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BRAFV600E Melanoma PatientsPhase 2NCT01721603

Dabrafenib and Trametinib With Radiosurgery in Melanoma Brain Mets

A Phase 2 study testing Dabrafenib, Gamma Knife Radiosurgery and Trametinib in people with BRAFV600E Melanoma Patients, run by University of California, San Francisco at 1 site in United States.

Terminated

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

Official record
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Trial summary

The purpose of this study is to test the safety and find out what effects, good and/or bad, dabrafenib (a BRAF inhibitor) alone or dabrafenib when given in combination with gamma knife radiosurgery has on participants with a certain type of skin cancer (BRAFV600E melanoma) and brain metastases (tumors that have spread… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
BRAFV600E Melanoma Patients
What is being tested?
Dabrafenib, Gamma Knife Radiosurgery and Trametinib
Could I receive a placebo?
No, everyone receives an active treatment
How many people
2 participants
Where
1 siteUnited States
Study dates
Apr 2013to Jan 2016
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

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

  • Histologically-confirmed BRAFV600E melanoma
  • Up to 4 untreated brain metastases (at least 1 > 0.5 cm) with no metastasis larger than 3 cm as assessed by a gadolinium-enhanced MRI of the brain. Detection of additional lesions at time of Gamma Knife radiosurgery MRI scan will not be considered exclusionary if the detection of these lesions are thought to be due solely to difference in imaging techniques (i. e. higher sensitivity, double gadolinium contrast MRI utilized at the time of Gamma Knife radiosurgery compared with conventional MRI imaging).
  • ECOG PS 0-2
  • 14 days elapsed from last treatment with surgery.
  • At least 28 days or five half-lives (whichever is longer) have elapsed from last dose of any approved or investigational therapy for metastatic melanoma.
  • Appropriate birth control for men and women with childbearing potential
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  • Corticosteroid dose stable for at least 14 days
  • Adequate end-organ function:
  • ANC ≥ 1.5x109/L
  • Hemoglobin ≥ 9 g/dL
  • Platelets ≥100 x109/L
  • Total bilirubin ≤ 1.5x ULN
  • AST and ALT ≤ 2.5x ULN
  • Creatinine ≤ 1.5 mg/dL
  • PT/PTT ≤ 1.5x ULN
  • LVEF ≥ 50%
  • Age ≥ 18 years
  • Recipients of prior radiation therapy to the brain including stereotactic radiosurgery or whole brain irradiation may be included if there are 1-4 untreated or progressing brain lesions. At his discretion, the Study Chair may review any enrollment decision regarding which subjects will be enrolled prior to the initiation of treatment on trial.

Who cannot join

  • Neurological symptoms from melanoma brain metastases
  • Patients may not have received prior therapy with dabrafenib, vemurafenib, or other potent, highly effective BRAF inhibitors. Prior therapy with sorafenib is permitted.
  • Any indication for urgent or emergent neurosurgery. Patient may enroll after neurosurgery at least 14 days after neurosurgery as long as they meet all other study qualifications.
  • Pregnant or lactating women. The effects of dabrafenib on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use a highly effective method of contraception including: hormonal contraceptives (oral contraceptives, Nuvaring, Depo Provera) an intrauterine device, true abstinence or two barrier methods of birth control including condoms with cervical cap or diaphragm. Baseline pregnancy testing is required for all women of child-bearing potential. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol who are sexually active with women of child bearing potential must also agree to use adequate contraception prior to and during the study as outlined above, and for, and four months after completion of study drug administration.
  • History of known cardiac arrhythmias or acute coronary syndromes within the past 24 weeks.
  • History of a second malignancy with evidence of active disease within the past 3 years except non-melanoma skin cancer, indolent prostate cancer, and stable CLL without lymphadenopathy
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  • Complete resection of a single brain metastasis or of all known brain metastases. Patients who have undergone subtotal resection are eligible providing residual disease is < 2.0 cm in maximum diameter.
  • Patients with metastases within 2 mm of the optic nerve or optic chiasm so that some portion of the optic nerve or chiasm would receive > 9 Gy from radiosurgery.
  • Patients with metastases in the brainstem.
  • Contraindication to MRI (such as cardiac pacemaker).
  • The following medications or non-drug therapies are prohibited:
  • Other anti-cancer therapy while on treatment in this study.
  • Use of other investigational drugs within 28 days preceding the first dose of dabrafenib.
  • Antiretroviral drugs. Subjects with known HIV are ineligible for study participation.
  • Herbal remedies (i.e., St. John's wort).
  • Drugs that are strong inhibitors or inducers of CYP3A or CYP2C8, p-glycoprotein (Pgp) or Bcrp transporter because they may alter dabrafenib concentrations. The list may be modified based on emerging data. These include but are not limited to those listed in Appendix 2; consider therapeutic substitutions for these medications.
  • Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Grade 2 or higher from previous anti-cancer therapy, except alopecia.
  • Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption of drugs. If clarification is needed as to whether a condition will significantly affect absorption of drugs, contact the Study Chair for permission to enroll the subject. Study Chair has final decision regarding which subjects will be enrolled.
  • A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection. Subjects with laboratory evidence of HBV clearance may be enrolled with permission of the GSK medical monitor.
  • A history of known glucose-6-phosphate dehydrogenase (G6PD) deficiency.
  • Corrected QT (QTc) interval ≥480 msecs; history of acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting within the past 24 weeks; Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system; abnormal cardiac valve morphology documented by echocardiogram (subjects with minimal abnormalities including mild regurgitation/stenosis can be entered on study with approval from the GSK medical monitor); or history of known cardiac arrhythmias.
  • Treatment refractory hypertension defined as a blood pressure of systolic> 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy.
  • History of RVO or CSR, or predisposing factors to RVO or CSR(e.g. uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as diabetes mellitus, hypertension, or history of hyperviscosity or hypercoagulability syndromes)
  • Visible retinal pathology as assessed by ophthalmic exam that is considered a risk factor for RVO or CSR such as:
  • Evidence of new optic disc cupping
  • Evidence of new visual field defects
  • Intraocular pressure > 21 mm Hg as measured by tonography
  • Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol; or unwillingness or inability to follow the procedures required in the protocol.

