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Study to Investigate the Objective Response Rate of Dabrafenib in Combination With Trametinib in Subjects With BRAF V600 Mutation-Positive Melanoma

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ClinicalTrials.gov Identifier: NCT02083354
Recruitment Status : Completed
First Posted : March 11, 2014
Results First Posted : March 17, 2021
Last Update Posted : May 13, 2021
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE February 13, 2014
First Posted Date  ICMJE March 11, 2014
Results First Submitted Date  ICMJE February 15, 2021
Results First Posted Date  ICMJE March 17, 2021
Last Update Posted Date May 13, 2021
Actual Study Start Date  ICMJE March 18, 2014
Actual Primary Completion Date February 23, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 22, 2021)
Objective Response Rate (ORR) [ Time Frame: Up to 35 months ]
To determine ORR of dabrafenib in combination with trametinib in subjects with BRAF V600 mutation-positive, unresectable or metastatic melanoma. ORR is defined as the percentage of subjects with evidence of a confirmed complete response (CR) or partial response (PR) as per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 and as assessed by the investigator.
Original Primary Outcome Measures  ICMJE
 (submitted: March 6, 2014)
Objective Response Rate (ORR) [ Time Frame: Up to 36 months ]
To determine ORR of dabrafenib in combination with trametinib in subjects with BRAF V600E/K mutation-positive, unresectable or metastatic ALM. ORR is defined as the percentage of subjects with evidence of a confirmed complete response (CR) or partial response (PR) as per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 16, 2021)
  • To Evaluate the Antitumor Activity by Assessing the Progression-free Survival (PFS) [ Time Frame: Up to 36 months ]
    PFS defined as the time from first dose of study treatment until the first date of either objective disease progression or death due to any cause
  • To Evaluate the Antitumor Activity by Assessing the Duration of Response [ Time Frame: Up to 36 months ]
    Duration of response is defined as the time from first documented evidence of CR or PR until the earliest date of documented radiological progression or death due to any cause among subjects who achieved a confirmed CR or PR
  • To Evaluate the Antitumor Activity by Assessing the Overall Survival (OS) [ Time Frame: Approximately 5 years ]
    OS defined as the interval from first dose of study treatment to the date of death, irrespective of the cause of death; subjects still alive will be censored at the date of the last contact
  • To Assess Exposures to Dabrafenib, Dabrafenib Metabolites, and Trametinib, and Characterize the Population Pharmacokinetics of Dabrafenib and Trametinib [ Time Frame: Pre-dose (within 30 minutes prior to dosing) and 1, 2, 4, 6, and 8 hours after dosing on Day 15. For subjects in China: Pre-dose (within 30 minutes prior to dosing) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours after dosing on Day 1 and Day 15 ]
    PK parameters will include maximum peak concentration (Cmax), Time to Cmax (tmax), Predose concentration (Ctau), Area under the concentration-time curve (AUC) from time 0 to last time of quantifiable concentration (AUC [0-t]), and from time 0 to 8 hours of quantifiable concentration (AUC[0-8]); AUC from time 0 to 12 hours of quantifiable concentration (AUC[0-12]) (dabrafenib and metabolites only), AUC (0-24) (trametinib only) and the metabolite to dabrafenib ratio of AUC(0-t). Population PK parameters will include, apparent clearance following oral dosing (CL/F), volume of distribution (V/F), and absorption rate constant (Ka) for dabrafenib and trametinib
  • Safety and Tolerability of Dabrafenib and Trametinib as Assessed by Physical Examinations [ Time Frame: Screening, every 4 weeks and at treatment discontinuation (approximately 1 year but can be up to 5 years) ]
    Complete physical examination will include assessments of eyes, neurological and cardiovascular systems, lungs, abdomen, and any other areas with signs and symptoms of disease, and of the head, neck, ears, nose, mouth, throat, thyroid, lymph nodes, extremities, and a full skin exam to assess cutaneous malignancies and proliferative skin diseases. Also, thorough genitourinary (pelvic) and rectal examinations to assess secondary malignancies
  • Safety and Tolerability of Dabrafenib and Trametinib as Assessed by Vital Signs [ Time Frame: Screening, every 4 weeks and at treatment discontinuation (approximately 1 year but can be up to 5 years) ]
