ANZCTR - Registration

Technical difficulties have been reported by some users of the search function and is being investigated by technical staff. Thank you for your patience and apologies for any inconvenience caused.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers

Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT01072175

Registration number

NCT01072175

Ethics application status

Date submitted

12/02/2010

Date registered

19/02/2010

Date last updated

5/07/2019

Titles & IDs

Public title

Investigate Safety, Pharmacokinetics and Pharmacodynamics of GSK2118436 & GSK1120212

Scientific title

An Open-Label, Dose-Escalation, Phase I/II Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of the BRAF Inhibitor GSK2118436 in Combination With the MEK Inhibitor GSK1120212 in Subjects With BRAF Mutant Metastatic Melanoma

Secondary ID [1]

113220

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Cancer

Condition category

Condition code

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Treatment: Drugs - GSK2118436
Treatment: Drugs - GSK1120212

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

Experimental: Arm Part B - GSK2118436 + GSK1120212 Dose escalation to a maximum tolerated combination dose

Experimental: Arm Part C - GSK2118436 + GSK1120212 cohort expansion for safety and efficacy

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

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

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Control group

Outcomes

Primary outcome [1]

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

Timepoint [1]

Day 15

Primary outcome [2]

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

Timepoint [2]

Day 15

Primary outcome [3]

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

Timepoint [3]

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

Primary outcome [4]

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

Timepoint [4]

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

Primary outcome [5]

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

Timepoint [5]

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

Primary outcome [6]

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

Timepoint [6]

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

Primary outcome [7]

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

Timepoint [7]

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

Primary outcome [8]

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

Timepoint [8]

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

Primary outcome [9]

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

Timepoint [9]

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)

Primary outcome [10]

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

Timepoint [10]

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)

Primary outcome [11]

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

Timepoint [11]

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)

Primary outcome [12]

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

Timepoint [12]

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

Primary outcome [13]

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

Timepoint [13]

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)

Primary outcome [14]

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

Timepoint [14]

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

Primary outcome [15]

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

Timepoint [15]

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)

Primary outcome [16]

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

Timepoint [16]

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

Primary outcome [17]

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

Timepoint [17]

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

Primary outcome [18]

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

Timepoint [18]

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

Primary outcome [19]

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

Timepoint [19]

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

Primary outcome [20]

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

Timepoint [20]

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

Primary outcome [21]

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

Timepoint [21]

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

Primary outcome [22]

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

Timepoint [22]

Day 1 and Day 21

Primary outcome [23]

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

Timepoint [23]

Day 1 and Day 21

Primary outcome [24]

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

Timepoint [24]

Day 1 and Day 21

Primary outcome [25]

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

Timepoint [25]

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

Primary outcome [26]

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

Timepoint [26]

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

Primary outcome [27]

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

Timepoint [27]

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

Primary outcome [28]

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

Timepoint [28]

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

Primary outcome [29]

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

Timepoint [29]

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

Primary outcome [30]

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

Timepoint [30]

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

Secondary outcome [1]

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

Timepoint [1]

Day 15 and Day 16

Secondary outcome [2]

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

Timepoint [2]

Day 15 and Day 21

Secondary outcome [3]

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

Timepoint [3]

Day 15 and Day 21

Secondary outcome [4]

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

Timepoint [4]

Day 15 and Day 21

Secondary outcome [5]

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

Timepoint [5]

Day 15 and Day 21

Secondary outcome [6]

Part B (Analyte=GSK1120212): Ctau and Cmax Assessments of Trametinib in Combination With Dabrafenib

Timepoint [6]

Day 15 and Day 21

Secondary outcome [7]

Part B (Analyte=GSK1120212): Tmax Assessment of Trametinib in Combination With Dabrafenib

Timepoint [7]

Day 15 and Day 21

Secondary outcome [8]

Part B: Number of Participants With BRAFi-naïve Mutant Metastatic Melanoma With the Best Overall Response as Assessed by Investigator

Timepoint [8]

From the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 8 years)

