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Malignant Melanoma Stage IVPhase 2RadioCoBRIMNCT03430947

Vemurafenib Plus Cobimetinib After Radiosurgery in Patients With BRAF-mutant Melanoma Brain Metastases

A Phase 2 study testing Vemurafenib and Cobimetinib in people with Malignant Melanoma Stage IV and BRAF V600 Mutation, run by Technische Universität Dresden at 3 sites in Germany.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

This is a phase II, open label, non-randomised study of vemurafenib and cobimetinib after radiosurgery in adult patients with BRAFV600-mutant melanoma brain metastases. All patients will receive vemurafenib 960 mg twice a day on days 1 - 28 combined with cobimetinib 60 mg once a day on days 1 - 21 of each 28-day… Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Vemurafenib and Cobimetinib
Could I receive a placebo?
No, everyone receives an active treatment
How many people
20 participants
Where
3 sitesGermany
Study dates
1 Jul 2018to 10 Feb 2023
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

  • Signed informed consent
  • Female and male patients ≥ 18 years of age
  • Histologically confirmed metastatic melanoma (stage IV, per AJCC staging), carrying BRAF V600-mutation
  • Performed SRS 14 ±7 days before baseline using a harmonized protocol in patients with at least one measurable intracranial target lesion for which the following criteria are met:
  • Previously untreated (Lesions in previously irradiated area should not be selected)
  • Largest diameter of ≥ 0.5 but ≤ 4 cm as determined by contrast-enhanced MRI and
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  • ≤ 10 brain metastases
  • ECOG performance status 0 - 2
  • Life expectancy ≥ 12 weeks
  • Adequate bone marrow function as indicated by the following:
  • ANC ≥ 1500/µL,
  • Platelets ≥ 100,000/µL and
  • Hemoglobin ≥ 9 g/dL
  • Adequate renal function, as indicated by creatinine ≤ 1.5 x ULN
  • Adequate liver function, as indicated by bilirubin < 1.5 x ULN and AST and ALT < 3 x ULN (documented liver metastases: AST and ALT < 5 x ULN)
  • Adequate coagulation within 28 days prior to baseline visit
  • Patients without therapeutic anticoagulation: INR or aPTT ≤ 1.5 x ULN
  • Patients receiving therapeutic anticoagulation: stable anticoagulation regimen and stable INR
  • Able to swallow pills

Who cannot join

  • Symptomatic brain metastases requiring immediate local interventions such as neurosurgery or radiosurgery
  • Leptomeningeal disease (also synchronous with brain metastases)
  • Prior therapy with BRAF or MEK inhibitors within 12 weeks prior to baseline visit (prior therapies for metastatic melanoma including chemo-, cytokine-, immuno-, biological and vaccine-therapy will be al-lowed) A period of at least 6 weeks must be observed between the last dose of ipilimumab and the first administration of the study treatments. Prior treatment with anti-programmed cell death (PD)-1 or anti-PD ligand 1 (PD-L1) is allowed.
  • Prior whole brain irradiation (Patients with prior local therapy of brain metas-tases are eligible)
  • Patients receiving therapeutic steroids are not stable on corticoster-oids 2 weeks before SRS
  • Active and uncontrolled infection
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  • Known HIV infection or active HBV or HCV infection
  • Active HBV infection (chronic and acute), defined as having a posi-tive hepatitis B surface antigen (HBsAg) test at screening (past or resolved HBV infection, defined as negative HBsAg test and a posi-tive total hepatitis B core antibody test at screening, are eligible)
  • Active HCV infection, defined as positive HCV antibody test and positive HCV RNA test at screening
  • Intracranial radiation therapy within 14 days prior to SRS
  • Extracranial radiation therapy within the last 14 days prior to baseline visit
  • Treatment with strong CYP3A4/5 inhibitors (e.g. ketoconazole) and inducers (e.g. phenytoin, carbamazepine). (anticonvulsant levetiracetam is allowed; patient should be stable on levetiracetam for 2 weeks)
  • Unresolved toxicity of National Cancer Institute Common Terminology Crite-ria for Adverse Events, version 4.0 (NCI v4.0) [NCI, 2009] Grade 2 or higher from previous anti-cancer therapy, except alopecia.
  • Conditions that will interfere significantly with the absorption of drugs (e.g. Colitis ulcerosa)
  • Inability to undergo MRI secondary to:
  • Metal,
  • Claustrophobia, or
  • Gadolinium contrast allergy
  • Previous malignancies active within the last 3 years, with the exception of locally curable cancers that have been treated to complete remis-sion or untreated stage I chronic lymphoid leukemia.
  • Unwillingness or inability to comply with study and follow-up procedures
  • Known hypersensitivity to any of the excipients of cobimetinib and vemuraf-enib
  • The following foods/supplements are prohibited at least 7 days prior to initia-tion of and during study treatment:
  • St. John's wort or hyperforin (potent cytochrome P450 CYP3A4 enzyme inducer)
  • Grapefruit juice (potent cytochrome P450 CYP3A4 enzyme inhibitor)
  • Patient is included in another interventional trial
  • Use of any investigational or non-registered product within 4 weeks prior to baseline visit
  • Woman of childbearing age with the exception they meet at least one of the following criteria:
  • Post-menopausal,
  • Sterilization,
  • Consistently \& correct application of contraceptives (Pearl Index < 1%),
  • sexual abstinence, or
  • vasectomy of the partner
  • Pregnant or lactating women
  • History, risk factor or retinal pathology that increases the risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR): evidence of retinal pathology that is considered a risk factor for RVO or CSR, or a history of retinal detachment, central serous chorioretinopathy or reti-nal vein thrombosis. The risk factors for RVO are listed below:
  • Uncontrolled glaucoma with intraocular pressures > 21 mm Hg,
  • Serum cholesterol ≥ Grade 2 (≥ 7.75 mmol/L),
  • Hypertriglyceridemia ≥ Grade 2 (≥ 3.42 mmol/L), Hyperglycemia (fasting) ≥ Grade 2 (≥ 8.9 mmol/L).
  • History of clinically significant cardiac dysfunction including:
  • Myocardial infarction,
  • Severe/unstable angina pectoris,
  • Symptomatic congestive heart failure (NYHA stage ≥ 2),
  • cerebrovascular accident or transient ischemic attack within the previous 6 months,
  • History of congenital long QT syndrome or mean QTcF > 450 msec or uncorrectable electrolyte abnormalities,
  • Hypertension > Grade 2 not controlled by medications
  • Left ventricular ejection fraction (LVEF) < 50%, or
  • Uncontrolled arrhythmias