    Vital sign measurements will include systolic and diastolic blood pressure, body temperature, pulse rate, body weight, and height (only at Screening)
  • Safety and Tolerability of Dabrafenib and Trametinib as Assessed by 12-lead Electrocardiograms (ECG), Echocardiogram (ECHO) [ Time Frame: ECG Screening, Day 15, Week 4, 8 and 12, every 12 weeks after Week 12 and treatment Discontinuation(approximately 1 year but can be up to 5 years). ECHO Screening, Week 4 and every 12 weeks ]
    Clinical assessments including 12-lead (ECG, ECHO will be done to assess cardiac safety
  • Safety and Tolerability of Dabrafenib and Trametinib as Assessed by Eye Examinations [ Time Frame: Screening and Week 4 and as clinically warranted ]
    Safety as measured by clinical assessments including eye exams
  • Safety and Tolerability of Dabrafenib and Trametinib by Laboratory Assessments [ Time Frame: Screening, every 4 weeks and at treatment Discontinuation (approximately 1 year but can be up to 5 years) ]
    Laboratory assessments will include clinical chemistry and hematology parameters
  • Safety and Tolerability of Dabrafenib and Trametinib as Assessed Adverse Events (AEs) [ Time Frame: From the first dose of study treatment until 30 days after discontinuation of study treatment (approximately 1 year but can be up to 5 years) ]
Original Secondary Outcome Measures  ICMJE
 (submitted: March 6, 2014)
  • To evaluate the antitumor activity by assessing the progression-free survival (PFS) [ Time Frame: Up to 36 months ]
    PFS defined as the time from first dose of study treatment until the first date of either objective disease progression or death due to any cause
  • To evaluate the antitumor activity by assessing the duration of response [ Time Frame: Up to 36 months ]
    Duration of response is defined as the time from first documented evidence of CR or PR until the earliest date of documented radiological progression or death due to any cause among subjects who achieved a confirmed CR or PR
  • To evaluate the antitumor activity by assessing the overall survival (OS) [ Time Frame: Approximately 5 years ]
    OS defined as the interval from first dose of study treatment to the date of death, irrespective of the cause of death; subjects still alive will be censored at the date of the last contact
  • To assess single dose (Chinese subjects only) and steady state (all subjects) exposures to dabrafenib, dabrafenib metabolites, and trametinib, and characterize the population pharmacokinetics of dabrafenib and trametinib [ Time Frame: Pre-dose (within 30 minutes prior to dosing) and 1, 2, 4, 6, and 8 hours after dosing on Day 15. For subjects in China: Pre-dose (within 30 minutes prior to dosing) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours after dosing on Day 1 and Day 15 ]
    PK parameters will include maximum peak concentration (Cmax), Time to Cmax (tmax), Predose concentration (Ctau), Area under the concentration-time curve (AUC) from time 0 to last time of quantifiable concentration (AUC [0-t]), and from time 0 to 8 hours of quantifiable concentration (AUC[0-8]); AUC from time 0 to 12 hours of quantifiable concentration (AUC[0-12]) (dabrafenib and metabolites only), AUC (0-24) (trametinib only) and the metabolite to dabrafenib ratio of AUC(0-t). Population PK parameters will include, apparent clearance following oral dosing (CL/F), volume of distribution (V/F), and absorption rate constant (Ka) for dabrafenib and trametinib
  • Safety and Tolerability of dabrafenib and trametinib as assessed by Physical examinations [ Time Frame: Screening, every 4 weeks and at treatment discontinuation (approximately 1 year but can be up to 5 years) ]
    Complete physical examination will include assessments of eyes, neurological and cardiovascular systems, lungs, abdomen, and any other areas with signs and symptoms of disease, and of the head, neck, ears, nose, mouth, throat, thyroid, lymph nodes, extremities, and a full skin exam to assess cutaneous malignancies and proliferative skin diseases. Also, thorough genitourinary (pelvic) and rectal examinations to assess secondary malignancies
  • Safety and Tolerability of dabrafenib and trametinib as assessed by vital signs [ Time Frame: Screening, every 4 weeks and at treatment discontinuation (approximately 1 year but can be up to 5 years) ]
    Vital sign measurements will include systolic and diastolic blood pressure, body temperature, pulse rate, body weight, and height (only at Screening)
  • Safety and Tolerability of dabrafenib and trametinib as assessed by 12-lead electrocardiograms (ECG), echocardiogram (ECHO) [ Time Frame: ECG Screening, Day 15, Week 4, 8 and 12, every 12 weeks after Week 12 and treatment Discontinuation(approximately 1 year but can be up to 5 years). ECHO Screening, Week 4 and every 12 weeks ]
