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
Title
- Brief Title: Concurrent Dabrafenib + Trametinib With Sterotactic Radiation in 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
Interventions
Drug | Synonyms | Arms |
---|
Dabrafenib | | Dabrafenib and Trametinib |
Trametinib | | Dabrafenib 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
Name | Type | Description | Interventions |
---|
Dabrafenib and Trametinib | Experimental | Dabrafenib, PO, 150mg BID Continuously Trameteinib, PO 2mg OD Continuously | |
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 |
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 |
Details
Phase: | Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Terminated |
Lead Sponsor: | Canadian Cancer Trials Group |
Last Updated
August 20, 2021