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Concurrent Dabrafenib and Trametinib With Sterotactic Radiation in Patients With BRAF Mutation-Positive Malignant Melanoma and Brain Metastases

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02974803
Recruitment Status : Active, not recruiting
First Posted : November 28, 2016
Last Update Posted : April 26, 2019
Information provided by (Responsible Party):
Canadian Cancer Trials Group

Brief Summary:
Dabrafenib and trametinib are drugs that are usually given for the treatment of melanoma. Combinations of dabrafenib and trametinib have also been studied and when used together have shown to increase tumour shrinkage in animals compared to either drug alone. Dabrafenib and trametinib have also shown potential to penetrate the blood-brain-barrier when given together and have an effect on brain metastases. Giving these drugs at the same time and then giving brain stereotactic radiosurgery (SRS) may also be preferred in patients with brain metastases

Condition or disease Intervention/treatment Phase
Melanoma Brain Metastases Drug: Dabrafenib Drug: Trametinib Phase 2

Detailed Description:

The purpose of this study is to find out the effects of giving dabrafenib in combination with trametinib continuously with stereotactic radiotherapy (SRS) has on melanoma and brain metastases.

Stereotactic Radiosurgery (SRS) is a non-surgical radiation therapy used to treat tumours of the brain. It can deliver precisely targeted radiation. Currently SRS alone is the usual treatment for patients with up to 4 brain lesions. This study will include 2 groups 1) patients with 1-4 brain lesions treated with SRS concurrently with dabrafenib and trametinib and 2) patients with 5-10 brain lesions treated with SRS concurrently with dabrafenib and trametinib.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 6 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Concurrent Dabrafenib and Trametinib With Stereotactic Radiation in the Management of Patients With BRAF Mutation-Positive Malignant Melanoma and Brain Metastases
Actual Study Start Date : November 23, 2016
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : June 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Melanoma

Arm Intervention/treatment
Experimental: Dabrafenib and Trametinib
Dabrafenib, PO, 150mg BID Continuously Trameteinib, PO 2mg OD Continuously
Drug: Dabrafenib
Drug: Trametinib

Primary Outcome Measures :
  1. Intracranial objective response rate to concurrent dabrafenib and trametinib with stereotactic radiation in patients with BRAF mutation-positive malignant melanoma and brain metastases [ Time Frame: 24 months ]

Secondary Outcome Measures :
  1. Extra-cranial objective response rate [ Time Frame: 24 months ]
    Response will be assessed using RECIST v1.1

  2. Duration of response [ Time Frame: 24 months ]
    Response will be assessed using RECIST v1.1

  3. Intracranial progression free survival [ Time Frame: 24 months ]
    Response will be assessed using RECIST v1.1

  4. Overall progression free survival [ Time Frame: 24 months ]
    Response will be assessed using RECIST v1.1

  5. Number and severity of adverse events [ Time Frame: 24 months ]
    using CTCAE v.4

Other Outcome Measures:
  1. Overall objective response rate [ Time Frame: 24 months ]
    Response will be assessed using RECIST v1.1

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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

Inclusion Criteria:

  • Histologically confirmed melanoma metastatic to brain and determined to be BRAF V600 mutated.
  • Age ≥ 18 years.
  • Karnofsky Performance Status of 70-100 (Appendix I).
  • Patients must have a life expectancy of at least 12 weeks.
  • Presence of measurable disease (i.e. present with at least one measurable CNS lesion per RECIST 1.1).
  • Presence of 1-10 brain metastases as confirmed on a thin slice axial T1 post-gadolinium MRI sequence. The maximum diameter of a single brain lesion should be ≤ 4 cm and presence of a measurable lesion ≥ 1cm based on baseline MRI of brain.
  • All CNS metastases amenable to single fraction SRS and or fractionated SRS. Hemorrhagic lesions are allowed if the treating radiation oncologist deems the lesion amenable to focal SRS.
  • Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
  • Laboratory requirements (within 14 days prior to registration):

    • ANC ≥ 1.2 x 10^9/L
    • Hemoglobin ≥ 90 g/L
    • Platelet count ≥ 100 x 10^9/L
    • PT/INR & PTT ≤ 1.3 x ULN
    • Total bilirubin ≤ 1.5 x ULN
    • AST and ALT ≤ 2.5 x ULN
    • Serum creatinine or ≤ 1.5 x ULN or Creatinine Clearance ≥ 50 ml/min (calculated by Cockcroft and Gault)
    • LVEF ≥ LLN (within 28 days prior to registration)
    • No prior treatment with a BRAF inhibitor or MEK inhibitor.
    • No known ocular or primary mucosal melanoma.
    • No prior systemic anti-cancer treatment within the last 2 weeks preceding the frist dose of dabrafenib and trametinib. Patients must have recoved from clinical manifestations of toxicity related to prior systemic therapy and have adequate washout as follows: Longest of one of the following:

      • two weeks
      • 5 half-lives for investigational agents
      • Standard cycle length of standard therapies
    • Prior systemic treatment in the adjuvant setting is allowed.
    • No current use of a prohibited medication as described in section 7.2.
    • No history of malignancy with confirmed activating RAS mutation at any time.
    • No history of malignancy other than disease under study within 3 years of study enrollment.
    • No leptomeningeal metastases or metastases causing spinal cord compression that are symptomatic or untreated or not stable for ≥ 3 months. Subjects on stable dose of corticosteroids > 2 weeks or who have been off of corticosteroids for at least 2 weeks can be enrolled with approval of CCTG.
    • No serious or unstable pre-existing medical conditions, psychiatric disorders or other conditions that could interfere with the subject's safety, obtaining informed consent or compliance with study procedures.
    • No history of Hepatitis B Virus or Hepatitis C Virus infection
    • No history or evidence of cardiovascular risk No history or current eveidence/risk of retinal vein occlusion or central serous retinopathy
    • No known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide.
    • No pregnant or lactating women.
    • No hisotry of interstitial lung disease or active pneumonitis.
    • Presence of any one brain metastases >4cm in maximal diameter, and/or presence of brain metastase of less than 1cm.
    • No prior whole brain radiation
    • No brainstem metastses
    • No contrindications to MRI and/or Gadolinimum contrast or sterotactic brain radiation therapy.

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 identifier (NCT number): NCT02974803

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Canada, Nova Scotia
QEII Health Sciences Centre
Halifax, Nova Scotia, Canada, B3H 1V7
Canada, Ontario
Juravinski Cancer Centre at Hamilton Health Sciences
Hamilton, Ontario, Canada, L8V 5C2
Odette Cancer Centre
Toronto, Ontario, Canada, M4N 3M5
University Health Network
Toronto, Ontario, Canada, M5G 2M9
Canada, Quebec
Centre hospitalier universitaire de Sherbrooke
Sherbrooke, Quebec, Canada, J1H 5N4
Canada, Saskatchewan
Saskatoon Cancer Centre
Saskatoon, Saskatchewan, Canada, S7N 4H4
Sponsors and Collaborators
Canadian Cancer Trials Group
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Study Chair: Arjun Sahgal Odette Cancer Centre, Toronto, ON Canada
Study Chair: Teresa Petrella Odette Cancer Centre, Toronto, ON Canada

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Responsible Party: Canadian Cancer Trials Group Identifier: NCT02974803     History of Changes
Other Study ID Numbers: I224
First Posted: November 28, 2016    Key Record Dates
Last Update Posted: April 26, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Additional relevant MeSH terms:
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Neoplasm Metastasis
Brain Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
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
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action