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

NCT02083354 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 200104CDRB436B2205
• Study Type: interventional
• Target: 77
• Locations: 5 countries
• Sites: 13

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.

Conditions

Cancer; Melanoma

Keywords

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

Outcome Measures

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.

  Up to 35 months

Secondary Outcomes (35)

• Progression-free Survival (PFS) - Median

  Up to 36 months

• Progression-free Survival (PFS)

  Up to 36 months

• Duration of Response (DOR) - Estimate for Duration of Response - Median

  Up to 36 months

• Duration of Response (DOR)

  Up to 36 months

• Overall Survival (OS) - Median

  Approximately 5 years

Study Arms (1)

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

Drug: Dabrafenib; Drug: Trametinib

Interventions

Dabrafenib DRUG

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)

Arm 1

Trametinib DRUG

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)

Arm 1

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (13)

Novartis Investigative Site

Guangzhou, Guangdong, 510060, China

Location

Novartis Investigative Site

Kunming, Yunnan, 650106, China

Location

Novartis Investigative Site

Hangzhou, Zhejiang, 310022, China

Location

Novartis Investigative Site

Beijing, 100036, China

Location

Novartis Investigative Site

Tuenmen, Hong Kong

Location

Novartis Investigative Site

Seoul, 110-744, South Korea

Location

Novartis Investigative Site

Seoul, 120-752, South Korea

Location

Novartis Investigative Site

Kaohsiung City, 807, Taiwan

Location

Novartis Investigative Site

Taipei, 100, Taiwan

Location

Novartis Investigative Site

Taoyuan District, 333, Taiwan

Location

Novartis Investigative Site

Bangkok, 10320, Thailand

Location

Novartis Investigative Site

Bangkok, 10400, Thailand

Location

Novartis Investigative Site

Songkhla, 90110, Thailand

Location

Related Publications (2)

• 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.

  PMID: 34504796 DERIVED

• 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.

  PMID: 32534242 DERIVED

MeSH Terms

Conditions

Neoplasms; Melanoma; Skin Neoplasms

Interventions

dabrafenib; trametinib

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Nevi and Melanomas; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@Novartis.com

+ 1 862 778 8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 13, 2014
• First Posted: March 11, 2014
• Study Start: March 18, 2014
• Primary Completion: February 23, 2018
• Study Completion: April 19, 2021
• Last Updated: February 1, 2022
• Results First Posted: March 17, 2021

Record last verified: 2022-01

Locations

CN (4); TH (3); TW (3); HK (1); KR (2)