Investigate Safety, Pharmacokinetics and Pharmacodynamics of GSK2118436 & GSK1120212

NCT01072175 | Completed Phase 2 Results FDA Drug

• 1 other identifier: 113220
• Study Type: interventional
• Target: 430
• Locations: 2 countries
• Sites: 15

Brief Summary

This was an open-label, dose escalation study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK2118436 and GSK1120212 in combination. This study was designed in four parts. In Part A, the effect of repeat doses of GSK1120212 on the pharmacokinetics of single dose GSK2118436 was investigated prior to evaluating combination regimens. In Part B, the range of tolerated dose combinations was identified using a dose-escalation procedure. In Part C, different dose combinations of GSK2118436 and GSK1120212 were evaluated, based on results from the dose escalation cohorts. In Part D, the pharmacokinetics and safety of GSK2118436 administered as HPMC capsules alone and in combination with GSK1120212 was evaluated.

Conditions

Cancer

Keywords

drug-drug interaction; BRAF inhibitor; expansion cohorts; melanoma; dose escalation; MEK inhibitor

Outcome Measures

Primary Outcomes (30)

• Part A: Maximum Plasma Concentration (Cmax) of a Single Dose of Dabrafenib Administered Alone and in Combination With Trametnib

  Blood samples for PK analysis of dabrafenib and its the metabolites hydroxy-dabrafenib (GSK2285403), carboxy-dabrafenib (GSK2298683) and desmethyl-dabrafenib (GSK2167542) were obtained at pre-dose and at 1, 2, 3, 4, 6, 8, 10, and 24 hours after dabrafenib administration. From the plasma concentration-time curve, the PK parameter Cmax was determined by standard non-compartmental analysis using WinNonlin. Cmax data are reported as geometric least squares means.

  Day 15

• Part A: AUC (0-t) and AUC (0-inf) of Dabrafenib and Its Metabolites

  Blood samples for PK analysis of dabrafenib and its metabolites hydroxy-dabrafenib (GSK2285403), carboxy-dabrafenib (GSK2298683) and desmethyl-dabrafenib (GSK2167542) were obtained at pre-dose and at 1, 2, 3, 4, 6, 8, 10, and 24 hours after dabrafenib administration. AUC is defined as the area under the dabrafenib concentration-time curve as a measure of drug exposure. AUC (0-inf) is defined as the area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time. AUC (0-t) is defined as area under the concentration-time curve from time zero (pre-dose) to the last time of quantifiable concentration. Date are reported as geometric least square means.

  Day 15

• Part B: Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)

  An AE is defined as 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. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury.

  From Baseline (Day 1) until Follow-up visit (up to approximately 8 years)

• Part B: Number of Participants With Worst-case Chemistry Toxicity Grade Change From Baseline

  Clinical Chemistry parameters were summarized according to National Cancer Institutes (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred. Participants with missing Baseline Grade were assumed to have Baseline Grade of 0. All increases were an increase in grade from Baseline. Only descriptive analysis.

  From Baseline (Day 1) until Follow-up visit (up to approximately 8 years)

• Part B: Number of Participants With Worst-case Chemistry Change From Baseline With Respect to Normal Range

  For Clinical Chemistry parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Participants with missing Baseline were assumed to be within normal range. Participants were counted twice if the subject "Decreased to Low" and Increase to High" during the post-baseline period. Only descriptive analysis.

  From Baseline (Day 1) until Follow-up visit (up to approximately 8 years)

• Part B: Number of Participants With Worst-case Hematology Toxicity Grade Change From Baseline

  Hematology parameters were summarized according to National Cancer Institutes (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred. Participants with missing Baseline Grade were assumed to have Baseline Grade of 0. All increases were an increase in grade from Baseline. Only descriptive analysis.

  From Baseline (Day 1) until Follow-up visit (up to approximately 8 years)

• Part B: Number of Participants With Worst-case Hematology Change From Baseline With Respect to Normal Range

  For Hematology parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Participants with missing Baseline were assumed to be within normal range. Participants were counted twice if the subject "Decreased to Low" and Increase to High" during the post-baseline period. Only descriptive analysis.

