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CompletedNCT02083354Updated Feb 1, 2022Results posted

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

A Phase 2 interventional study of Dabrafenib and Trametinib in Cancer and Melanoma, sponsored by Novartis Pharmaceuticals. Completed at 13 sites in 5 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2022-02-01.

Sponsored by Novartis Pharmaceuticals (part of Novartis) · Phase 2, Interventional, and Treatment

Phase
Phase 2
Study type
Interventional
Enrollment
77
Allocation
Not applicable
Ages
18 Years and older
Sex
All
01

Study summary

This was 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 evaluated 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. Enrolled subjects were administered dabrafenib 150 milligram (mg) orally twice daily and trametinib 2 mg orally once daily. Treatment continued until disease progression, death, unacceptable toxicity, or withdrawal of consent, or study closure. After treatment discontinuation, subjects were followed for survival and disease progression as applicable.

Read the detailed description

This was an open-label, single arm, Phase IIA, multi-center study to evaluate the Objective response rate (ORR) of dabrafenib and trametinib combination therapy in East Asian subjects that have BRAF V600 mutationpositive Stage IIIC (unresectable) or Stage IV (metastatic) acral lentiginous melanoma (ALM) or cutaneous melanoma.

All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. A primary analysis presented the efficacy, safety and pharmacokinetics (PK) data up to the data cut-off date of 23-Feb-2018. Based on these results, dabrafenib and trametinib combination was approved in the People's Republic of China (PRC) for the treatment of BRAF-mutation positive unresectable or metastatic melanoma. Data from Mainland Chinese subjects from 01-Jul-2019 onwards are not included due to local regulations in China.

Subjects continued study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study completion. After treatment discontinuation, subjects went into follow-up for survival and disease progression as applicable. Subjects could continue study treatment after disease progression if they achieved clinical response per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 or stable disease with tumour reduction; had no overt signs of toxicity; had Eastern Cooperative Oncology Group (ECOG) performance status of ≤1 and did not require immediate surgical or radiological intervention.

02

Conditions studied

  • Cancer
  • Melanoma

Keywords

  • melanoma
  • dabrafenib
  • trametinib
  • malignant skin cancer
  • skin cancer
  • BRAF V600 Mutation-Positive Melanoma
03

In context

Neoplasms

9,610 studies on the registry are indexed under Neoplasms; 2,508 are open to participants now.

This study's enrollment of 77 is above the median of 50 across 7,429 interventional studies indexed under Neoplasms.

Browse Neoplasms studies →

Lead sponsor

Novartis Pharmaceuticals is the lead sponsor of 2,711 studies on the registry; 218 are open to participants now.

Of its 582 completed or terminated interventional studies of FDA-regulated products, 435 (75%) have results posted.

Browse Novartis Pharmaceuticals studies →All Novartis studies →

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.

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

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.
05

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrollment
77 participants (actual)

Study arms

  • 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

    Drug: Dabrafenib · Drug: Trametinib

Interventions

  • DrugDabrafenib

    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)

  • DrugTrametinib

    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)

06

What researchers measure

Primary outcomes

  1. Objective Response Rate (ORR)

    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.

    Time frame: Up to 35 months

Secondary outcomes

  1. Progression-free Survival (PFS) - Median

    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

    Time frame: Up to 36 months

  2. Progression-free Survival (PFS)

    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. Censored, follow-up ongoing - These subjects show as ongoing in the clinical database even though no subjects are currently ongoing, as no changes to the data were permitted after 30-Jun-2019 due to local regulations in China.

    Time frame: Up to 36 months

  3. Duration of Response (DOR) - Estimate for Duration of Response - Median

    Duration of response is defined as the time from first documented evidence of complete response (CR) or partial response (PR) until the earliest date of documented radiological progression or death due to any cause among subjects who achieved a confirmed CR or PR.