Trial locations and contacts

1 site in 1 country.

United States1 site
  • University of San Francisco, California

    San Francisco, California, 94115

Other trials in United States

About this study

Official title: A Phase 2 Prospective Trial of Dabrafenib and Trametinib With Stereotactic Radiosurgery in BRAF Mutant Melanoma Brain Metastases

The purpose of this study is to test the safety and find out what effects, good and/or bad, dabrafenib (a BRAF inhibitor) alone or dabrafenib when given in combination with gamma knife radiosurgery has on participants with a certain type of skin cancer (BRAFV600E melanoma) and brain metastases (tumors that have spread to the brain).

Read the detailed description

This is a single arm Phase II clinical trial. All patients will receive continuous dosing of dabrafenib at 150 mg PO bid and trametinib beginning at Cycle 3 Day 1, at a starting dose of 2 mg PO once daily until progression of disease, withdrawal of consent, or the development of intolerable treatment associated toxicity. An MRI will be performed after 28 days of treatment with dabrafenib. Patients who have unequivocal disease progression in the brain at that time will be deemed to have disease progression at 4 weeks. Patients with a complete response of all lesions in the brain will continue to receive dabrafenib and trametinib on study but they will not undergo SRS. For patients with stable disease or partial tumor responses in the brain, Gamma Knife radiosurgery will be performed on treatment cycle 2, day 1 (+/- 3 days, 28 day cycle) using a stereotactic head frame and MRI imaging in accordance with FDA-approved procedures.

Melanoma brain metastases

Cutaneous melanoma is the most aggressive form of all skin cancers. Worldwide, it is currently expected that approximately 132,000 people will be diagnosed with melanoma each year and some 37,000 people are expected to die of the disease annually. Brain metastases are a major source of morbidity and mortality in patients with metastatic melanoma and approximately 3 out of 4 develop brain metastases at some point in their disease course. The prognosis of metastatic melanoma with CNS involvement is dismal1, and, until recently, no medical therapy demonstrated clear evidence of activity against melanoma in the brain. For patients with fewer than 4 brain lesions and no brain lesion greater than 3 cm in diameter, stereotactic radiosurgery (SRS) is the standard-of-care. By delivering highly focal irradiation to melanoma brain metastases, SRS confers local control rates exceeding 80% for lesions under 2 cm in diameter. However, SRS does not treat micrometastatic disease in the brain, and new brain metastases develop in approximately half of patients treated.

Furthermore, local control rates are lower for lesions larger than 2 cm in diameter. As a result, the median overall survival for melanoma patient treated with SRS is only 7 months.

BRAF mutant melanoma

The RAS/RAF/MEK/ERK pathway is a critical proliferation pathway in many human cancers. This pathway can be constitutively activated by alterations in specific proteins, including BRAF, which phosphorylates MEK1 and MEK2 on two regulatory serine residues. Approximately 90% of all identified BRAF mutations that occur in human result in a V600 E/D/Kamino acid substitution. This mutation appears to mimic regulatory phophorylation and increases BRAF activity approximately 10-fold compared to wild type. BRAF mutations have been identified at a high frequency in specific cancers, including approximately 40-60% of melanoma. The frequency of this activating mutation and the pathway addiction to which it leads makes mutated BRAF an extremely attractive target.

