Clinical Trials /

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

NCT02974803

Description:

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

Related Conditions:
  • Melanoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: I224
  • NCT ID: NCT02974803

Conditions

  • Melanoma
  • Brain Metastases

Interventions

DrugSynonymsArms
DabrafenibDabrafenib and Trametinib
TrametinibDabrafenib and Trametinib

Purpose

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

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.
    

Trial Arms

NameTypeDescriptionInterventions
Dabrafenib and TrametinibExperimentalDabrafenib, PO, 150mg BID Continuously Trameteinib, PO 2mg OD Continuously
  • Dabrafenib
  • Trametinib

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Extra-cranial objective response rate
Time Frame:24 months
Safety Issue:
Description:Response will be assessed using RECIST v1.1
Measure:Duration of response
Time Frame:24 months
Safety Issue:
Description:Response will be assessed using RECIST v1.1
Measure:Intracranial progression free survival
Time Frame:24 months
Safety Issue:
Description:Response will be assessed using RECIST v1.1
Measure:Overall progression free survival
Time Frame:24 months
Safety Issue:
Description:Response will be assessed using RECIST v1.1
Measure:Number and severity of adverse events
Time Frame:24 months
Safety Issue:
Description:using CTCAE v.4

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Canadian Cancer Trials Group

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