    Time frame: Up to 36 months

  4. Duration of Response (DOR)

    Duration of response is defined as the time from first documented evidence of complete response (CR) or partial response (PR) until the earliest date of documented radiological progression or death due to any cause among subjects who achieved a confirmed CR or PR. Censored, follow-up ongoing - These subjects show as ongoing in the clinical database even though no subjects are currently ongoing, as no changes to the data were permitted after 30-Jun-2019 due to local regulations in China.

    Time frame: Up to 36 months

  5. Overall Survival (OS) - Median

    OS is 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

    Time frame: Approximately 5 years

  6. Overall Survival (OS)

    OS is 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. Censored, follow-up ongoing - These subjects show as ongoing in the clinical database even though no subjects are currently ongoing, as no changes to the data were permitted after 30-Jun-2019 due to local regulations in China.

    Time frame: Approximately 5 years

  7. Number of Participants With Adverse Events

    An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse.

    Time frame: Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of 51 months (for both dabrafenib and also Rametinib).

  8. Population Pharmacokinetics of Dabrafenib - Cmax

    Cmax is the maximum peak concentration.

    Time frame: Day 1 and Day 15

  9. Population Pharmacokinetics of Dabrafenib - Tmax

    Tmax is Time to Cmax (maximum peak concentration).

    Time frame: Day 1 and Day 15

  10. Population Pharmacokinetics of Dabrafenib - AUC(0-12)

    AUC is the area under the concentration-time curve.

    Time frame: Day 1 and Day 15

  11. Population Pharmacokinetics of Dabrafenib - Ctrough

    Ctrough is trough concentration.

    Time frame: Day 1 and Day 15

  12. Population Pharmacokinetics of Dabrafenib - Racc

    Racc is the accumulation ratio.

    Time frame: Day 1 and Day 15

  13. Population Pharmacokinetics of Hydroxydabrafenib - Cmax

    Cmax is the maximum peak concentration.

    Time frame: Day 1 and Day 15

  14. Population Pharmacokinetics of Hydroxydabrafenib - Tmax

    Tmax is Time to Cmax (maximum peak concentration).

    Time frame: Day 1 and Day 15

  15. Population Pharmacokinetics of Hydroxydabrafenib - AUC(0-12)

    AUC is the area under the concentration-time curve.

    Time frame: Day 1 and Day 15

  16. Population Pharmacokinetics of Hydroxydabrafenib - Rm/p

    Rm/p is the metabolite-to-parent ratio.

    Time frame: Day 1 and Day 15

  17. Population Pharmacokinetics of Hydroxydabrafenib - Ctrough

    Ctrough is trough concentration.

    Time frame: Day 1 and Day 15

  18. Population Pharmacokinetics of Hydroxydabrafenib - Racc

    Racc is the accumulation ratio.

    Time frame: Day 1 and Day 15

  19. Population Pharmacokinetics of Desmethyl-dabrafenib - Cmax

    Cmax is the maximum peak concentration.

    Time frame: Day 1 and Day 15

  20. Population Pharmacokinetics of Desmethyl-dabrafenib - Tmax

    Tmax is Time to Cmax (maximum peak concentration).

    Time frame: Day 1 and Day 15

  21. Population Pharmacokinetics of Desmethyl-dabrafenib - AUC(0-12)

    AUC is the area under the concentration-time curve. AUC0-12 and Rm/p could not be calculated on Day 1 because all desmethyl-dabrafenib PK profiles on Day 1 were still ascending. Therefore, the Racc on Day 15 could not be calculated for desmethyldabrafenib.

    Time frame: Day 1 and Day 15

  22. Population Pharmacokinetics of Desmethyl-dabrafenib - Rm/p

    Rm/p is the metabolite-to-parent ratio. AUC0-12 and Rm/p could not be calculated on Day 1 because all desmethyl-dabrafenib PK profiles on Day 1 were still ascending. Therefore, the Racc on Day 15 could not be calculated for desmethyldabrafenib.

