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

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ClinicalTrials.gov Identifier: NCT03430947
Recruitment Status : Recruiting
First Posted : February 13, 2018
Last Update Posted : October 22, 2019
Sponsor:
Information provided by (Responsible Party):
Technische Universität Dresden

Brief 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 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.


Condition or disease Intervention/treatment Phase
Malignant Melanoma Stage IV BRAF V600 Mutation Brain Metastases Drug: Vemurafenib Drug: Cobimetinib Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 32 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : July 1, 2018
Estimated Primary Completion Date : July 1, 2022
Estimated Study Completion Date : July 1, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Melanoma

Arm Intervention/treatment
Experimental: Treatment
all patients will be treated with Vemurafenib + Cobimetinib
Drug: Vemurafenib
Vemurafenib (960 mg twice a day) will be taken on days 1 - 28 of each 28-day treatment cycle.

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




Primary Outcome Measures :
  1. Best overall response rate in the brain [ Time Frame: 2 years ]
    Best overall response rate in the brain defined as the rate of patients with complete response or partial response


Secondary Outcome Measures :
  1. Extracranial best overall response rate [ Time Frame: 2 years ]
  2. Best overall response rate calculated for the whole body tumor sites [ Time Frame: 2 years ]
  3. Intracranial duration of response [ Time Frame: 2 years ]
  4. Extracranial duration of response [ Time Frame: 2 years ]
  5. Progression-free survival [ Time Frame: 2 years ]
  6. Overall survival [ Time Frame: 2 years ]
  7. Incidence of adverse events [ Time Frame: 2 years ]
    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.

  8. Radiomics for long-term control of brain metastases [ Time Frame: every 6 weeks up to 2 years ]
    Radiomics features predictive of long-term local control of brain metastases using Magnetic Resonance Imaging

  9. Radiomics for intracranial Treatment-related toxicity [ Time Frame: every 6 weeks up to 2 years ]
    Radiomics features predicting treatment-related toxicity (e.g. radionecrosis, hemorrhage, edema) using Magnetic Resonance Imaging



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria

  • 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
    • ≤ 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

Exclusion criteria

  • 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
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03430947


Contacts
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Contact: Friedegund Meier, MD +49 351 458 ext 2497 friedegund.meier@uniklinikum-dresden.de
Contact: Esther Troost, MD +49 351 458 ext 2394 esther.troost@uniklinikum-dresden.de

Locations
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Germany
Technische Universität Dresden Recruiting
Dresden, Germany, 01307
Contact: Friedegund Meier, MD    +49 351 458 ext 2497    friedegund.meier@uniklinikum-dresden.de   
Contact: Esther Troost, MD    +49 351 458 ext 2394    esther.troost@uniklinikum-dresden.de   
Principal Investigator: Friedegund Meier, MD         
Principal Investigator: Esther Troost, MD, PhD         
Ruprecht-Karls-University of Heidelberg, Faculty of Medicine Recruiting
Heidelberg, Germany, 69120
Contact: Jessica Hassel, MD         
Eberhard Karls University of Tübingen, University Medical Center Recruiting
Tuebingen, Germany, 72076
Contact: Thomas Eigentler, MD         
Sponsors and Collaborators
Technische Universität Dresden
Investigators
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Principal Investigator: Friedegund Meier, MD Technische Universität Dresden

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Responsible Party: Technische Universität Dresden
ClinicalTrials.gov Identifier: NCT03430947     History of Changes
Other Study ID Numbers: TUD-CoBRIM-67
2017-000768-13 ( EudraCT Number )
First Posted: February 13, 2018    Key Record Dates
Last Update Posted: October 22, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: After publication of the primary objective, the data might be provided to interested sci-entists 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.
Supporting Materials: Clinical Study Report (CSR)
Time Frame: within 5 years

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Technische Universität Dresden:
Stereotactic radiosurgery
BRAF inhibitor
MEK inhibitor
Vemurafenib
Cobimetinib
Additional relevant MeSH terms:
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Melanoma
Neoplasm Metastasis
Brain Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Neoplastic Processes
Pathologic Processes
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vemurafenib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action