CancerPhase 2NCT02083354
Study to Investigate the Objective Response Rate of Dabrafenib in Combination With Trametinib in Subjects With BRAF V600 Mutation-Positive Melanoma
A Phase 2 study testing Dabrafenib and Trametinib in people with Cancer and Melanoma, run by Novartis Pharmaceuticals at 13 sites in 5 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- What is being tested?
- Dabrafenib and Trametinib
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 77 participants
- Where
- 13 sitesin 5 countries
- Study dates
- 18 Mar 2014to 19 Apr 2021
- 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
- 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.
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- 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.
Who cannot join
- 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).
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- 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.
Trial locations and contacts
13 sites in 5 countries.
13 sites in 5 countries
China4 sites
Novartis Investigative Site
Beijing, 100036
Novartis Investigative Site
Guangzhou, Guangdong, 510060
Novartis Investigative Site
Hangzhou, Zhejiang, 310022
Novartis Investigative Site
Kunming, Yunnan, 650106
Taiwan3 sites
Novartis Investigative Site
Kaohsiung City, 807
Novartis Investigative Site
Taipei, 100
Novartis Investigative Site
Taoyuan, 333
Thailand3 sites
Novartis Investigative Site
Bangkok, 10320
Novartis Investigative Site
Bangkok, 10400
Novartis Investigative Site
Songkhla, 90110
South Korea2 sites
Novartis Investigative Site
Seoul, 110-744
Novartis Investigative Site
Seoul, 120-752
About this study
Official title: 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
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.
- Being tested
- Dabrafenib, Trametinib
- Keywords
- melanoma, dabrafenib, trametinib, malignant skin cancer, skin cancer, BRAF V600 Mutation-Positive Melanoma
- Medical subject headings
- Neoplasms, Melanoma, Skin Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DabrafenibDrug
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)
TrametinibDrug
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 group | Role | What they receive |
|---|---|---|
| Arm 1 | Experimental | 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 Receives: Drug: Dabrafenib; Drug: Trametinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Up to 35 months
Secondary outcomes (35)
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
Measured: Up to 36 months
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.
Measured: Up to 36 months
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.
Measured: Up to 36 months
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.
Measured: Up to 36 months
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
Measured: Approximately 5 years
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.
Measured: Approximately 5 years
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.
Measured: 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).
Population Pharmacokinetics of Dabrafenib - Cmax
Cmax is the maximum peak concentration.
Measured: Day 1 and Day 15
Population Pharmacokinetics of Dabrafenib - Tmax
Tmax is Time to Cmax (maximum peak concentration).
Measured: Day 1 and Day 15
Population Pharmacokinetics of Dabrafenib - AUC(0-12)
AUC is the area under the concentration-time curve.
Measured: Day 1 and Day 15
Population Pharmacokinetics of Dabrafenib - Ctrough
Ctrough is trough concentration.
Measured: Day 1 and Day 15
Population Pharmacokinetics of Dabrafenib - Racc
Racc is the accumulation ratio.
Measured: Day 1 and Day 15
Population Pharmacokinetics of Hydroxydabrafenib - Cmax
Cmax is the maximum peak concentration.
Measured: Day 1 and Day 15
Population Pharmacokinetics of Hydroxydabrafenib - Tmax
Tmax is Time to Cmax (maximum peak concentration).
Measured: Day 1 and Day 15
Population Pharmacokinetics of Hydroxydabrafenib - AUC(0-12)
AUC is the area under the concentration-time curve.
Measured: Day 1 and Day 15
Population Pharmacokinetics of Hydroxydabrafenib - Rm/p
Rm/p is the metabolite-to-parent ratio.
Measured: Day 1 and Day 15
Population Pharmacokinetics of Hydroxydabrafenib - Ctrough
Ctrough is trough concentration.
Measured: Day 1 and Day 15
Population Pharmacokinetics of Hydroxydabrafenib - Racc
Racc is the accumulation ratio.
Measured: Day 1 and Day 15
Population Pharmacokinetics of Desmethyl-dabrafenib - Cmax
Cmax is the maximum peak concentration.
Measured: Day 1 and Day 15
Population Pharmacokinetics of Desmethyl-dabrafenib - Tmax
Tmax is Time to Cmax (maximum peak concentration).
Measured: Day 1 and Day 15
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.
Measured: Day 1 and Day 15
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.
Measured: Day 1 and Day 15
Population Pharmacokinetics of Desmethyl-dabrafenib - Ctrough
Ctrough is trough concentration.
Measured: Day 1 and Day 15
Population Pharmacokinetics of Carboxydabrafenib - Cmax
Cmax is the maximum peak concentration.
Measured: Day 1 and Day 15
Population Pharmacokinetics of Carboxydabrafenib - Tmax
Tmax is Time to Cmax (maximum peak concentration).
Measured: Day 1 and Day 15
Population Pharmacokinetics of Carboxydabrafenib - AUC(0-12)
AUC is the area under the concentration-time curve.
Measured: Day 1 and Day 15
Population Pharmacokinetics of Carboxydabrafenib - Rm/p
Rm/p is the metabolite-to-parent ratio.
Measured: Day 1 and Day 15
Population Pharmacokinetics of Carboxydabrafenib - Ctrough
Ctrough is trough concentration.
Measured: Day 1 and Day 15
Population Pharmacokinetics of Carboxydabrafenib - Racc
Racc is the accumulation ratio.
Measured: Day 1 and Day 15
Population Pharmacokinetics of Trametinib - Cmax
Cmax is the maximum peak concentration.
Measured: Day 1 and Day 15
Population Pharmacokinetics of Trametinib - Tmax
Tmax is Time to Cmax (maximum peak concentration).
Measured: Day 1 and Day 15
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
Measured: Day 1 and Day 15
Population Pharmacokinetics of Trametinib - AUC(0-24)
AUC is the area under the concentration-time curve.
Measured: Day 1 and Day 15
Population Pharmacokinetics of Trametinib - Ctrough
Ctrough is trough concentration.
Measured: Day 1 and Day 15
Population Pharmacokinetics of Trametinib - Racc
Racc is the accumulation ratio.
Measured: Day 1 and Day 15
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Mar 2014 (estimated)
- Study start18 Mar 2014
- Primary completion23 Feb 2018
- Study completion19 Apr 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for CancerStudies of the same condition, open and under way.
- More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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
- 77 participants (actual)
Sponsor and investigators
- Lead sponsor
- Novartis Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02083354
- Sponsor's protocol ID
- 200104
- Other IDs
- CDRB436B2205
- Status last verified
- Jan 2022
- First submitted
- 13 Feb 2014
- Last updated
- 1 Feb 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- 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
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 34504796Si 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 at a glance
From the registry record, last updated by the sponsor on 1 Feb 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT02083354
- Acronym / sponsor ID
- 200104
- Keywords
- melanoma, dabrafenib, trametinib, malignant skin cancer, skin cancer, BRAF V600 Mutation-Positive Melanoma
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 77 participants (actual)
- Lead sponsor
- Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
- Study start
- 18 Mar 2014 (actual)
- Primary completion
- 23 Feb 2018 (actual)
- Study completion
- 19 Apr 2021 (actual)
- First posted
- 11 Mar 2014 (estimated)
- Results
- Posted 17 Mar 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Arm 1 | Experimental | Drug: Dabrafenib, Drug: TrametinibAll 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 |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- 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.
Key exclusion criteria (16 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DabrafenibDabrafenib 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 | Arm 1 |
| TrametinibTrametinib 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) | Drug | Arm 1 |
Primary outcome
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.
35 secondary outcomes
Progression-free Survival (PFS) - Median
Time frame: Up to 36 months
Progression-free Survival (PFS)
Time frame: Up to 36 months
Duration of Response (DOR) - Estimate for Duration of Response - Median
Time frame: Up to 36 months
Duration of Response (DOR)
Time frame: Up to 36 months
Overall Survival (OS) - Median
Time frame: Approximately 5 years
Overall Survival (OS)
Time frame: Approximately 5 years
Number of Participants With Adverse Events
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).
Population Pharmacokinetics of Dabrafenib - Cmax
Time frame: Day 1 and Day 15
Population Pharmacokinetics of Dabrafenib - Tmax
Time frame: Day 1 and Day 15
Population Pharmacokinetics of Dabrafenib - AUC(0-12)
Time frame: Day 1 and Day 15
Population Pharmacokinetics of Dabrafenib - Ctrough
Time frame: Day 1 and Day 15
Population Pharmacokinetics of Dabrafenib - Racc
Time frame: Day 1 and Day 15
Population Pharmacokinetics of Hydroxydabrafenib - Cmax
Time frame: Day 1 and Day 15
Population Pharmacokinetics of Hydroxydabrafenib - Tmax
Time frame: Day 1 and Day 15
Population Pharmacokinetics of Hydroxydabrafenib - AUC(0-12)
Time frame: Day 1 and Day 15
Population Pharmacokinetics of Hydroxydabrafenib - Rm/p
Time frame: Day 1 and Day 15
Population Pharmacokinetics of Hydroxydabrafenib - Ctrough
Time frame: Day 1 and Day 15
Population Pharmacokinetics of Hydroxydabrafenib - Racc
Time frame: Day 1 and Day 15
Population Pharmacokinetics of Desmethyl-dabrafenib - Cmax
Time frame: Day 1 and Day 15
Population Pharmacokinetics of Desmethyl-dabrafenib - Tmax
Time frame: Day 1 and Day 15
Population Pharmacokinetics of Desmethyl-dabrafenib - AUC(0-12)
Time frame: Day 1 and Day 15
Population Pharmacokinetics of Desmethyl-dabrafenib - Rm/p
Time frame: Day 1 and Day 15
Population Pharmacokinetics of Desmethyl-dabrafenib - Ctrough
Time frame: Day 1 and Day 15
Population Pharmacokinetics of Carboxydabrafenib - Cmax
Time frame: Day 1 and Day 15
Population Pharmacokinetics of Carboxydabrafenib - Tmax
Time frame: Day 1 and Day 15
Population Pharmacokinetics of Carboxydabrafenib - AUC(0-12)
Time frame: Day 1 and Day 15
Population Pharmacokinetics of Carboxydabrafenib - Rm/p
Time frame: Day 1 and Day 15
Population Pharmacokinetics of Carboxydabrafenib - Ctrough
Time frame: Day 1 and Day 15
Population Pharmacokinetics of Carboxydabrafenib - Racc
Time frame: Day 1 and Day 15
Population Pharmacokinetics of Trametinib - Cmax
Time frame: Day 1 and Day 15
Population Pharmacokinetics of Trametinib - Tmax
Time frame: Day 1 and Day 15
Population Pharmacokinetics of Trametinib - AUC(0-t)
Time frame: Day 1 and Day 15
Population Pharmacokinetics of Trametinib - AUC(0-24)
Time frame: Day 1 and Day 15
Population Pharmacokinetics of Trametinib - Ctrough
Time frame: Day 1 and Day 15
Population Pharmacokinetics of Trametinib - Racc
Time frame: Day 1 and Day 15
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Feb 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 34504796Mao 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.
- Derived from this study: PubMed 32534242Si 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.
- Individual participant dataSharing planned: 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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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Novartis Pharmaceuticals study director
Novartis Pharmaceuticals
13 sites in 5 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Dabrafenib and Trametinib in people with Cancer and Melanoma, run by Novartis Pharmaceuticals at 13 sites in 5 countries.
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 10 inclusion and 16 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: finished, as of the sponsor's last update on 1 Feb 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 13 sites in China, Taiwan, Thailand, South Korea, Hong Kong. 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 17 Mar 2021). 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?
Objective Response Rate (ORR) (time frame: Up to 35 months). 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 NCT02083354, which also lists 2 linked publications.
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 1 Feb 2022.