Being tested
Dabrafenib, Gamma Knife Radiosurgery, Trametinib
Keywords
BRAFV600E melanoma patients, melanoma, stereotactic radiosurgery, BRAFV600E melanoma brain metastases, dabrafenib, SRS
Medical subject headings
Melanoma

What participants receive

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

  • DabrafenibDrug

    Also called GSK2118436

    150 mg capsule by mouth twice daily

  • Gamma Knife RadiosurgeryProcedure or surgery

    Also called SRS, Stereotactic Radiosurgery

    This will be delivered using Gamma Knife technology. Patients will be fitted with a stereotactic head-frame for stereotactic localization of brain metastases.

  • TrametinibDrug

    Also called GSK1120212

    2 mg by mouth once daily from beginning at Cycle 3 Day 1, until progression of disease, withdrawal of consent, or the development of intolerable treatment associated toxicity.

Study groups in NCT01721603
Study groupRoleWhat they receive
Dabrafenib + Trametinib + gamma knife radiosurgeryExperimentalNot described
Receives: Drug: Dabrafenib; Procedure: Gamma Knife Radiosurgery; Drug: Trametinib

What is being measured

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

  1. Patients Reaching 6 Month Distant Brain Metastasis-free Survival (DBMFS)

    Determine whether dabrafenib combined with stereotactic radiosurgery (SRS) and trametinib improves the 6 month DBMFS rate of BRAFV600E melanoma patients for whom the standard of care is stereotactic radiosurgery (≤4 brain lesions and no lesion > 3 cm) in comparison with similar historical controls treated with radiosurgery alone.

    Measured: Up to 6 months after surgery

Secondary outcomes (7)
  1. Patients Displaying 6-month Local Control Rate

    Determine whether dabrafenib combined with SRS and trametinib improves the 6-month local control rate of BRAFV600E melanoma brain metastases compared with historical controls treated with SRS.

    Measured: From surgery up to 6 months

  2. Best Overall Response Rate (by RECIST v1.1 )

    Determine the best overall response rate (by RECIST v1.1 ).

    Measured: From surgery up to 12 months

  3. Median Duration of Freedom From New Brain Metastases( by RECIST v1.1 )

    Determine median duration of freedom from new brain metastases of BRAFV600E melanoma brain metastases patients treated with SRS, trametinib and dabrafenib. RECIST v1.1 will be used as the primary determinant of disease progression.

    Measured: From surgery up to 12 months

  4. Median Time to Progression

    Determine the median time to progression in the brain of BRAFV600E melanoma brain metastases patients treated with SRS, trametinib and dabrafenib. RECIST v1.1 will be used as the primary determinant of disease progression. Disease response will be assessed at scheduled visits by MRI of the brain and clinical exam every two months thereafter. The proportion of patients that progression free at 6 months will be calculated.

    Measured: From surgery up to 12 months

  5. Systemic Overall Response Rate

    Determine the systemic best overall response rate of BRAFV600E melanoma brain metastasis patients treated with SRS, trametinib and dabrafenib.

    The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).

    The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that recurrent disease is objectively documented.

    Measured: From surgery up to 12 months

  6. Median Progression-free Survival

    Determine the median progression-free survival of BRAFV600E melanoma brain metastasis patients treated with SRS, trametinib and dabrafenib.

    Measured: From surgery up to 12 months

  7. Median Overall Survival

    Determine the median overall survival of BRAFV600E melanoma brain metastasis patients treated with SRS, trametinib and dabrafenib.

    Measured: From surgery up to 12 months

Timeline

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

  1. First posted6 Nov 2012 (estimated)
  2. Study startApr 2013
  3. Primary completionJan 2016
  4. Study completionJan 2016

Why it stopped: Low accrual

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
2 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01721603
Sponsor's protocol ID
12857
Status last verified
Dec 2017
First submitted
1 Nov 2012
Last updated
23 Jan 2018
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • Patel KR, Chowdhary M, Switchenko JM, Kudchadkar R, Lawson DH, Cassidy RJ, Prabhu RS, Khan MK. BRAF inhibitor and stereotactic radiosurgery is associated with an increased risk of radiation necrosis. Melanoma Res. 2016 Aug;26(4):387-94. doi: 10.1097/CMR.0000000000000268.

    PubMed 27223498

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Dabrafenib, Gamma Knife Radiosurgery and Trametinib in people with BRAFV600E Melanoma Patients, run by University of California, San Francisco at 1 site in United States.

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 18 inclusion and 28 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 23 Jan 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. 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?

Yes. Results are posted in the registry (first posted 23 Jan 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

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?

Patients Reaching 6 Month Distant Brain Metastasis-free Survival (DBMFS) (time frame: Up to 6 months after surgery). 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 NCT01721603, which also lists 1 linked publication.

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 23 Jan 2018.

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