BRAF Mutant Melanoma, Stage III Melanoma, Stage IV Melanoma, Unresectable Melanoma
Conditions
Keywords
Melanoma, Stage III, Stage IV, Unresectable, BRAF Mutant, Dabrafenib, Trametinib, Kinome, Resistance, Sequencing, Mutations, Kinases, Mechanism
Brief summary
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.
Detailed description
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.
Interventions
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.
Sponsors
GlaxoSmithKline
UNC Lineberger Comprehensive Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Main Study Inclusion Criteria: Subject must meet all of the inclusion criteria to participate in this study: Age ≥18 years Signed written informed consent Histologically confirmed V600E or V600K BRAF mutant melanoma Unresectable Stage III/IV melanoma ECOG PS 0-2 Normal organ function as defined by the following: * Absolute neutrophil count \>1.2 × 109/L * Hemoglobin \>9 g/dL, platelets \>75 × 109/L * PT/INR and PTT ≤1.5 x ULN (Note: subjects receiving anticoagulation treatment may enroll with INR established within the therapeutic range prior to D1 of treatment) * Albumin \>2.5 g/dL * Total bilirubin \<1.5 x ULN (patients with elevated bilirubin due to Gilbert's disease will not be excluded) * AST and ALT \< 2.5× ULN * CrCl ≥50mL/min per Cockcroft-Gault Prior anti-cancer treatment related toxicities except alopecia and lab values as outlined in the criterion above must be less than or equal to Grade 1 as per CTCAEv4 Willing to undergo biopsy for research purposes only Females of child-bearing potential: willing to use two forms of effective contraception, and to continue use for 16 weeks post last dose of study medication. Effective contraception is defined as any medically recommended method (or combination of methods) as per standard of care, including abstinence. Females of non-childbearing potential are those who are postmenopausal (defined as greater than 1 year without menses with appropriate clinical profile, e.g., age appropriate: \>45 years in the absence of hormone replacement therapy (HRT). In questionable cases, the subject must have a follicle stimulating hormone (FSH) value \>40 mIU/mL and an estradiol value \<40pg/mL (\<140 pmol/L); or who have had a bilateral tubal ligation or tubal occlusion, bilateral oophorectomy, or hysterectomy. Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception as described from D1 of treatment, throughout the treatment period, and for 16 weeks after the last dose of study treatment. If a subject becomes pregnant during the treatment period of the study, the study treatments should be stopped immediately. In women of child-bearing potential, negative serum pregnancy test within 48 hours prior to day 1 of study treatment and agree to use effective contraception. Effective contraception is defined as: (a) an intrauterine device with a documented failure rate of less than 1% per year. (b) male partner sterilization prior to the female subject's entry, and this male is the sole sexual partner for that female. (c) complete abstinence from sexual intercourse for 14 days prior to enrollment throughout study treatment, and for at least 4 months after the last dose of study treatment. Abstinence is only acceptable when in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar ovulation, symptothermal, post-ovulation methods, etc) and withdrawal are not acceptable methods of contraception. (d) double- barrier contraception: condom and occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/cream/suppository). Note: hormonal based methods (e.g. oral contraceptives) are not permitted. Female subjects who are lactating must discontinue nursing prior to the first dose of study treatment and must refrain from nursing throughout the treatment period and for 4 months following the last dose of study treatment Measurable disease as defined by RECIST v1.1 Able to swallow and retain oral medication Left ventricular ejection fraction by ECHO ≥ institutional lower limit of normal Main Study
Exclusion criteria
Any subject meeting any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Kinase Expression | Baseline and One year post treatment | 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 |
| Kinome Signature Predictive of Resistance | One year post treatment | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Overall Response | One year post treatment | 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. |
| BRAF and MEK Inhibition Associated With New Functional Mutations in the Approximately 150 Oncogenes | One year | 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). |
| Rate of Overall Survival (OS) at 12 Months | One year post treatment | The rate of overall survival is defined as the percentage of patients still alive at one year from Day 1 of protocol treatment |
| Progression Free Survival (PFS) | One year post treatment | 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. |
| Overall Response Rate (ORR) | One year post treatment | 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 |
Countries
United States
Participant flow
Recruitment details
A total of 17 participants were recruited from University of North Carolina Hospitals (Chapel Hill, NC) between January 2013 and July 2016
Pre-assignment details
In addition to the 17 patients who were enrolled and participated in the trial, 6 additional patients consented, but were found to be ineligible and 1 additional patient withdrew consent prior to starting the study.