  From Baseline (Day 1) until Follow-up visit (up to approximately 8 years)

• Part B: Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure

  Blood pressure and heart rate were summarized according to NCI CTCAE grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to G3 or G4 occurred. Blood pressure measurement included systolic blood pressure (SBP, millimeters of mercury \[mmHg\]) and diastolic BP (DBP). Heart rate is the measure of heart beats per minute (bpm). Changes in heart rate, either decrease to \<60 bpm, change to normal or no change, or increase to \>100 bpm are presented.

  From Baseline (Day 1) until Follow-up visit (up to approximately 8 years)

• Part C (Randomized): Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response as Assessed by the Investigator

  Best overall response is defined as complete response (CR: the disappearance of all target lesions. Any pathological lymph nodes must be \<10 millimeters \[mm\] in the short axis.) or partial reponse (PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters \[e.g., percent change from Baseline\]). Participants with unknown or missing responses were considered as non-responders. To be assigned a status of PR or CR, a confirmatory disease assessment should have been performed no less than 28 days after the criteria for response were first met. Response was evaluated by an investigator as per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.

  From the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 7 years)

• Part C (Randomized): Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response Assessed by Blinded Independent Central Review (BICR)

  Best overall response is defined as complete response (CR: the disappearance of all target lesions. Any pathological lymph nodes must be \<10 mm in the short axis.) or partial reponse (PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters \[e.g., percent change from Baseline\]). Participants with unknown or missing responses were considered as non-responders. To be assigned a status of PR or CR, a confirmatory disease assessment should have been performed no less than 28 days after the criteria for response were first met. Response was evaluated by BICR as per RECIST, version 1.1.

  From the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 19 months)

• Part C (Crossover): Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response as Assessed by the Investigator

  Best overall response is defined as complete response (CR: the disappearance of all target lesions. Any pathological lymph nodes must be \<10 mm in the short axis.) or partial reponse (PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters \[e.g., percent change from Baseline\]). Participants with unknown or missing responses were considered as non-responders. To be assigned a status of PR or CR, a confirmatory disease assessment should have been performed no less than 28 days after the criteria for response were first met. Response was evaluated by an investigator as per RECIST, version 1.1.

  From the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 7 years)

• Part C (Randomized): Progression-free Survival (PFS) as Assessed by the Investigator

  PFS is defined as the interval between the date of randomization and the earliest date of PD or death due to any cause. PD was based on radiographic or photographic evidence, and assessments were made by the investigator according to RECIST, version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. Participants who received anti-cancer therapy prior to the date of documented events, were censored at the last adequate assessment prior to the initiation of therapy. If the participant did not had a documented date of events, PFS and survival were censored at the date of the last adequate assessment.

  From the date of randomization to the earliest date of disease progression (PD) or death due to any cause (up to approximately 7 years)

• Part C (Crossover): Progression-free Survival (PFS) as Assessed by the Investigator

  PFS is defined as the interval between the first dose of study medication and the earliest date of PD or death due to any cause. PD was based on radiographic or photographic evidence, and assessments were made by the investigator according to RECIST, version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. Participants received anti-cancer therapy prior to the date of documented events, and censored at the last adequate assessment, prior to the initiation of therapy. If the participant did not have a documented date of events, PFS and survival were censored at the date of the last adequate assessment.

  From the first dose of study medication to the earliest date of disease progression (PD) or death due to any cause (up to approximately 7 years)

• Part C (Randomized): Progression-free Survival (PFS) as Assessed by the Blinded Independent Central Review (BICR)

  PFS is defined as the interval between the date of randomization and the earliest date of PD or death due to any cause. PD was based on radiographic or photographic evidence, and assessments were made by the BICR according to RECIST, version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. Participants who received anti-cancer therapy prior to the date of documented events, were censored at the last adequate assessment prior to the initiation of therapy. If the participant did not had a documented date of events, PFS and survival were censored at the date of the last adequate assessment

  From the date of randomization to the earliest date of disease progression (PD) or death due to any cause (up to approximately 19 months)

• Part C (Randomized): Duration of Response as Assessed by the Investigator and Blinded Independent Central Review (BICR)

  Duration of response for participants with either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be \<10 mm in the short axis.) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters \[e.g., percent change from Baseline\]) is defined as the time from the first documented evidence of a PR or CR until the first documented sign of disease progression (PD) or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm.