    Time frame: Day 1 and Day 15

  23. Population Pharmacokinetics of Desmethyl-dabrafenib - Ctrough

    Ctrough is trough concentration.

    Time frame: Day 1 and Day 15

  24. Population Pharmacokinetics of Carboxydabrafenib - Cmax

    Cmax is the maximum peak concentration.

    Time frame: Day 1 and Day 15

  25. Population Pharmacokinetics of Carboxydabrafenib - Tmax

    Tmax is Time to Cmax (maximum peak concentration).

    Time frame: Day 1 and Day 15

  26. Population Pharmacokinetics of Carboxydabrafenib - AUC(0-12)

    AUC is the area under the concentration-time curve.

    Time frame: Day 1 and Day 15

  27. Population Pharmacokinetics of Carboxydabrafenib - Rm/p

    Rm/p is the metabolite-to-parent ratio.

    Time frame: Day 1 and Day 15

  28. Population Pharmacokinetics of Carboxydabrafenib - Ctrough

    Ctrough is trough concentration.

    Time frame: Day 1 and Day 15

  29. Population Pharmacokinetics of Carboxydabrafenib - Racc

    Racc is the accumulation ratio.

    Time frame: Day 1 and Day 15

  30. Population Pharmacokinetics of Trametinib - Cmax

    Cmax is the maximum peak concentration.

    Time frame: Day 1 and Day 15

  31. Population Pharmacokinetics of Trametinib - Tmax

    Tmax is Time to Cmax (maximum peak concentration).

    Time frame: Day 1 and Day 15

  32. Population Pharmacokinetics of Trametinib - AUC(0-t)

    Area under the concentration-time curve from time zero (predose) to last time of quantifiable concentration within a subject across all treatments

    Time frame: Day 1 and Day 15

  33. Population Pharmacokinetics of Trametinib - AUC(0-24)

    AUC is the area under the concentration-time curve.

    Time frame: Day 1 and Day 15

  34. Population Pharmacokinetics of Trametinib - Ctrough

    Ctrough is trough concentration.

    Time frame: Day 1 and Day 15

  35. Population Pharmacokinetics of Trametinib - Racc

    Racc is the accumulation ratio.

    Time frame: Day 1 and Day 15

07

Results

Posted Mar 17, 2021

Participant flow

Participant flow — Overall Study
MilestoneArm 1
Started77
Completed13
Not completed64
Withdrew: Withdrawal by subject9
Withdrew: Lost to follow-up1
Withdrew: Adverse event3
Withdrew: Disease progression46
Withdrew: Study closed/terminated5

Outcome measures

PrimaryObjective Response Rate (ORR)

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.

Time frame:
Up to 35 months
Reported as:
Number · Percentage of Participants
Objective Response Rate (ORR)
Percentage of ParticipantsArm 1
Objective Response Rate (ORR)61 (49.2 to 72.0)
SecondaryProgression-free Survival (PFS) - Median

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

Time frame:
Up to 36 months
Reported as:
Median · months
Progression-free Survival (PFS) - Median
monthsArm 1
Progression-free Survival (PFS) - Median9.17 (7.26 to 12.88)
SecondaryProgression-free Survival (PFS)

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. Censored, follow-up ongoing - These subjects show as ongoing in the clinical database even though no subjects are currently ongoing, as no changes to the data were permitted after 30-Jun-2019 due to local regulations in China.

Time frame:
Up to 36 months
Reported as:
Count of participants · Participants
Progression-free Survival (PFS)
ParticipantsArm 1
Progressive Disease (PD) (event)52
Died (event)4
Censored, follow-up ended10
Censored, follow-up ongoing11
SecondaryDuration of Response (DOR) - Estimate for Duration of Response - Median

Duration of response is defined as the time from first documented evidence of complete response (CR) or partial response (PR) until the earliest date of documented radiological progression or death due to any cause among subjects who achieved a confirmed CR or PR.

