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Dabrafenib and Trametinib in Treating Patients With Stage III-IV BRAF Mutant Melanoma That Cannot Be Removed by Surgery

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ClinicalTrials.gov Identifier: NCT02196181
Recruitment Status : Active, not recruiting
First Posted : July 21, 2014
Last Update Posted : September 6, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE July 18, 2014
First Posted Date  ICMJE July 21, 2014
Last Update Posted Date September 6, 2019
Actual Study Start Date  ICMJE July 22, 2014
Estimated Primary Completion Date June 15, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 18, 2018)
Progression-free survival (PFS) [ Time Frame: Measured from date of randomization, assessed up to 5 years ]
Testing of the superiority of intermittent dosing of dabrafenib and trametinib compared to continuous dosing with these two same agents will be based on progression-free survival. Stratified Cox regression models stratified by stratification factors will be used for all analyses.
Original Primary Outcome Measures  ICMJE
 (submitted: July 18, 2014)
Superiority of intermittent dosing of dabrafenib and trametinib compared to continuous dosing with these two same agents based on progression-free survival [ Time Frame: Measured from date of randomization, assessed up to 5 years ]
Stratified Cox regression models stratified by stratification factors will be used for all analyses.
Change History Complete list of historical versions of study NCT02196181 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 2, 2018)
  • Overall survival [ Time Frame: Up to 5 years ]
    Overall survival between patients on each arm and survival after progression will be compared using Cox regression models.
  • Response rates [ Time Frame: Up to 5 years ]
    Response rates between arms will be compared using Fisher's exact test.
  • Rates of fever [ Time Frame: Up to 5 years ]
    Defined as >= grade 3 per Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0 with attribution possibly, probably, or definitely related to treatment; or any >= grade 1 per CTCAE v4.0 with attribution possibly, probably, or definitely related to treatment with chills, dehydration, hypotension, dizziness, or muscle weakness per CTCAE v4.0 with attribution possibly, probably, or definitely related to treatment reported during the same course. Rates of fever between arms will also be compared using Fisher's exact test.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 18, 2014)
  • Overall survival [ Time Frame: Up to 5 years ]
    Overall survival between patients on each arm and survival after progression will be compared using Cox regression models.
  • Response rates [ Time Frame: Up to 5 years ]
    Response rates between arms will be compared using Fisher's exact test.
  • Rates of fever [ Time Frame: Up to 5 years ]
    Defined as >= grade 3 per CTCAE v4.0 with attribution possibly, probably, or definitely related to treatment; or any >= grade 1 per CTCAE v4.0 with attribution possibly, probably, or definitely related to treatment with chills, dehydration, hypotension, dizziness, or muscle weakness per CTCAE v4.0 with attribution possibly, probably, or definitely related to treatment reported during the same cycle. Rates of fever between arms will also be compared using Fisher's exact test.
Current Other Pre-specified Outcome Measures
 (submitted: October 18, 2018)
  • Molecular events leading to reactivation of the MAPK pathway [ Time Frame: Up to 5 years ]
    Compared between patients of the two treatment groups.
  • Change in biomarkers associated with PFS of archived tissue [ Time Frame: Baseline up to 5 years ]
    Cox regression analyses will be used to evaluate biomarkers' associations with PFS.
  • Interaction between baseline biomarkers and treatment arm [ Time Frame: Baseline up to 5 years ]
    Cox regression analyses will be used to evaluate biomarkers' associations with PFS.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Dabrafenib and Trametinib in Treating Patients With Stage III-IV BRAF Mutant Melanoma That Cannot Be Removed by Surgery
Official Title  ICMJE A Randomized Phase II Trial of Intermittent Versus Continuous Dosing of Dabrafenib (NSC-763760) and Trametinib (NSC-763093) in BRAF V600E/K Mutant Melanoma
Brief Summary This randomized phase II trial studies how well dabrafenib and trametinib work in treating patients with stage III-IV melanoma that cannot be removed by surgery and contains a B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutation. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Detailed Description

PRIMARY OBJECTIVES:

I. To compare progression-free survival with intermittent dosing and continuous dosing of dabrafenib and trametinib among patients with metastatic BRAF V600E/K mutant melanoma.

SECONDARY OBJECTIVES:

I. To estimate the frequency and severity of toxicities of the two dosing schedules.

II. To compare the frequency and severity of fever >= grade 1 per Common Terminology Criteria for Adverse Events (CTCAE) 4.0 of the two dosing schedules.

III. To compare the response rate (complete and partial response, confirmed and unconfirmed), overall survival, and survival after progression between the two dosing schedules on step 2.