Participants by arm
| Arm | Count |
|---|---|
| BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors 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. | 17 |
| Total | 17 |
Baseline characteristics
| Characteristic | BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors |
|---|---|
| Age, Continuous | 54 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 17 Participants |
| Region of Enrollment United States | 17 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 6 / 17 |
| other Total, other adverse events | 17 / 17 |
| serious Total, serious adverse events | 11 / 17 |
Outcome results
Primary
Change in Kinase Expression
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
Time frame: Baseline and One year post treatment
Population: Progression samples were not available for 7 participants; 3 additional participants did not have samples that were evaluable by MIB/MS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors | Change in Kinase Expression | PTK6 | -19.64376 Sum Log 2 Fold Change Kinase Expression |
| BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors | Change in Kinase Expression | RIPK2 | -20.87259 Sum Log 2 Fold Change Kinase Expression |
| BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors | Change in Kinase Expression | BRAF | -16.41738 Sum Log 2 Fold Change Kinase Expression |
| BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors | Change in Kinase Expression | CDK1 | -12.5401 Sum Log 2 Fold Change Kinase Expression |
| BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors | Change in Kinase Expression | PAK4 | -12.31239 Sum Log 2 Fold Change Kinase Expression |
| BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors | Change in Kinase Expression | LIMK1 | -12.38811 Sum Log 2 Fold Change Kinase Expression |
| BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors | Change in Kinase Expression | EIF2AK2 | -12.51229 Sum Log 2 Fold Change Kinase Expression |
| BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors | Change in Kinase Expression | AURKA | -10.87395 Sum Log 2 Fold Change Kinase Expression |
| BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors | Change in Kinase Expression | PI4K2B | -7.66173 Sum Log 2 Fold Change Kinase Expression |
| BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors | Change in Kinase Expression | PKMYT1 | -11.3527 Sum Log 2 Fold Change Kinase Expression |
| BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors | Change in Kinase Expression | MAP4K3 | -9.8909 Sum Log 2 Fold Change Kinase Expression |
| BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors | Change in Kinase Expression | WEE1 | -9.61838 Sum Log 2 Fold Change Kinase Expression |
| BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors | Change in Kinase Expression | TEC | -10.15407 Sum Log 2 Fold Change Kinase Expression |
| BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors | Change in Kinase Expression | CSNK1D | -9.57122 Sum Log 2 Fold Change Kinase Expression |
| BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors | Change in Kinase Expression | EPHA4 | -9.5134 Sum Log 2 Fold Change Kinase Expression |
| BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors | Change in Kinase Expression | AURKB | -5.70255 Sum Log 2 Fold Change Kinase Expression |
| BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors | Change in Kinase Expression | ZAK | -9.14964 Sum Log 2 Fold Change Kinase Expression |
| BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors | Change in Kinase Expression | LIMK2 | -7.86008 Sum Log 2 Fold Change Kinase Expression |
| BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors | Change in Kinase Expression | ADCK4 | -8.56373 Sum Log 2 Fold Change Kinase Expression |
| BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors | Change in Kinase Expression | NME4 | -5.34905 Sum Log 2 Fold Change Kinase Expression |
Primary
Kinome Signature Predictive of Resistance
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.
Time frame: One year post treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors | Kinome Signature Predictive of Resistance | 0 predictive kinase signatures |
Secondary
BRAF and MEK Inhibition Associated With New Functional Mutations in the Approximately 150 Oncogenes
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).
Time frame: One year
Population: Progression samples were not available for 7 participants; 3 additional participants did not have samples that were evaluable by MIB/MS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors | BRAF and MEK Inhibition Associated With New Functional Mutations in the Approximately 150 Oncogenes | 0 Functional mutation predictors |
Secondary
Duration of Overall Response
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.
Time frame: One year post treatment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors | Duration of Overall Response | 13 Months |
Secondary
Overall Response Rate (ORR)
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
Time frame: One year post treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors | Overall Response Rate (ORR) | 76 percentage of patients with response |
Secondary
Progression Free Survival (PFS)
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.
Time frame: One year post treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors | Progression Free Survival (PFS) | 17 Months |
Secondary
Rate of Overall Survival (OS) at 12 Months
The rate of overall survival is defined as the percentage of patients still alive at one year from Day 1 of protocol treatment
Time frame: One year post treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors | Rate of Overall Survival (OS) at 12 Months | 70 percentage of patients alive at 1 year |