first, assested up to 24 month
ORR
Time frame: Patients enrolled will receive study medication until disease progression, unaccettable toxicity, withdrawal of consent or death, whichever comes first, assested up to 24 month
Results and safety
The study was stopped early (reason given: low enrolment rate). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Apr 2021.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Paolo Antonio Ascierto study chair
IRCCS Fondazione Pascale Naploli
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Vemurafenib and Cobimetinib in people with Melanoma and Melanoma (Skin), run by Fondazione Melanoma Onlus at 1 site in Italy.
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 10 inclusion and 20 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: stopped early, as of the sponsor's last update on 26 Apr 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. 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 was stopped early (reason given: low enrolment rate). 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?
Overall Survival (time frame: Patients enrolled will receive study medication until disease progression, unaccettable toxicity, withdrawal of consent or death, whichever comes first, assested up to 24 month). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 26 Apr 2021.