    Clinical assessments including 12-lead (ECG, ECHO will be done to assess cardiac safety
  • Safety and Tolerability of dabrafenib and trametinib as assessed by eye examinations [ Time Frame: Screening and Week 4 and as clinically warranted ]
    Safety as measured by clinical assessments including eye exams
  • Safety and Tolerability of dabrafenib and trametinib by laboratory assessments [ Time Frame: Screening, every 4 weeks and at treatment Discontinuation (approximately 1 year but can be up to 5 years) ]
    Laboratory assessments will include clinical chemistry and hematology parameters
  • Safety and Tolerability of dabrafenib and trametinib as assessed adverse events (AEs) [ Time Frame: From the first dose of study treatment until 30 days after discontinuation of study treatment (approximately 1 year but can be up to 5 years) ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study to Investigate the Objective Response Rate of Dabrafenib in Combination With Trametinib in Subjects With BRAF V600 Mutation-Positive Melanoma
Official Title  ICMJE An Open-Label, Multi-Center Study to Investigate the Objective Response Rate of Dabrafenib in Combination With Trametinib in Subjects With BRAF V600 Mutation-Positive Melanoma
Brief Summary This is a single-arm, open-label, multi-center, Phase II study to evaluate dabrafenib and trametinib combination therapy in subjects with BRAF V600 mutation-positive, unresectable or metastatic Acral lentiginous or cutaneous melanoma. This study will evaluate the objective response rate (ORR), progression free survival (PFS), duration of response, overall survival (OS), safety and efficacy, to assess steady state (all subjects) exposure to dabrafenib, dabrafenib metabolites, and trametinib and characterize the population pharmacokinetics (PK) and pharmacodynamics (PD) of dabrafenib and trametinib. Subjects will be enrolled and will receive dabrafenib 150 milligram (mg) orally twice daily and trametinib 2 mg orally once daily. Treatment will continue until disease progression, death, unacceptable toxicity, or withdrawal of consent, or study closure. After treatment discontinuation, subjects will be followed for survival and disease progression as applicable.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Cancer
  • Melanoma
Intervention  ICMJE
  • Drug: Dabrafenib
    Dabrafenib will be provided as 50 mg and 75 mg capsules. Each capsule will contain 50 mg or 75 mg of free base (present as the mesylate salt)
  • Drug: Trametinib
    Trametinib study medication will be provided as 0.5 mg and 2.0 mg tablets. Each tablet will contain 0.5 mg or 2.0 mg of trametinib parent (present as the DMSO solvate)
Study Arms  ICMJE Experimental: Arm 1
All subjects will receive the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone will be administered approximately 12 hours after the morning dose. Subjects will continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Interventions:
  • Drug: Dabrafenib
  • Drug: Trametinib
Publications *

*   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 Completed
Actual Enrollment  ICMJE
 (submitted: March 16, 2021)
77
Original Estimated Enrollment  ICMJE
 (submitted: March 6, 2014)
35
Actual Study Completion Date  ICMJE April 19, 2021
Actual Primary Completion Date February 23, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Signed written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
  • >=18 years of age.
  • Histologically confirmed acral lentiginous or cutaneous melanoma that is either Stage IIIC (unresectable) or Stage IV (metastatic), and BRAF V600 mutation-positive. The test was to have been conducted at a designated central laboratory.
  • Measurable disease (i.e., present with at least one measurable lesion) by RECIST version1.1.
  • Performance status score of 0 or 1 according to the Eastern Cooperative Oncology Group (ECOG) scale.
  • All prior anti-cancer treatment-related toxicities (except alopecia and laboratory values) must be <=Grade 1 according to the Common Terminology Criteria for Adverse Events version 4 (CTCAE version 4.0) at the time of enrolment.
  • Able to swallow and retain oral medication and must not have had any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
  • Women of child-bearing potential must have had a negative serum pregnancy test within 14 days of first dose of study treatment and agree to use effective contraception, from 14 days prior to enrolment, throughout the treatment period and for 4 months after the last dose of study treatment.