  First documented evidence of PR or CR until the date of the first documented sign of disease progression or the date of death due to any cause (up to approximately 19 months)

• Part C (Randomized): Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)

  An AE is defined as 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. An SAE is any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury.

  From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)

• Part C (Randomized): Number of Participants With Worst-case Chemistry Toxicity Grade Change From Baseline

  Clinical Chemistry parameters were summarized according to National Cancer Institutes (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred. Participants with missing Baseline Grade were assumed to have Baseline Grade of 0. All increases were an increase in grade from Baseline. Only descriptive analysis.

  From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)

• Part C (Randomized): Number of Participants With Worst-case Chemistry Change From Baseline With Respect to Normal Range

  For Clinical Chemistry parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Participants with missing Baseline were assumed to be within normal range. Participants were counted twice if the subject "Decreased to Low" and Increase to High" during the post-baseline period. Only descriptive analysis.

  From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)

• Part C (Randomized): Number of Participants With Worst-case Hematology Toxicity Grade Change From Baseline

  Hematology parameters were summarized according to National Cancer Institutes (NCI) CTCAE grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3, Severe; Grade 4, Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase Grade 3 or Grade 4 occurred. Participants with missing Baseline Grade were assumed to have Baseline Grade of 0. All increases were an increase in grade from Baseline. Only descriptive analysis.

  From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)

• Part C (Randomized): Number of Participants With Worst-case Hematology Change From Baseline With Respect to Normal Range

  For Hematology parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Participants with missing Baseline were assumed to be within normal range. Participants were counted twice if the subject "Decreased to Low" and Increase to High" during the post-baseline period. Only descriptive analysis.

  From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)

• Part C (Randomized): Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure

  Blood pressure were summarized according to National Cancer Institutes (NCI) CTCAE grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to G3 or G4 occurred.lood pressure measurement included systolic blood pressure (BP, milimeter of mercury \[mmHg\]) and diastolic BP (DBP). Worst case change from Baseline was calculated as the post-Baseline value minus the Baseline value. Heart Rate is the measure of heart beats per minute (bpm). Changes in heart rate, either decrease to \<60 bpm, change to normal or no change, or increase to \>100 bpm are presented.

  From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)

• Part D (Analyte=GSK2118436): Maximum Plasma Concentration (Cmax) of a Single and Repeat Dose of Dabrafenib Alone and in Combination With Trametinib

  The PK parameter Cmax was assessed. Blood samples for PK analysis of dabrafenib were obtained at pre-dose Day 1 and Day 21 pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours (24 hour on Day 1 only) post-dose administration. From the plasma concentration-time curve, the PK parameter tmax was determined by standard non-compartmental analysis using WinNonlin. Cmax data are reported as geometric least squares means.

  Day 1 and Day 21

• Part D (Analyte=GSK2118436): Tmax of a Single and Repeat Dose of Dabrafenib Alone and in Combination With Trametinib

  tmax is defined as the time of occurenceof Cmax. Blood samples for PK analysis of dabrafenib were obtained at Day 1 and Day 21 pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours (24 hour on Day 1 only) post-dose administration. From the plasma concentration-time curve, the PK parameter tmax was determined by standard non-compartmental analysis using WinNonlin.

  Day 1 and Day 21

• Part D (Analyte=GSK2118436): AUC (0-tau) and AUC (0-inf) of Single and Repeat Doses of Dabrafenib Alone and in Combination With Trametinib

  The PK parameters were determined for area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration AUC (0-tau) and from time zero (pre-dose) extrapolated to infinite time AUC (0-inf). Blood samples for PK analysis of the metabolites of dabrafenib were obtained at Day 1 and Day 21 pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours (24 hour only on Day 1) post-dose administration.

