Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

Melanoma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Trametinib

Dabrafenib

Protein Kinase Inhibitors

Enzyme Inhibitors

Patients will receive the BRAF inhibitor dabrafenib and MEK inhibitor trametinib orally at the RP2D determined in the Phase I/II study (BRF113220): trametinib 2mg QD and dabrafenib 150 mg BID on a continuous basis. A cycle will be defined as 3 weeks in duration. Cycles will be repeated until disease progression (clinical or radiological). Patients may remain on treatment after progression (at the discretion of the investigator) as long as they are still experiencing clinical benefit.

BRAF inhibitor dabrafenib and MEK inhibitor trametinib

Carrie Lee, MD

This phase II study in 20 patients with BRAFV600E mutant, unresectable stage III/IV melanoma is designed to explore the mechanisms by which tumors acquire resistance to the combination of a BRAF inhibitor (dabrafenib) and MEK inhibitor (trametinib). Tissue will be collected at baseline and at progression.If a subject is removed from the study for one of a variety of reasons including, but not limited to, an inability to tolerate the combination of dabrafenib and trametinib, a need to receive other therapy or completion of 3-years of study treatment without progression, and the subject later receives, as part of his/her standard of care, the combination of dabrafenib and trametinib and progresses on the standard of care regimen, then the subject may be contacted by the treating physician to be put back on to the LCCC 1128 protocol and have a progression biopsy at this progression time point. Markers of resistance will be explored by performing near kinome-wide profiling on tumor samples, and in patients who co-enroll in institutional protocol LCCC1108, by sequencing tumors using NextGen DNA sequencing technology. Overall response rate and duration to this combination will also be assessed.

The present phase II study in 20 patients with BRAFV600E mutant, unresectable stage III/IV melanoma is designed to explore the mechanisms by which tumors acquire resistance to the combination of BRAF and MEK inhibition. Overall response rate and duration to this combination will also be assessed.

Tissue will be collected at baseline and at progression (clinical or radiological). Patients may remain on treatment after progression (at the discretion of the investigator) as long as they are still experiencing clinical benefit. We anticipate that up to 50% of patients may continue on therapy post-progression for 2-8 weeks.

BRF113220, the phase I/II trial of the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib is ongoing in metastatic melanoma to establish the safety of this combination, and to determine the recommended phase 2 doses (RP2D) for each agent. Expansion cohorts at the RP2D for these drugs in combination were included in the phase I to characterize the safety in more detail, and to explore the efficacy of this combination. The combination was well tolerated as described in section 1.5, with decreased frequency of rash compared to either agent alone and with just 1 report of cutaneous SCC.

This proposed study will utilize the RP2D determined in the Phase I/II study: trametinib 2mg QD and dabrafenib 150 mg BID. Despite a very promising overall response rate of 81%, these patients will also likely go on to develop resistance as a result of new resistance mutations, and given the cooperative signaling network of kinases that sense inhibition of key nodal kinases and induce compensatory responses that offset pharmacological intervention. The study objectives are as follows: Objectives Primary Objective To identify kinases that are differentially expressed pre- and post-treatment with BRAF (dabrafenib) and MEK (trametinib) inhibitors, and to determine a kinome signature predictive of resistance to BRAF/MEK inhibition in stage III/IV melanoma Secondary Objectives To explore whether resistance to BRAF and MEK inhibition is associated with new functional mutations in the approximately 150 oncogenes / tumor suppressor genes that are assessed in more than 10% of the tumors (using NextGen DNA sequencing technology) in the subset of patients who co-enroll in LCCC1108, with particular focus on one of five established resistance genes (BRAF, NRAS, MEK1, MAP3K8 or COT, and PTEN) To determine the overall response rate (ORR: complete response + partial response) as measured via RECISTv1.1 To estimate the duration of ORR as measured via RECISTv1.1 To estimate progression-free survival (PFS) as defined by RECISTv1.1 To estimate the rate of overall survival (OS) at 1 year from day 1 of treatment

Primary Endpoint Kinome signature pathway will be based on comparison of kinome expression from pre- and post-treatment biopsies using Multiplexed Inhibitor Beads (MIBs) coupled with mass spectrometry.

