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

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.

Study Overview

• Status: Completed
• Conditions: Melanoma; Cancer
• Intervention / Treatment: Drug: Dabrafenib; Drug: Trametinib

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 Type: Interventional
• Enrollment (Actual): 77
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Beijing, China, 100036
    • Novartis Investigative Site
  • Guangdong
    • Guangzhou, Guangdong, China, 510060
      • Novartis Investigative Site
  • Yunnan
    • Kunming, Yunnan, China, 650106
      • Novartis Investigative Site
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310022
      • Novartis Investigative Site
• Hong Kong
  • Tuen Mun, Hong Kong
    • Novartis Investigative Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 120-752
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 110-744
    • Novartis Investigative Site
• Taiwan
  • Kaohsiung, Taiwan, 807
    • Novartis Investigative Site
  • Taipei, Taiwan, 100
    • Novartis Investigative Site
  • Taoyuan, Taiwan, 333
    • Novartis Investigative Site
• Thailand
  • Bangkok, Thailand, 10400
    • Novartis Investigative Site
  • Bangkok, Thailand, 10320
    • Novartis Investigative Site
  • Songkla, Thailand, 90110
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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; Dabrafenib will be provided as 50 mg and 75 mg capsules. Each capsule will contain 50 mg or 75 mg of free base (present as the mesylate salt); Drug: Trametinib; Trametinib study medication will be provided as 0.5 mg and 2.0 mg tablets. Each tablet will contain 0.5 mg or 2.0 mg of trametinib parent (present as the DMSO solvate)

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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General 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.
• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 18, 2014
• Primary Completion (ACTUAL): February 23, 2018
• Study Completion (ACTUAL): April 19, 2021

Study Registration Dates

• First Submitted: February 13, 2014
• First Submitted That Met QC Criteria: March 6, 2014
• First Posted (ESTIMATE): March 11, 2014

Study Record Updates

• Last Update Posted (ACTUAL): February 1, 2022
• Last Update Submitted That Met QC Criteria: January 4, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: melanoma; trametinib; dabrafenib; skin cancer; malignant skin cancer; BRAF V600 Mutation-Positive Melanoma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Trametinib; Dabrafenib
• Other Study ID Numbers: 200104; CDRB436B2205 (OTHER: Novartis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

IPD Plan Description

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

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No