  Day 1 and Day 21

• Part D: Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)

  An AE is defined as 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. An SAE is any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event for possible drug-induced liver injury.

  From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)

• Part D: Number of Participants With Worst-case Chemistry Toxicity Grade Change From Baseline

  Clinical Chemistry parameters were summarized according to National Cancer Institutes (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred. Participants with missing Baseline Grade were assumed to have Baseline Grade of 0. All increases were an increase in grade from Baseline. Only descriptive analysis.

  From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)

• Part D: Number of Participants With Worst-case Chemistry Change From Baseline With Respect to Normal Range

  For Clinical Chemistry parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Participants with missing Baseline were assumed to be within normal range. Participants were counted twice if the subject "Decreased to Low" and Increase to High" during the post-baseline period. Only descriptive analysis.

  From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)

• Part D: Number of Participants With Worst-case Hematology Toxicity Grade Change From Baseline

  Hematology parameters were summarized according to National Cancer Institutes (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred. Participants with missing Baseline Grade were assumed to have Baseline Grade of 0. All increases were an increase in grade from Baseline. Only descriptive analysis.

  From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)

• Part D: Number of Participants With Worst-case Hematology Change From Baseline With Respect to Normal Range

  For Hematology parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Participants with missing Baseline were assumed to be within normal range. Participants were counted twice if the subject "Decreased to Low" and Increase to High" during the post-baseline period. Only descriptive analysis.

  From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)

• Part D: Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure

  Blood pressure were summarized according to National Cancer Institutes (NCI) CTCAE grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to G3 or G4 occurred.lood pressure measurement included systolic blood pressure (BP, milimeter of mercury \[mmHg\]) and diastolic BP (DBP). Worst case change from Baseline was calculated as the post-Baseline value minus the Baseline value. Heart Rate is the measure of heartbeats per minute (bpm). Changes in heart rate, either decrease to \<60 bpm, change to normal or no change, or increase to \>100 bpm are presented

  From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)

Secondary Outcomes (27)

• Part A: Steady State Concentration of Trametinib With Concomitant Administration of Dabrafenib

  Day 15 and Day 16

• Part B: AUC [0-tau] of Dabrafenib (DAB) and Its Metabolite in Combination With Trametinib

  Day 15 and Day 21

• Part B: Pre-dose (Trough) Concentration at the End of the Dosing Interval (Ctau) and Maximum Plasma Concentration (Cmax) of Dabrafenib and Its Metabolite in Combination With Trametinib

  Day 15 and Day 21

• Part B: Tmax of Dabrafenib and Its Metabolite in Combination With Trametinib

  Day 15 and Day 21

• Part B (Analyte=GSK1120212): AUC (0-tau) Assessment of Trametinib in Combination With Dabrafenib

  Day 15 and Day 21

Study Arms (3)

Arm Part A

EXPERIMENTAL

Day 1: GSK2118436 75mg; Day 2 through Day 16: GSK1120212 2mg; Day 15: GSK2118436 75mg +GSK1120212 2mg Drug-drug interaction

Drug: GSK2118436; Drug: GSK1120212

Arm Part B

EXPERIMENTAL

GSK2118436 + GSK1120212 Dose escalation to a maximum tolerated combination dose

Drug: GSK2118436

Arm Part C

EXPERIMENTAL

GSK2118436 + GSK1120212 cohort expansion for safety and efficacy

Drug: GSK2118436; Drug: GSK1120212

Interventions

GSK2118436 DRUG

GSK2118436 is a potent and selective inhibitor of BRAF kinase activity with a mode of action consistent with adenosine triphosphate-competitive inhibition.

Arm Part A; Arm Part B; Arm Part C

GSK1120212 DRUG

GSK1120212 is a potent and highly selective inhibitor of MEK1/2 activation and kinase activity.