LCCC 1128: Open Label Phase II Trial of the BRAF Inhibitor (Dabrafenib) and the MEK Inhibitor (Trametinib) in Unresectable Stage III and Stage IV BRAF Mutant Melanoma; Correlation of Resistance With the Kinome and Functional Mutations

The primary outcome of this study is to identify kinases that are differentially expressed pre- and post-treatment with BRAF (dabrafenib) and MEK (trametinib) inhibitors. The kinases will be profiled using Multiplexed Inhibitor Beads (MIBs) coupled with mass spectrometry (MS) and reported as a sum of the Log 2 Fold Change between baseline and one year post treatment across all patients

Prediction analysis of microarrays (PAM) based on nearest shrunken centroid will also be carried out to identify a subset of kinases that predicts resistance to BRAF+MEK inhibition.

The secondary outcome measure is to explore whether resistance to BRAF and MEK inhibition is associated with new functional mutations in the approximately 150 oncogenes / tumor suppressor genes that are assessed in more than 10% of the tumors (using Next Generation (NextGen) DNA sequencing technology) in the subset of patients who co-enroll in a correlative study, with particular focus on one of five established resistance genes (BRAF, NRAS, MEK1, Mitogen-Activated Protein Kinase Kinase Kinase 8 (MAP3K8) or Cancer Osaka Thyroid (COT), and PTEN).

To determine the disease overall response rate (ORR: complete response (CR) + partial response (PR)/total number of patients) as measured radiographically via Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions. CR is defined as the disappearance of all target lesions; PR is a \>=30% decrease in the sum of the longest diameter of target lesions

Duration of overall response is defined as the time from documentation of response (Complete or Partial) to time of disease progression or death. Response was measured radiographically using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions. Complete Response is defined as the disappearance of all target lesions; Partial Response as a \>=30% decrease in the sum of the longest diameter of target lesions, and Progressive Disease as a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesions.

PFS is defined as the time from Day 1 of protocol treatment to the date of progression as measured radiographically using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) or to the date of death. Per RECIST, Progressive Disease as a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesions.

The rate of overall survival is defined as the percentage of patients still alive at one year from Day 1 of protocol treatment

GlaxoSmithKline

UNC Lineberger Comprehensive Cancer Center

BRAF inhibitor dabrafenib and MEK inhibitor trametinib: Patients received the BRAF inhibitor dabrafenib and MEK inhibitor trametinib orally at the RP2D determined in the Phase I/II study (BRF113220): trametinib 2mg QD and dabrafenib 150 mg BID on a continuous basis. A cycle is defined as 3 weeks in duration. Cycles were repeated until disease progression (clinical or radiological). Patients could remain on treatment after progression (at the discretion of the investigator) as long as they are still experiencing clinical benefit.

BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Robin Johnson

RIPK2

PTK6

BRAF

CDK1

PAK4

LIMK1

EIF2AK2

AURKA

PI4K2B

PKMYT1

MAP4K3

WEE1

CSNK1D

EPHA4

AURKB

LIMK2

ADCK4

NME4

Progression samples were not available for 7 participants; 3 additional participants did not have samples that were evaluable by MIB/MS

Change in Kinase Expression

Kinome Signature Predictive of Resistance

BRAF and MEK Inhibition Associated With New Functional Mutations in the Approximately 150 Oncogenes

Overall Response Rate (ORR)

Duration of Overall Response

Progression Free Survival (PFS)

Rate of Overall Survival (OS) at 12 Months

BRAF inhibitor dabrafenib and MEK inhibitor trametinib: Patients received the BRAF inhibitor dabrafenib and MEK inhibitor trametinib orally at the Recommend Phase 2 Dose (RP2D) determined in the Phase I/II study (BRF113220): trametinib 2mg once a day (QD) and dabrafenib 150 mg twice a day (BID) on a continuous basis. A cycle is defined as 3 weeks in duration. Cycles were repeated until disease progression (clinical or radiological). Patients could remain on treatment after progression (at the discretion of the investigator) as long as they are still experiencing clinical benefit.

Overall Study

Vemurafenib

Participants will receive placebo orally once daily on Days 1-21 of each 28-day cycle plus vemurafenib 960 milligrams (mg) orally twice a day on Days 1-28 of each 28-day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.

Participants will receive cobimetinib 60 mg orally once daily on Days 1-21 of each 28-day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28-day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.

Placebo

Cobimetinib

Clinical Trials

To evaluate the efficacy of vemurafenib in combination with cobimetinib (GDC-0973), compared with vemurafenib and placebo, in previously untreated BRAF V600 mutation-positive patients with unresectable locally advanced or metastatic melanoma, as measured by progression-free survival (PFS), assessed by the study site investigator.