Time frame:
Up to 36 months
Reported as:
Median · Months
Duration of Response (DOR) - Estimate for Duration of Response - Median
MonthsArm 1
Duration of Response (DOR) - Estimate for Duration of Response - Median12.65 (5.62 to 25.23)
SecondaryDuration of Response (DOR)

Duration of response is defined as the time from first documented evidence of complete response (CR) or partial response (PR) until the earliest date of documented radiological progression or death due to any cause among subjects who achieved a confirmed CR or PR. Censored, follow-up ongoing - These subjects show as ongoing in the clinical database even though no subjects are currently ongoing, as no changes to the data were permitted after 30-Jun-2019 due to local regulations in China.

Time frame:
Up to 36 months
Reported as:
Count of participants · Participants
Duration of Response (DOR)
ParticipantsArm 1
PFS - Disease Progression27
PFS - Death2
PFS - Censored, follow-up ended9
PFS - Censored, follow-up ongoing10
SecondaryOverall Survival (OS) - Median

OS is 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

Time frame:
Approximately 5 years
Reported as:
Median · Months
Overall Survival (OS) - Median
MonthsArm 1
Overall Survival (OS) - Median22.90 (16.62 to 27.40)
SecondaryOverall Survival (OS)

OS is 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. Censored, follow-up ongoing - These subjects show as ongoing in the clinical database even though no subjects are currently ongoing, as no changes to the data were permitted after 30-Jun-2019 due to local regulations in China.

Time frame:
Approximately 5 years
Reported as:
Count of participants · Participants
Overall Survival (OS)
ParticipantsArm 1
Died (Event)43
Censored, follow-up ended13
Censored, follow-up ongoing21
SecondaryNumber of Participants With Adverse Events

An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse.

Time frame:
Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of 51 months (for both dabrafenib and also Rametinib).
Reported as:
Count of participants · Participants
Number of Participants With Adverse Events
ParticipantsArm 1
Adverse events - all grades76
Adverse events - Treatment-related - all grades69
SAEs - all grades18
SAEs - Treatment-related - all grades9
Fatal SAEs - all grades4
Fatal SAEs - Treatment-related - all grades1
AEs leading to discontinuation - all grades6
AEs leading to discontinuation - Treatment-related - all grades3
AEs leading to dose adjustment/interruption - all grades39
AEs leading to dose reduction - all grades23
SecondaryPopulation Pharmacokinetics of Dabrafenib - Cmax

Cmax is the maximum peak concentration.

Time frame:
Day 1 and Day 15
Reported as:
Geometric mean · ng/mL
Population Pharmacokinetics of Dabrafenib - Cmax
ng/mLArm 1
Day 12950 ± 72.8
Day 15 (n=18)2300 ± 70.6
SecondaryPopulation Pharmacokinetics of Dabrafenib - Tmax

Tmax is Time to Cmax (maximum peak concentration).

Time frame:
Day 1 and Day 15
Reported as:
Median · hr
Population Pharmacokinetics of Dabrafenib - Tmax
hrArm 1
Day 11.95 (0.933 to 10)
Day 15 (n=18)1.5 (0.5 to 3)
SecondaryPopulation Pharmacokinetics of Dabrafenib - AUC(0-12)

AUC is the area under the concentration-time curve.

Time frame:
Day 1 and Day 15
Reported as:
Geometric mean · h.ng/mL
Population Pharmacokinetics of Dabrafenib - AUC(0-12)
h.ng/mLArm 1
Day 111400 ± 46.1
Day 156600 ± 55.6
SecondaryPopulation Pharmacokinetics of Dabrafenib - Ctrough

Ctrough is trough concentration.

Time frame:
Day 1 and Day 15
Reported as:
Geometric mean · ng/mL
Population Pharmacokinetics of Dabrafenib - Ctrough
ng/mLArm 1
Population Pharmacokinetics of Dabrafenib - Ctrough77 ± 84.3
SecondaryPopulation Pharmacokinetics of Dabrafenib - Racc

Racc is the accumulation ratio.