Arm Part A; Arm Part C

Eligibility Criteria

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

You may qualify if:

• Capable of given written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
• Male or female age 18 years or greater; able to swallow and retain oral medication.
• BRAF mutation positive melanoma or colorectal cancer; other BRAF mutation positive tumor types may be considered.
• Measurable disease according to RECIST version 1.1.
• Eastern Cooperative Oncology Group Performance Status of 0 or 1 for Parts A and B. Subjects with Eastern Cooperative Oncology Group Performance Status of 2 or less may be entered into Part C with approval of medical monitor.
• Agree to contraception requirements.
• Calcium phosphorus product less than 4.0mmol2/L2.
• Adequate organ system function.

You may not qualify if:

• Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, or biologic therapy).
• Part A and Part B: Prior exposure to BRAF or MEK inhibitors unless approved by the GSK Medical Monitor.
• Part C: Prior exposure to BRAF or MEK inhibitors. Prior anti-cancer therapy in the metastatic setting, with the exception of up to one regimen of chemotherapy and/or interleukin-2 (IL-2).
• Part D: Prior exposure to BRAF inhibitors. A washout period of 6 weeks is required for ipilimumab.
• Received an investigational anti-cancer drug within 4 weeks or 5 half-lives (whichever is shorter) of study drug administration--- at least 14 days must have passed between the last dose of prior investigational anti-cancer drug and the first dose of study drug.
• Current use of a prohibited medication or requires any of these medications during treatment with study drug.
• Current use of therapeutic warfarin.
• Any major surgery, radiotherapy, or immunotherapy within the last 4 weeks. Limited radiotherapy within the last 2 weeks.
• Chemotherapy regimens with delayed toxicity within the last 4 weeks. Chemotherapy regimens given continuously or on a weekly basis with limited potential for delayed toxicity within the last 2 weeks.
• Unresolved toxicity greater than National Cancer Institute-Common Terminology Criteria for Adverse Events version 4 Grade 1 from previous anti-cancer therapy except alopecia.
• History of retinal vein occlusion, central serous retinopathy or glaucoma.
• Predisposing factors to retinal vein occlusion including uncontrolled hypertension, uncontrolled diabetes, uncontrolled hyperlipidemia, and coagulopathy.
• Visible retinal pathology as assessed by ophthalmologic exam that is considered a risk factor for retinal vein occlusion or central serous retinopathy.
• Intraocular pressure greater than 21mm Hg as measured by tonography.
• Glaucoma diagnosed within one month prior to study Day 1.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (15)

Novartis Investigative Site

Los Angeles, California, 90025, United States

Location

Novartis Investigative Site

San Francisco, California, 94115, United States

Location

Novartis Investigative Site

Aurora, Colorado, 80045, United States

Location

Novartis Investigative Site

New Haven, Connecticut, 06520, United States

Location

Novartis Investigative Site

Tampa, Florida, 33612, United States

Location

Novartis Investigative Site

Lutherville-Timonium, Maryland, 21093, United States

Location

Novartis Investigative Site

Boston, Massachusetts, 02114, United States

Location

Novartis Investigative Site

Boston, Massachusetts, 02215, United States

Location

Novartis Investigative Site

Rochester, Minnesota, 55905, United States

Location

Novartis Investigative Site

Philadelphia, Pennsylvania, 19104, United States

Location

Novartis Investigative Site

Nashville, Tennessee, 37203, United States

Location

Novartis Investigative Site

Nashville, Tennessee, 37232, United States

Location

Novartis Investigative Site

Houston, Texas, 77030-4009, United States

Location

Novartis Investigative Site

Westmead, New South Wales, 2145, Australia

Location

Novartis Investigative Site

Heidelberg, Victoria, 3084, Australia

Location

Related Publications (9)

• Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, Hamid O, Schuchter L, Cebon J, Ibrahim N, Kudchadkar R, Burris HA 3rd, Falchook G, Algazi A, Lewis K, Long GV, Puzanov I, Lebowitz P, Singh A, Little S, Sun P, Allred A, Ouellet D, Kim KB, Patel K, Weber J. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012 Nov 1;367(18):1694-703. doi: 10.1056/NEJMoa1210093. Epub 2012 Sep 29.