Trial locations and contacts

3 sites in 1 country.

Germany3 sites

  • Technische Universität Dresden

    Dresden, 01307

  • Ruprecht-Karls-University of Heidelberg, Faculty of Medicine

    Heidelberg, 69120

  • Eberhard Karls University of Tübingen, University Medical Center

    Tübingen, 72076

Other trials in Germany

About this study

Official title: An Open-label Phase II Multicenter Study of Vemurafenib (Zelboraf®) Plus Cobimetinib (Cotellic®) After Radiosurgery in Patients With Active BRAF-V600-mutant Melanoma Brain Metastases

This is a phase II, open label, non-randomised study of vemurafenib and cobimetinib after radiosurgery in adult patients with BRAFV600-mutant melanoma brain metastases. All patients will receive vemurafenib 960 mg twice a day on days 1 - 28 combined with cobimetinib 60 mg once a day on days 1 - 21 of each 28-day treatment cycle until disease progression, drug toxicity or death.

The primary objective of this study is to determine the best overall response rate (BORR) in the brain. The extracranial BORR, intra- and extracranial duration of response, progression-free survival and overall survival, adverse events, quality of life and radiomics features predicting long-term local control of brain metastases and treatment-related toxicity will also be examined.

Being tested
Vemurafenib, Cobimetinib
Keywords
Stereotactic radiosurgery, BRAF inhibitor, MEK inhibitor, Vemurafenib, Cobimetinib
Medical subject headings
Melanoma, Brain Neoplasms

What participants receive

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

  • VemurafenibDrug

    Vemurafenib (960 mg twice a day) will be taken on days 1 - 28 of each 28-day treatment cycle.

  • CobimetinibDrug

    Cobimetinib (60 mg once a day) will be taken on days 1 - 21 of each 28-day treatment cycle.

Study groups in NCT03430947
Study groupRoleWhat they receive
TreatmentExperimentalall patients will be treated with Vemurafenib + Cobimetinib
Receives: Drug: Vemurafenib; Drug: Cobimetinib

What is being measured

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

  1. Best overall response rate in the brain

    rate of patients with complete response or partial response (intracranial)

    Measured: 2 years

Secondary outcomes (9)

  1. Extracranial best overall response rate

    rate of patients with complete response or partial response (extracranial)

    Measured: 2 years

  2. Best overall response rate calculated for the whole body tumor sites

    rate of patients with complete response or partial response

    Measured: 2 years

  3. Intracranial duration of response

    time from best overall response in the brain to first documentation of intracranial progression

    Measured: 2 years

  4. Extracranial duration of response

    time from best extracranial overall response to first documentation of extracranial progression

    Measured: 2 years

  5. Progression-free survival

    time from first dose of study treatment until progression

    Measured: 2 years

  6. Overall survival

    time from first dose of study treatment until death due to any cause

    Measured: 2 years

  7. Incidence of adverse events

    Adverse events by type, frequency and severity using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03; number of patients who withdraw from the study due to intolerable adverse events.

    Measured: 2 years

  8. Radiomics for long-term control of brain metastases

    Radiomics features predictive of long-term local control of brain metastases using Magnetic Resonance Imaging

    Measured: every 6 weeks up to 2 years

  9. Radiomics for intracranial Treatment-related toxicity

    Radiomics features predicting treatment-related toxicity (e.g. radionecrosis, hemorrhage, edema) using Magnetic Resonance Imaging

    Measured: every 6 weeks up to 2 years

Timeline

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

  1. First posted13 Feb 2018
  2. Study start1 Jul 2018
  3. Primary completion10 Feb 2023
  4. Study completion10 Feb 2023

Why it stopped: Due to insufficient recruitment, the clinical trial was terminated prematurely

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
20 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03430947
Sponsor's protocol ID
TUD-CoBRIM-67
Other IDs
2017-000768-13, 2017
Acronym
RadioCoBRIM
Status last verified
Sep 2023
First submitted
10 Jan 2018
Last updated
14 Sep 2023
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: After publication of the primary objective, the data might be provided to interested scientists on request (e.g. for meta-analyses or other scientific research) in an anonymized way within 5 years (according to the General Data Protection Regulation), provided that the sponsor and the coordinating principal investigators have given their prior written consent.

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Vemurafenib and Cobimetinib in people with Malignant Melanoma Stage IV and BRAF V600 Mutation, run by Technische Universität Dresden at 3 sites in Germany.

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 19 inclusion and 46 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 14 Sep 2023. 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 Germany. 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: Due to insufficient recruitment, the clinical trial was terminated prematurely). 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?

Best overall response rate in the brain (time frame: 2 years). 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 NCT03430947.

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 14 Sep 2023.

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