Time frame:
Day 1 and Day 15
Reported as:
Geometric mean · ratio
Population Pharmacokinetics of Dabrafenib - Racc
ratioArm 1
Population Pharmacokinetics of Dabrafenib - Racc0.624 ± 42.7
SecondaryPopulation Pharmacokinetics of Hydroxydabrafenib - Cmax

Cmax is the maximum peak concentration.

Time frame:
Day 1 and Day 15
Reported as:
Geometric mean · ng/mL
Population Pharmacokinetics of Hydroxydabrafenib - Cmax
ng/mLArm 1
Day 11230 ± 44.1
Day 15 (n=18)1200 ± 58.7
SecondaryPopulation Pharmacokinetics of Hydroxydabrafenib - Tmax

Tmax is Time to Cmax (maximum peak concentration).

Time frame:
Day 1 and Day 15
Reported as:
Median · hr
Population Pharmacokinetics of Hydroxydabrafenib - Tmax
hrArm 1
Day 13.08 (1.45 to 10)
Day 15 (n=18)1.96 (0.967 to 3)
SecondaryPopulation Pharmacokinetics of Hydroxydabrafenib - AUC(0-12)

AUC is the area under the concentration-time curve.

Time frame:
Day 1 and Day 15
Reported as:
Geometric mean · h.ng/mL
Population Pharmacokinetics of Hydroxydabrafenib - AUC(0-12)
h.ng/mLArm 1
Day 1 (n=17)7930 ± 43
Day 154440 ± 43.4
SecondaryPopulation Pharmacokinetics of Hydroxydabrafenib - Rm/p

Rm/p is the metabolite-to-parent ratio.

Time frame:
Day 1 and Day 15
Reported as:
Geometric mean · ratio
Population Pharmacokinetics of Hydroxydabrafenib - Rm/p
ratioArm 1
Day 1 (n=17)0.68 ± 17
Day 150.653 ± 21.4
SecondaryPopulation Pharmacokinetics of Hydroxydabrafenib - Ctrough

Ctrough is trough concentration.

Time frame:
Day 1 and Day 15
Reported as:
Geometric mean · ng/mL
Population Pharmacokinetics of Hydroxydabrafenib - Ctrough
ng/mLArm 1
Population Pharmacokinetics of Hydroxydabrafenib - Ctrough94 ± 61.9
SecondaryPopulation Pharmacokinetics of Hydroxydabrafenib - Racc

Racc is the accumulation ratio.

Time frame:
Day 1 and Day 15
Reported as:
Geometric mean · ratio
Population Pharmacokinetics of Hydroxydabrafenib - Racc
ratioArm 1
Population Pharmacokinetics of Hydroxydabrafenib - Racc0.56 ± 35.5
SecondaryPopulation Pharmacokinetics of Desmethyl-dabrafenib - Cmax

Cmax is the maximum peak concentration.

Time frame:
Day 1 and Day 15
Reported as:
Geometric mean · ng/mL
Population Pharmacokinetics of Desmethyl-dabrafenib - Cmax
ng/mLArm 1
Day 148.9 ± 93.5
Day 15 (n=18)466 ± 51.6
SecondaryPopulation Pharmacokinetics of Desmethyl-dabrafenib - Tmax

Tmax is Time to Cmax (maximum peak concentration).

Time frame:
Day 1 and Day 15
Reported as:
Median · hr
Population Pharmacokinetics of Desmethyl-dabrafenib - Tmax
hrArm 1
Day 19.9 (7.92 to 10)
Day 15 (n=18)2.48 (0 to 10.1)
SecondaryPopulation Pharmacokinetics of Desmethyl-dabrafenib - AUC(0-12)

AUC is the area under the concentration-time curve. AUC0-12 and Rm/p could not be calculated on Day 1 because all desmethyl-dabrafenib PK profiles on Day 1 were still ascending. Therefore, the Racc on Day 15 could not be calculated for desmethyldabrafenib.

Time frame:
Day 1 and Day 15
Reported as:
Geometric mean · h.ng/mL
Population Pharmacokinetics of Desmethyl-dabrafenib - AUC(0-12)
h.ng/mLArm 1
Population Pharmacokinetics of Desmethyl-dabrafenib - AUC(0-12)3960 ± 52.9
SecondaryPopulation Pharmacokinetics of Desmethyl-dabrafenib - Rm/p

Rm/p is the metabolite-to-parent ratio. AUC0-12 and Rm/p could not be calculated on Day 1 because all desmethyl-dabrafenib PK profiles on Day 1 were still ascending. Therefore, the Racc on Day 15 could not be calculated for desmethyldabrafenib.

Time frame:
Day 1 and Day 15
Reported as:
Geometric mean · ratio
Population Pharmacokinetics of Desmethyl-dabrafenib - Rm/p
ratioArm 1
Population Pharmacokinetics of Desmethyl-dabrafenib - Rm/p0.616 ± 51.4
SecondaryPopulation Pharmacokinetics of Desmethyl-dabrafenib - Ctrough

Ctrough is trough concentration.

Time frame:
Day 1 and Day 15
Reported as:
Geometric mean · ng/mL
Population Pharmacokinetics of Desmethyl-dabrafenib - Ctrough
ng/mLArm 1
Population Pharmacokinetics of Desmethyl-dabrafenib - Ctrough365 ± 63.7
SecondaryPopulation Pharmacokinetics of Carboxydabrafenib - Cmax

Cmax is the maximum peak concentration.

Time frame:
Day 1 and Day 15
Reported as:
Geometric mean · ng/mL
Population Pharmacokinetics of Carboxydabrafenib - Cmax
ng/mLArm 1
Day 13760 ± 75.7
Day 15 (n=18)9750 ± 32.8
SecondaryPopulation Pharmacokinetics of Carboxydabrafenib - Tmax

Tmax is Time to Cmax (maximum peak concentration).

Time frame:
Day 1 and Day 15
Reported as:
Median · hr
Population Pharmacokinetics of Carboxydabrafenib - Tmax
hrArm 1
Day 18.94 (4 to 10.1)
Day 15 (n=18)3.5 (2 to 6.08)
SecondaryPopulation Pharmacokinetics of Carboxydabrafenib - AUC(0-12)

AUC is the area under the concentration-time curve.

Time frame:
Day 1 and Day 15
Reported as:
Geometric mean · h.ng/mL
Population Pharmacokinetics of Carboxydabrafenib - AUC(0-12)
h.ng/mLArm 1
Day 1 (n=1)34400 ± NA
Day 1586500 ± 34.1
SecondaryPopulation Pharmacokinetics of Carboxydabrafenib - Rm/p

Rm/p is the metabolite-to-parent ratio.

Time frame:
Day 1 and Day 15
Reported as:
Geometric mean · ratio
Population Pharmacokinetics of Carboxydabrafenib - Rm/p
ratioArm 1
Day 1 (n=1)3.34 ± NA
Day 1512.4 ± 55.8
SecondaryPopulation Pharmacokinetics of Carboxydabrafenib - Ctrough

Ctrough is trough concentration.

Time frame:
Day 1 and Day 15
Reported as:
Geometric mean · ng/mL
Population Pharmacokinetics of Carboxydabrafenib - Ctrough
ng/mLArm 1
Population Pharmacokinetics of Carboxydabrafenib - Ctrough5160 ± 46
SecondaryPopulation Pharmacokinetics of Carboxydabrafenib - Racc

Racc is the accumulation ratio.

Time frame:
Day 1 and Day 15
Reported as:
Geometric mean · ratio
Population Pharmacokinetics of Carboxydabrafenib - Racc
ratioArm 1
Population Pharmacokinetics of Carboxydabrafenib - Racc1.51 ± NA
SecondaryPopulation Pharmacokinetics of Trametinib - Cmax

Cmax is the maximum peak concentration.

Time frame:
Day 1 and Day 15
Reported as:
Geometric mean · ng/mL
Population Pharmacokinetics of Trametinib - Cmax
ng/mLArm 1
Day 19.87 ± 58.1
Day 15 (n=18)25.9 ± 33.3
SecondaryPopulation Pharmacokinetics of Trametinib - Tmax

Tmax is Time to Cmax (maximum peak concentration).

Time frame:
Day 1 and Day 15
Reported as:
Median · hr
Population Pharmacokinetics of Trametinib - Tmax
hrArm 1
Day 11.5 (0.483 to 4)
Day 15 (n=18)11.3 (6.64 to 17)
SecondaryPopulation Pharmacokinetics of Trametinib - AUC(0-t)

Area under the concentration-time curve from time zero (predose) to last time of quantifiable concentration within a subject across all treatments

Time frame:
Day 1 and Day 15
Reported as:
Geometric mean · h.ng/mL
Population Pharmacokinetics of Trametinib - AUC(0-t)
h.ng/mLArm 1
Day 172.6 ± 27.3
Day 15 (n=18)346 ± 24
SecondaryPopulation Pharmacokinetics of Trametinib - AUC(0-24)

AUC is the area under the concentration-time curve.

Time frame:
Day 1 and Day 15
Reported as:
Geometric mean · h.ng/mL
Population Pharmacokinetics of Trametinib - AUC(0-24)
h.ng/mLArm 1
Day 172.7 ± 27.2
Day 15 (n=18)357 ± 22.7
SecondaryPopulation Pharmacokinetics of Trametinib - Ctrough

Ctrough is trough concentration.

Time frame:
Day 1 and Day 15
Reported as:
Geometric mean · ng/mL
Population Pharmacokinetics of Trametinib - Ctrough
ng/mLArm 1
Population Pharmacokinetics of Trametinib - Ctrough11.2 ± 25.2
SecondaryPopulation Pharmacokinetics of Trametinib - Racc

Racc is the accumulation ratio.

Time frame:
Day 1 and Day 15
Reported as:
Geometric mean · ratio
Population Pharmacokinetics of Trametinib - Racc
ratioArm 1
Population Pharmacokinetics of Trametinib - Racc5.16 ± 15.1
Post-hocAll Collected Deaths

Deaths are reported in the following categories: On-treatment deaths are defined as deaths that occurred after treatment start up to 30 days after study drug discontinuation. Post-treatment deaths are defined as deaths that occurred more than 30 days after study drug discontinuation until end of post-treatment follow up. Total deaths are the combination of on-treatment deaths and post-treatment deaths.

Time frame:
The collection period for mortality data occurred from start of treatment until the end of the post-treatment period, up to a maximum timeframe of 4.25 years.
Reported as:
Number · Participants
All Collected Deaths
ParticipantsArm 1
Total Deaths43
On-treatment Deaths16
Post-treatment Deaths27

Adverse events

Collected over Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of 51 months (for both dabrafenib and also Rametinib) (approx 4.25 years).. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
All Patients16/77 (20.8%)18/77 (23.4%)75/77 (97.4%)
Most frequent serious events
Showing 10 of 30
Most frequent serious events
EventAll Patients
Diarrhoea infectiousInfections and infestations2/77
AnaemiaBlood and lymphatic system disorders1/77
UveitisEye disorders1/77
Gastrointestinal haemorrhageGastrointestinal disorders1/77
PneumoperitoneumGastrointestinal disorders1/77
PyrexiaGeneral disorders1/77
Acute hepatic failureHepatobiliary disorders1/77
Liver injuryHepatobiliary disorders1/77
Arthritis infectiveInfections and infestations1/77
CellulitisInfections and infestations1/77
Most frequent other events
Showing 10 of 48
Most frequent other events
EventAll Patients
PyrexiaGeneral disorders46/77
AnaemiaBlood and lymphatic system disorders37/77
White blood cell count decreasedInvestigations35/77
HyperglycaemiaMetabolism and nutrition disorders32/77
Neutrophil count decreasedInvestigations29/77
RashSkin and subcutaneous tissue disorders29/77
Aspartate aminotransferase increasedInvestigations24/77
NauseaGastrointestinal disorders22/77
NasopharyngitisInfections and infestations22/77
Blood lactate dehydrogenase increasedInvestigations21/77