  PMID: 23020132 BACKGROUND

• Long GV, Eroglu Z, Infante J, Patel S, Daud A, Johnson DB, Gonzalez R, Kefford R, Hamid O, Schuchter L, Cebon J, Sharfman W, McWilliams R, Sznol M, Redhu S, Gasal E, Mookerjee B, Weber J, Flaherty KT. Long-Term Outcomes in Patients With BRAF V600-Mutant Metastatic Melanoma Who Received Dabrafenib Combined With Trametinib. J Clin Oncol. 2018 Mar 1;36(7):667-673. doi: 10.1200/JCO.2017.74.1025. Epub 2017 Oct 9.

  PMID: 28991513 DERIVED

• Long GV, Grob JJ, Nathan P, Ribas A, Robert C, Schadendorf D, Lane SR, Mak C, Legenne P, Flaherty KT, Davies MA. Factors predictive of response, disease progression, and overall survival after dabrafenib and trametinib combination treatment: a pooled analysis of individual patient data from randomised trials. Lancet Oncol. 2016 Dec;17(12):1743-1754. doi: 10.1016/S1470-2045(16)30578-2. Epub 2016 Nov 16.

  PMID: 27864013 DERIVED

• Long GV, Weber JS, Infante JR, Kim KB, Daud A, Gonzalez R, Sosman JA, Hamid O, Schuchter L, Cebon J, Kefford RF, Lawrence D, Kudchadkar R, Burris HA 3rd, Falchook GS, Algazi A, Lewis K, Puzanov I, Ibrahim N, Sun P, Cunningham E, Kline AS, Del Buono H, McDowell DO, Patel K, Flaherty KT. Overall Survival and Durable Responses in Patients With BRAF V600-Mutant Metastatic Melanoma Receiving Dabrafenib Combined With Trametinib. J Clin Oncol. 2016 Mar 10;34(8):871-8. doi: 10.1200/JCO.2015.62.9345. Epub 2016 Jan 25.

  PMID: 26811525 DERIVED

• Corcoran RB, Atreya CE, Falchook GS, Kwak EL, Ryan DP, Bendell JC, Hamid O, Messersmith WA, Daud A, Kurzrock R, Pierobon M, Sun P, Cunningham E, Little S, Orford K, Motwani M, Bai Y, Patel K, Venook AP, Kopetz S. Combined BRAF and MEK Inhibition With Dabrafenib and Trametinib in BRAF V600-Mutant Colorectal Cancer. J Clin Oncol. 2015 Dec 1;33(34):4023-31. doi: 10.1200/JCO.2015.63.2471. Epub 2015 Sep 21.

  PMID: 26392102 DERIVED

• Latimer NR, Amonkar MM, Stapelkamp C, Sun P. Adjusting for confounding effects of treatment switching in a randomized phase II study of dabrafenib plus trametinib in BRAF V600+ metastatic melanoma. Melanoma Res. 2015 Dec;25(6):528-36. doi: 10.1097/CMR.0000000000000193.

  PMID: 26340744 DERIVED

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• Carlino MS, Gowrishankar K, Saunders CA, Pupo GM, Snoyman S, Zhang XD, Saw R, Becker TM, Kefford RF, Long GV, Rizos H. Antiproliferative effects of continued mitogen-activated protein kinase pathway inhibition following acquired resistance to BRAF and/or MEK inhibition in melanoma. Mol Cancer Ther. 2013 Jul;12(7):1332-42. doi: 10.1158/1535-7163.MCT-13-0011. Epub 2013 May 3.

  PMID: 23645591 DERIVED

MeSH Terms

Conditions

Neoplasms; Melanoma

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; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@novartis.com

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: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 12, 2010
• First Posted: February 19, 2010
• Study Start: March 26, 2010
• Primary Completion: May 31, 2012
• Study Completion: February 27, 2018
• Last Updated: July 5, 2019
• Results First Posted: November 21, 2013

Record last verified: 2019-06

Locations

AU (2); US (13)