  • Adequate baseline organ function as defined below: Absolute Neutrophil Count:>= 1.2 × 10^9/liter (L); Hemoglobin: >=9 grams (g)/deciliter (dL); Platelet count: >=100 x 10^9/L; Prothrombin Time/International Normalized Ratio (INR) (Subjects receiving anticoagulation treatment may be allowed to participate with INR established within the therapeutic range prior to enrolment) and Partial Thromboplastin Time: <=1.5 x Upper Limit of Normal (ULN); Albumin: >=2.5 g/dL; Total bilirubin: <=1.5 x ULN; Aspartate aminotransferase and Alanine aminotransferase: <=2.5 x ULN; Calculated creatinine clearance (Calculate creatinine clearance using standard Cockcroft-Gault formula): >=50 milliliter (mL)/ minute (min); Left Ventricular Ejection Fraction (LVEF) (ECHO scans must be used throughout the study) : >= Lower limit of normal (LLN) by ECHO.
  • Subjects with East Asian origin.

Exclusion Criteria:

  • Primary mucosal or ocular melanoma.
  • Prior treatment with a BRAF inhibitor (including but not limited to dabrafenib, vemurafenib, LGX818, and XL281/BMS-908662) or a MEK inhibitor (including but not limited to trametinib, AZD6244, and RDEA119).
  • Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic anti-cancer therapy, or immuno anti-cancer therapy within 21 days prior to enrolment /or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to enrolment. (Note: Ipilimumab, pembrolizumab and nivolumab treatment must ended at least 8 weeks prior to enrollment).
  • Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days), whichever is shorter, prior to enrolment. (Note: in case ipilimuamb, pembrolizmab and nivolumab are investigational drug in the regions and countries, and in case of PD-L1 antibody, these investigational treatment must have ended at least 8 weeks prior to enrollment ).
  • Current use of a prohibited medication.
  • Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO).
  • A history of Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (subjects with laboratory evidence of cleared HBV and/or HCV will be permitted).
  • Leptomeningeal or brain metastases or metastases causing spinal cord compression that were: symptomatic or untreated or not stable for 3 months (must be documented by imaging) or requiring corticosteroids. Subjects that were on a stable dose of corticosteroids >1 month or on replacement dose only, or have been off of corticosteroids for at least 2 weeks can be enrolled with approval of the medical monitor. Subjects must also have been off of enzyme-inducing anticonvulsants for >4 weeks.
  • History of malignancy other than disease under study within 3 years of study enrolment with exceptions of subjects with a history of completely resected non-melanoma skin cancer, or subjects with indolent second malignancies were eligible only after the approval of the sponsor's medical monitor.
  • History of malignancy with confirmed activating RAS mutation at any time. Note: Prospective RAS testing was not required. However, if the results of previous RAS testing were known, they must have been used in assessing eligibility
  • Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could have interfered with the subject's safety, obtaining informed consent, or compliance with study procedures.
  • A history or evidence of cardiovascular risk including any of the following: Current LVEF < Institutional LLN; A QTc interval corrected for heart rate >=480 millisecond (msec) (using Bazett's formula); A history or evidence of current clinically significant uncontrolled arrhythmias. Clarification: Subjects with atrial fibrillation controlled for >30 days prior to dosing are eligible; A history of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization; A history or evidence of current >=Class II congestive heart failure as defined by the New York Heart Association (NYHA) guidelines; Patients with intra-cardiac defibrillators; Treatment refractory hypertension defined as a blood pressure of systolic >140 millimeters of mercury (mmHg) and/or diastolic >90 mmHg which cannot be controlled by anti-hypertensive therapy; Known cardiac metastases; Abnormal cardiac valve morphology (>=grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study). Subjects with moderate valvular thickening should not have been entered in study.
  • Uncorrectable electrolyte abnormalities (e.g. hypokalaemia, hypomagnesaemia, hypocalcaemia determined by blood chemistry), long QT syndrome or taking medicinal products known to prolong the QT interval.
  • A history or current evidence of retinal vein occlusion (RVO) .
  • Pregnant or nursing females.
  • History of or current diagnosis of interstitial lung disease or pneumonitis.
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 China,   Hong Kong,   Korea, Republic of,   Taiwan,   Thailand
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02083354
Other Study ID Numbers  ICMJE 200104
CDRB436B2205 ( Other Identifier: Novartis )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Plan Description:

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date April 2021

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