Secondary outcome [9]

Part B: Duration of Response as Assessed by the Investigator in Participants With BRAFi-naïve Mutant Metastatic Melanoma

Timepoint [9]

First documented evidence of PR or CR until the earlier of date of disease progression or date of death due to any cause (up to approximately 8 years)

Secondary outcome [10]

Part B: Progression-free Survival (PFS) as Assessed by the Investigator in Participants With BRAFi-naïve Mutant Metastatic Melanoma

Timepoint [10]

From the date of first dose to the earliest date of disease progression (PD) or death due to any cause (up to approximately 8 years)

Secondary outcome [11]

Part B: Overall Survival (OS) in BRAFi Naïve Melanoma Participants

Timepoint [11]

From the date of first dose until date of death due to any cause (up to approximately 8 years)

Secondary outcome [12]

Part B: Pre- and Post-dose H-scores for Individual Participants

Timepoint [12]

Screening and at disease progression (up to approximately 8 years)

Secondary outcome [13]

Part C (Randomized): Overall Survival (OS)

Timepoint [13]

From the date of randomization until date of death due to any cause (up to approximately 7 years)

Secondary outcome [14]

Part C: Plasma Concentrations of Dabrafenib and Its Metabolites

Timepoint [14]

Day 15, Week 8, Week 16, Week 24, Week 32, Week 40, Week 48, and Week 56

Secondary outcome [15]

Part C: Plasma Concentrations of Trametinib

Timepoint [15]

Day 15, Week 8, Week 16, Week 24, Week 32, Week 40, Week 48, and Week 56

Secondary outcome [16]

Part C: Oral Clearance (CL/F) of Dabrafenib and Trametinib

Timepoint [16]

Day 15, Week 8, Week 16, Week 24, Week 32, Week 40, and Week 48

Secondary outcome [17]

Part C: Oral Volume of Distribution (V/F) of Dabrafenib and Trametinib

Timepoint [17]

Day 15, Week 8, Week 16, Week 24, Week 32, Week 40, and Week 48

Secondary outcome [18]

Part D: Cmax of Dabrafenib Metabolites

Timepoint [18]

Day 1: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose. Day 21: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours post-dose

Secondary outcome [19]

Part D: Tmax of Dabrafenib Metabolites

Timepoint [19]

Day 1: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose. Day 21: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours post-dose

Secondary outcome [20]

Part D: Area Under the Concentration-time Curve (AUC) of Dabrafenib Metabolites

Timepoint [20]

Day 1: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose. Day 21: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours post-dose

Secondary outcome [21]

Part D: Cmax Assessment of Trametinib

Timepoint [21]

Day 1: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose. Day 21: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours post-dose

Secondary outcome [22]

Part D: Tmax Assessment of Trametinib

Timepoint [22]

Day 1: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose. Day 21: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours post-dose

Secondary outcome [23]

Part D: Area Under the Concentration-time Curve Assessment of Trametinib

Timepoint [23]

Day 1: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose. Day 21: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours post-dose

Secondary outcome [24]

Part D: Number of Participants With the Best Overall Response as Assessed by the Investigator in Participants

Timepoint [24]

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

Secondary outcome [25]

Part D: Duration of Response as Assessed by the Investigator

Timepoint [25]

First documented evidence of PR or CR until the earlier of date of disease progression or date of death due to any cause (up to approximately 7 years)

Secondary outcome [26]

Part D: Progression-free Survival (PFS) as Assessed by the Investigator

Timepoint [26]

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

Secondary outcome [27]

Part D: Overall Survival (OS)

Timepoint [27]

From the date of first dose until date of death due to any cause (up to approximately 7 years)

Eligibility

Key inclusion criteria

Key

- 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.

Key

Minimum age

18 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

- 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.

- Presence of active gastrointestinal disease or other condition that will interfere
significantly with the absorption, distribution, metabolism or excretion of drugs.

- Known human immunodeficiency virus, Hepatitis B or Hepatitis C infection.