TRANSLATIONAL MEDICINE OBJECTIVES:

I. To evaluate whether acquired molecular events leading to reactivation of the MAPK pathway are more common among patients on the continuous dosing arm than on the intermittent dosing arm using circulating tumor deoxyribonucleic acid (DNA) (ctDNA).

II. To assess the prognostic association between baseline biomarkers and early molecular events with progression free survival (PFS).

III. To explore the potential interaction between treatment arm and baseline biomarkers/early molecular events with PFS.

IV. To bank tissue and whole blood in anticipation of future studies to evaluate molecular events associated with clinical benefit and disease progression in patients treated with continuous versus intermittent dabrafenib and trametinib.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I (CONTINUOUS DOSING): Patients receive dabrafenib orally (PO) twice daily (BID) and trametinib PO once daily (QD) on days 1-56. Cycles repeat every 56 days in the absence of disease progression or unacceptable toxicity.

ARM II (INTERMITTENT DOSING): Patients receive dabrafenib PO BID and trametinib PO QD on days 1-7 and 29-56. Cycles repeat every 56 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for 3 years and then yearly for 2 years.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • BRAF V600E Mutation Present
  • BRAF V600K Mutation Present
  • Stage III Cutaneous Melanoma AJCC v7
  • Stage IIIA Cutaneous Melanoma AJCC v7
  • Stage IIIB Cutaneous Melanoma AJCC v7
  • Stage IIIC Cutaneous Melanoma AJCC v7
  • Stage IV Cutaneous Melanoma AJCC v6 and v7
  • Unresectable Melanoma
Intervention  ICMJE
  • Drug: Dabrafenib
    Given PO
    Other Names:
    • BRAF Inhibitor GSK2118436
    • GSK-2118436
    • GSK-2118436A
    • GSK2118436
  • Drug: Dabrafenib Mesylate
    Given PO
    Other Names:
    • Dabrafenib Methanesulfonate
    • GSK2118436 Methane Sulfonate Salt
    • GSK2118436B
    • Tafinlar
  • Drug: Trametinib
    Given PO
    Other Names:
    • GSK1120212
    • JTP-74057
    • MEK Inhibitor GSK1120212
    • Mekinist
  • Drug: Trametinib Dimethyl Sulfoxide
    Given PO
Study Arms  ICMJE
  • Experimental: Arm I (continuous dosing)
    Patients receive dabrafenib PO BID and trametinib PO QD on days 1-56. Cycles repeat every 56 days in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: Dabrafenib
    • Drug: Dabrafenib Mesylate
    • Drug: Trametinib
    • Drug: Trametinib Dimethyl Sulfoxide
  • Experimental: Arm II (intermittent dosing)
    Patients receive dabrafenib PO BID and trametinib PO QD on days 1-7 and 29-56. Cycles repeat every 56 days in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: Dabrafenib
    • Drug: Dabrafenib Mesylate
    • Drug: Trametinib
    • Drug: Trametinib Dimethyl Sulfoxide
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: July 18, 2014)
280
Original Estimated Enrollment  ICMJE Same as current
Study Completion Date  ICMJE Not Provided
Estimated Primary Completion Date June 15, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients must have histologically or cytologically confirmed stage IV or unresectable stage III BRAF V600E or BRAF V600K mutant melanoma
  • Patients must have BRAF V600E or BRAF V600K mutation identified by a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory; acceptable analytic techniques include but are not restricted to DNA sequencing, pyrosequencing, polymerase chain reaction (PCR), melting point assays, and immunohistochemistry
  • Contrast-enhanced computed tomography (CT) scans of the neck, chest, abdomen and pelvis are required; a whole body positron emission tomography (PET)/CT scan with diagnostic quality images and intravenous iodinated contrast may be used in lieu of a contrast enhanced CT of the neck, chest, abdomen and pelvis; contrast may be omitted if the treating investigator believes that exposure to contrast poses an excessive risk to the patient; patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; all measurable lesions must be assessed within 28 days prior to registration; tests to assess non-measurable disease must be performed within 42 days prior to registration; all disease must be assessed and documented on the Baseline Tumor Assessment Form (RECIST 1.1)
  • Patients must not have received a prior BRAF or mitogen-activated protein kinase kinase (MEK) inhibitor
  • Patients with a history of brain metastases are eligible if the patient is asymptomatic with no residual neurological dysfunction and has not received enzyme-reducing anti-epileptic drugs or corticosteroids for at least 7 days prior to registration
  • Patients must not have received any anti-cancer drug within 28 days prior to registration, and must not have received any nitrosoureas or mitomycin C within 42 days prior to registration
  • Patients must not have received any major surgery or immunotherapy within 28 days prior to registration
  • Patients must not have any unresolved toxicity greater than National Cancer Institute (NCI)-CTCAE version (v) 4.0 grade 1 from previous anti-cancer therapy except alopecia within 7 days prior to registration
  • Absolute neutrophil count (ANC) >= 1,200/ul (obtained within 28 days prior to registration)
  • Platelets >= 100,000/ul (obtained within 28 days prior to registration)
  • Hemoglobin >= 9 g/dL (obtained within 28 days prior to registration)
  • Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (or =< 2.5 x upper limit of normal [ULN] with Gilbert's syndrome) (obtained within 28 days prior to registration)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x IULN (or < 5 x IULN for patients with known liver metastases) (obtained within 28 days prior to registration)
  • Serum albumin >= 2.5 g/dL (obtained within 28 days prior to registration)
  • Serum creatinine =< 1.5 x mg/dL OR measured or calculated creatinine clearance >= 50 mL/min; creatinine measurements must be obtained within 28 days prior to registration
  • Patients must have lactate dehydrogenase (LDH) obtained within 28 days prior to registration in order to obtain baseline stratification information
  • Patients must have a left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (ILLN) by echocardiogram (ECHO) or multi gated acquisition scan (MUGA) within 28 days prior to registration
  • Patients must have corrected QT (QTc) =< 480 msec by electrocardiogram (ECG) (corrected using the Bazett's formula) within 28 days prior to registration
  • Patients with known history or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR) are not eligible:

    • History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, 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 mmHg
    • NOTE: ophthalmic exam is required for all patients; exam must be obtained within 28 days prior to registration
  • Patients must be able to take oral medications; patients must not have any impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of protocol treatment (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)
  • Patients receiving anticoagulation treatment are allowed to participate with international normalized ratio (INR) established within the therapeutic range
  • Patients must not have a history of pneumonitis or interstitial lung disease
  • Patients must not have any grade II/III/IV cardiac disease as defined by the New York Heart Association criteria (i.e., patients with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort), unstable angina pectoris, myocardial infarction within 6 months, or serious uncontrolled cardiac arrhythmia; abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis]) can be entered on study; patients with a history of atrial fibrillation must have atrial fibrillation controlled for at least 30 days prior to registration
  • Patients with known hepatitis B or hepatitis C are not eligible, regardless of concomitant antiretroviral therapy or current viral load
  • Patients with known human immunodeficiency virus (HIV) may be eligible providing they meet the following additional criteria:

    • Cluster of differentiation (CD)4 cells >= 500/uL
    • Serum HIV viral load of < 25,000 IU/ml
    • No current antiretroviral therapy

      • Tests must be obtained within 28 days prior to registration; patients who are HIV positive (+) and do not meet all of these criteria are not eligible for this study (HIV/hepatitis testing are not required for patients without known infection)
  • Pre-study history and physical must be obtained with 28 days prior to registration
  • Patients must have dermatology exam obtained within 28 days prior to registration to obtain baseline measurement; exam to be performed by treating physician or designated dermatologist
  • Patients must have Zubrod performance status of 0, 1 or 2
  • No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years; exception: patients with known history of colon cancer, cancer of the pancreas, or any cancer known to harbor an activating RAS mutation are ineligible regardless of stage or time since diagnosis
  • Patients must not be pregnant or nursing because of the risk of fetal harm; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures; hormonal contraception is not allowed due to drug interactions which can render hormonal contraceptives ineffective
  • Patients must be offered the opportunity to participate in specimen banking
  • Patients with cutaneous or superficial lesions that do not require imaging guidance for biopsy must be willing to undergo biopsies for tissue submission and blood draws for translational medicine
  • Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines
  • As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system
  • STEP 2: RANDOMIZATION
  • After completing one cycle of therapy, patients will be registered for randomization between intermittent and continuous dosing, provided that they were eligible for the initial step 1 registration and satisfy the following criteria
  • Patients must not have unequivocal disease progression (by RECIST v1.1) during the first cycle; patients must have disease assessed using the same method as baseline within +/- 5 days of the day 56 scheduled assessment (between days 51-55 of cycle 1, or days 1-5 of cycle 2); all disease must be assessed and documented on the follow-up tumor assessment form (RECIST 1.1)
  • Patients must be registered to step 2: randomization within +/- 5 days of starting cycle 2; patients MUST NOT be registered prior to the day 56 disease assessment
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02196181
Other Study ID Numbers  ICMJE NCI-2014-01470
NCI-2014-01470 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
S1221
S1320
S1320 ( Other Identifier: SWOG )
S1320 ( Other Identifier: CTEP )
U10CA180888 ( U.S. NIH Grant/Contract )
U10CA032102 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Alain P Algazi Southwest Oncology Group
PRS Account National Cancer Institute (NCI)
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP