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

Study Overview
=================
Brief 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.

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.

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

Conditions
-----------------
Cancer, Melanoma

Intervention / Treatment
-----------------
* Drug: Dabrafenib
* Drug: Trametinib


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>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<br>* 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)<br>Drug: Trametinib<br>* 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)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 35 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | 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. | 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. | 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 | 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. | 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. | 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. | Day 1 and Day 15 | 
| Population Pharmacokinetics of Dabrafenib - Tmax | Tmax is Time to Cmax (maximum peak concentration). | Day 1 and Day 15 | 
| Population Pharmacokinetics of Dabrafenib - AUC(0-12) | AUC is the area under the concentration-time curve. | Day 1 and Day 15 | 
| Population Pharmacokinetics of Dabrafenib - Ctrough | Ctrough is trough concentration. | Day 1 and Day 15 | 
| Population Pharmacokinetics of Dabrafenib - Racc | Racc is the accumulation ratio. | Day 1 and Day 15 | 
| Population Pharmacokinetics of Hydroxydabrafenib - Cmax | Cmax is the maximum peak concentration. | Day 1 and Day 15 | 
| Population Pharmacokinetics of Hydroxydabrafenib - Tmax | Tmax is Time to Cmax (maximum peak concentration). | Day 1 and Day 15 | 
| Population Pharmacokinetics of Hydroxydabrafenib - AUC(0-12) | AUC is the area under the concentration-time curve. | Day 1 and Day 15 | 
| Population Pharmacokinetics of Hydroxydabrafenib - Rm/p | Rm/p is the metabolite-to-parent ratio. | Day 1 and Day 15 | 
| Population Pharmacokinetics of Hydroxydabrafenib - Ctrough | Ctrough is trough concentration. | Day 1 and Day 15 | 
| Population Pharmacokinetics of Hydroxydabrafenib - Racc | Racc is the accumulation ratio. | Day 1 and Day 15 | 
| Population Pharmacokinetics of Desmethyl-dabrafenib - Cmax | Cmax is the maximum peak concentration. | Day 1 and Day 15 | 
| Population Pharmacokinetics of Desmethyl-dabrafenib - Tmax | Tmax is Time to Cmax (maximum peak concentration). | 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. | 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. | Day 1 and Day 15 | 
| Population Pharmacokinetics of Desmethyl-dabrafenib - Ctrough | Ctrough is trough concentration. | Day 1 and Day 15 | 
| Population Pharmacokinetics of Carboxydabrafenib - Cmax | Cmax is the maximum peak concentration. | Day 1 and Day 15 | 
| Population Pharmacokinetics of Carboxydabrafenib - Tmax | Tmax is Time to Cmax (maximum peak concentration). | Day 1 and Day 15 | 
| Population Pharmacokinetics of Carboxydabrafenib - AUC(0-12) | AUC is the area under the concentration-time curve. | Day 1 and Day 15 | 
| Population Pharmacokinetics of Carboxydabrafenib - Rm/p | Rm/p is the metabolite-to-parent ratio. | Day 1 and Day 15 | 
| Population Pharmacokinetics of Carboxydabrafenib - Ctrough | Ctrough is trough concentration. | Day 1 and Day 15 | 
| Population Pharmacokinetics of Carboxydabrafenib - Racc | Racc is the accumulation ratio. | Day 1 and Day 15 | 
| Population Pharmacokinetics of Trametinib - Cmax | Cmax is the maximum peak concentration. | Day 1 and Day 15 | 
| Population Pharmacokinetics of Trametinib - Tmax | Tmax is Time to Cmax (maximum peak concentration). | 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 | Day 1 and Day 15 | 
| Population Pharmacokinetics of Trametinib - AUC(0-24) | AUC is the area under the concentration-time curve. | Day 1 and Day 15 | 
| Population Pharmacokinetics of Trametinib - Ctrough | Ctrough is trough concentration. | Day 1 and Day 15 | 
| Population Pharmacokinetics of Trametinib - Racc | Racc is the accumulation ratio. | Day 1 and Day 15 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
melanoma, dabrafenib, trametinib, malignant skin cancer, skin cancer, BRAF V600 Mutation-Positive Melanoma