- Primary malignancy of the central nervous system.

- Untreated or symptomatic brain metastasis, leptomeningeal disease or spinal cord
compression. Subjects who are on a stable dose of corticosteroids for more than 1
month or off corticosteroids for 2 weeks can be enrolled with approval of medical
monitor. Subjects are not permitted to receive enzyme-inducing anti-epileptic drugs.

- Subjects with brain metastases are excluded, unless

a. All known lesions must be previously treated with surgery or stereotactic
radiosurgery, and- b. Brain lesion(s), if still present, must be confirmed stable
(i.e. no increase in lesion size) for =90 days prior to first dose on study (must be
documented with two consecutive MRI or CT scans using contrast), and c. Asymptomatic
with no corticosteroids requirement for = 30 days prior to first dose on study, and d.
No enzyme-inducing anticonvulsants for = 30 days prior to first dose on study.

- History of alcohol or drug abuse within 6 months prior to screening.

- Psychological, familial, sociological or geographical conditions that do not permit
compliance with the protocol.

- QTc interval greater than or equal to 480msecs.

- History of acute coronary syndromes (including unstable angina), coronary angioplasty,
or stenting within the past 24 weeks.

- Class II, III, or IV heart failure as defined by the New York Heart Association
functional classification system.

- Abnormal cardiac valve morphology (subjects with minimal abnormalities can be entered
on study with approval from the medical monitor.

- Treatment refractory hypertension defined as a blood pressure of systolic> 140 mmHg
and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy

- Patients with intra-cardiac defibrillators or permanent pacemakers.

- Cardiac metastases

- Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to the study drugs or excipients.

- Pregnant or lactating female.

- Unwillingness or inability to follow the procedures required in the protocol.

- Uncontrolled diabetes, hypertension or other medical conditions that may interfere
with assessment of toxicity.

- Subjects with known glucose 6 phosphate dehydrogenase deficiency.

Study design

Purpose of the study

Treatment

Allocation to intervention

Non-randomised trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Other design features

Phase

Phase 2

Type of endpoint/s

Statistical methods / analysis

Recruitment

Recruitment status

Completed

Data analysis

Reason for early stopping/withdrawal

Other reasons

Date of first participant enrolment

Anticipated

Actual

26/03/2010

Date of last participant enrolment

Anticipated

Actual

Date of last data collection

Anticipated

Actual

27/02/2018

Sample size

Target

Accrual to date

Final

430

Recruitment in Australia

Recruitment state(s)

NSW,VIC

Recruitment hospital [1]

Novartis Investigative Site - Westmead

Recruitment hospital [2]

Novartis Investigative Site - Heidelberg

Recruitment postcode(s) [1]

2145 - Westmead

Recruitment postcode(s) [2]

3084 - Heidelberg

Recruitment outside Australia

Country [1]

United States of America

State/province [1]

California

Country [2]

United States of America

State/province [2]

Colorado

Country [3]

United States of America

State/province [3]

Connecticut

Country [4]

United States of America

State/province [4]

Florida

Country [5]

United States of America

State/province [5]

Maryland

Country [6]

United States of America

State/province [6]

Massachusetts

Country [7]

United States of America

State/province [7]

Minnesota

Country [8]

United States of America

State/province [8]

Pennsylvania

Country [9]

United States of America

State/province [9]

Tennessee

Country [10]

United States of America

State/province [10]

Texas

Funding & Sponsors

Primary sponsor type

Commercial sector/Industry

Name

Novartis Pharmaceuticals

Address

Country

Ethics approval

Ethics application status

Summary

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.

Trial website

https://clinicaltrials.gov/ct2/show/NCT01072175

Trial related presentations / publications

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.

Public notes

Contacts

Principal investigator

Name

Novartis Pharmaceuticals

Address

Novartis Pharmaceuticals

Country

Phone

Fax

Contact person for public queries

Name

Address

Country

Phone

Fax

Contact person for scientific queries

Trial Review

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT01072175