A Study Comparing Vemurafenib Versus Vemurafenib Plus Cobimetinib in Participants With Metastatic Melanoma

A Phase III, Double-Blind, Placebo-Controlled Study of Vemurafenib Versus Vemurafenib Plus GDC-0973 in Previously Untreated BRAF^600-Mutation Positive Patients With Unresectable Locally Advanced or Metastatic Melanoma

Progression-free survival was defined as the time from randomization to the first occurrence of disease progression, as determined by the investigator using Response Evaluation Criteria in Solid Tumors v1.1, or death from any cause, whichever came first. Disease progression was defined as: (1) at least a 20% increase in the sum (the increase in the sum must be at least 5 mm) of diameters of target lesions, taking as reference the smallest sum during the study; (2) unequivocal progression of existing non-target lesions; or (3) the appearance of 1 or more new lesions.

Overall survival was defined as the time from randomization until the date of death from any cause.

An objective response was defined as a complete response or a partial response determined on two consecutive occasions ≥ 4 weeks apart. Responses were determined by Response Evaluation Criteria in Solid Tumors v1.1. A complete response was defined as the disappearance of all target lesions or the disappearance of all non-target lesions and normalization of tumor marker level. A partial response was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of the longest diameter of target lesions.

Duration of response was defined as the time from first occurrence of a documented confirmed objective response until the time of disease progression, as determined by investigator review of tumor assessments using Response Evaluation Criteria in Solid Tumors v1.1 or death from any cause during the study. Disease progression was defined as: (1) at least a 20% increase in the sum (the increase in the sum must be at least 5 mm) of diameters of target lesions, taking as reference the smallest sum during the study; (2) unequivocal progression of existing non-target lesions; or (3) the appearance of 1 or more new lesions.

Hoffmann-La Roche

1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem.

All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.

Participants received cobimetinib 60 mg orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.

Cobimetinib + Vemurafenib

Participants received placebo orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.

Placebo + Vemurafenib

Total

Age, Categorical

Asian

More than one race

Native Hawaiian or other Pacific Islande

Black or African American

White

Unknown or Not Reported

Other

Race/Ethnicity, Customized

Hispanic or Latino

Not Hispanic or Latino

Not Stated

Unknown

Intent-to-treat population: All randomized participants, regardless of whether or not study treatment was received.

Medical Communications

Post hoc Efficacy Analysis: 16 January 2015

Primary Analysis: 9 May 2014

Extended 5-Year Analysis: 21 July 2019

Progression-free Survival

Primary Analysis 9 May 2014

Post hoc Analysis 16 January 2015

Final Analysis 28 August 2015

Extended 5-year Analysis 21 July 2019

Overall Survival

Percentage of Participants With an Objective Response

Intent-to-treat population: All randomized participants, regardless of whether or not study treatment was received. Only participants with an objective response were included in the analysis.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
LCCC 1128: Open Label Phase II Trial of the BRAF Inhibitor (Dabrafenib) and the MEK Inhibitor (Trametinib) in Unresectable Stage III and Stage IV BRAF Mutant Melanoma; Correlation of Resistance With the Kinome and Functional Mutations	NCT01726738	Stage III Melan... Stage IV Melano... Unresectable Me... BRAF Mutant Mel...	BRAF inhibitor ...	18 Years -	UNC Lineberger Comprehensive Cancer Center
LCCC 1128: Open Label Phase II Trial of the BRAF Inhibitor (Dabrafenib) and the MEK Inhibitor (Trametinib) in Unresectable Stage III and Stage IV BRAF Mutant Melanoma; Correlation of Resistance With the Kinome and Functional Mutations	NCT01726738	Stage III Melan... Stage IV Melano... Unresectable Me... BRAF Mutant Mel...	BRAF inhibitor ...	18 Years -	UNC Lineberger Comprehensive Cancer Center
LCCC 1128: Open Label Phase II Trial of the BRAF Inhibitor (Dabrafenib) and the MEK Inhibitor (Trametinib) in Unresectable Stage III and Stage IV BRAF Mutant Melanoma; Correlation of Resistance With the Kinome and Functional Mutations	NCT01726738	Stage III Melan... Stage IV Melano... Unresectable Me... BRAF Mutant Mel...	BRAF inhibitor ...	18 Years -	UNC Lineberger Comprehensive Cancer Center
A Study Comparing Vemurafenib Versus Vemurafenib Plus Cobimetinib in Participants With Metastatic Melanoma	NCT01689519	Malignant Melan...	Placebo Vemurafenib Cobimetinib	18 Years -	Hoffmann-La Roche

Spots Global Cancer Trial Database for braf mutant melanoma