Baseline characteristics

Age, Continuous
Age, Continuous(years)Arm 1
Mean50.6 ± 13.08
Sex: Female, Male
Sex: Female, Male(Participants)Arm 1
Female42
Male35
Race (NIH/OMB)
Race (NIH/OMB)(Participants)Arm 1
American Indian or Alaska Native0
Asian77
Native Hawaiian or Other Pacific Islander0
Black or African American0
White0
More than one race0
Unknown or Not Reported0
08

Study locations

13 sites
  • Novartis Investigative Site
    Guangzhou, Guangdong 510060, China
  • Novartis Investigative Site
    Kunming, Yunnan 650106, China
  • Novartis Investigative Site
    Hangzhou, Zhejiang 310022, China
  • Novartis Investigative Site
    Beijing, 100036, China
  • Novartis Investigative Site
    Tuenmen, Hong Kong
  • Novartis Investigative Site
    Seoul, 110-744, South Korea
  • Novartis Investigative Site
    Seoul, 120-752, South Korea
  • Novartis Investigative Site
    Kaohsiung City, 807, Taiwan
  • Novartis Investigative Site
    Taipei, 100, Taiwan
  • Novartis Investigative Site
    Taoyuan, 333, Taiwan
  • Novartis Investigative Site
    Bangkok, 10320, Thailand
  • Novartis Investigative Site
    Bangkok, 10400, Thailand
  • Novartis Investigative Site
    Songkhla, 90110, Thailand
09

References and documents

Publications

  • Mao L, Ding Y, Bai X, Sheng X, Dai J, Chi Z, Cui C, Kong Y, Fan Y, Xu Y, Wang X, Tang B, Lian B, Yan X, Li S, Zhou L, Wei X, Li C, Guo J, Zhang X, Si L. Overall Survival of Patients With Unresectable or Metastatic BRAF V600-Mutant Acral/Cutaneous Melanoma Administered Dabrafenib Plus Trametinib: Long-Term Follow-Up of a Multicenter, Single-Arm Phase IIa Trial. Front Oncol. 2021 Aug 24;11:720044. doi: 10.3389/fonc.2021.720044. eCollection 2021. PubMed 34504796 ↗
  • Si L, Zhang X, Shin SJ, Fan Y, Lin CC, Kim TM, Dechaphunkul A, Maneechavakajorn J, Wong CS, Ilankumaran P, Lee DY, Gasal E, Li H, Guo J. Open-label, phase IIa study of dabrafenib plus trametinib in East Asian patients with advanced BRAF V600-mutant cutaneous melanoma. Eur J Cancer. 2020 Aug;135:31-38. doi: 10.1016/j.ejca.2020.04.044. Epub 2020 Jun 10. PubMed 32534242 ↗

Study documents

  • Study protocol · Nov 27, 2019
  • Statistical analysis plan · May 5, 2021

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Undecided — 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

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Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Feb 1, 2022, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
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Registry details

Key details

Study ID
NCT02083354
Lead sponsor
Novartis Pharmaceuticals
Responsible party
Sponsor
First posted
Mar 11, 2014
Start date
Mar 18, 2014
Primary completion
Feb 23, 2018
Completion
Apr 19, 2021
Results posted
Mar 17, 2021
Last update
Feb 1, 2022

Study contacts

Novartis Pharmaceuticals
study director · Novartis Pharmaceuticals

Oversight

Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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