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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT00880321




Registration number
NCT00880321
Ethics application status
Date submitted
9/04/2009
Date registered
9/04/2009
Date last updated
8/11/2017

Titles & IDs
Public title
A Phase I Study to Investigate the Safety, Pharmacokinetics, and Pharmacodynamics of GSK2118436 in Subjects With Solid Tumors
Scientific title
A Phase I, Open-Label, Multiple-Dose, Dose-Escalation Study to Investigate the Safety, Pharmacokinetics, and Pharmacodynamics of the BRAF Inhibitor GSK2118436 in Subjects With Solid Tumors
Secondary ID [1] 0 0
112680
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cancer 0 0
Cancer 0 0
Condition category
Condition code

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - GSK2118436
Treatment: Drugs - GSK2118436
Treatment: Drugs - Midazolam
Treatment: Drugs - GSK2118436
Treatment: Drugs - GSK2118436
Treatment: Drugs - Midazolam

Experimental: Part 1 - Part 1 will identify the recommended Part 2 dose using a dose-escalation procedure. Escalation may proceed until either a maximum tolerated dose is established, or the toxicokinetic safety limit is reached. Subjects may dose up to three times a day.

Experimental: Part 2 - Part 2 will explore further the safety, tolerability, and clinical activity of GSK2118436 in subjects with BRAF mutation-positive tumors using the recommended part 2 dose identified during Part 1. Biologically active doses will be identified by measurement of pharmacodynamic markers in tumor tissue and blood across a range of doses and these doses may be explored in Part 2.

Experimental: Part 1 - Part 1 will identify the recommended Part 2 dose using a dose-escalation procedure. Escalation may proceed until either a maximum tolerated dose is established, or the toxicokinetic safety limit is reached. Subjects may dose up to three times a day.

Experimental: Part 2 - Part 2 will explore further the safety, tolerability, and clinical activity of GSK2118436 in subjects with BRAF mutation-positive tumors using the recommended part 2 dose identified during Part 1. Biologically active doses will be identified by measurement of pharmacodynamic markers in tumor tissue and blood across a range of doses and these doses may be explored in Part 2.


Treatment: Drugs: GSK2118436
Dose escalation with GSK2118436 may proceed until either a maximum tolerated dose is established, or the toxicokinetic safety limit is reached.

Treatment: Drugs: GSK2118436
Part 2 will use the recommended Part 2 dose of GSK2118436 identified during Part 1 of the study. Biologically active doses will be identified by measurement of pharmacodynamic markers in tumor tissue and blood across a range of doses and these doses may be explored in Part 2.

Treatment: Drugs: Midazolam
Midazolam will be administered alone and with GSK2118436 in a sub-set of subjects in Part 2 to study the effect of GSK2118436 on CYP3A using midazolam as a probe.

Treatment: Drugs: GSK2118436
Dose escalation with GSK2118436 may proceed until either a maximum tolerated dose is established, or the toxicokinetic safety limit is reached.

Treatment: Drugs: GSK2118436
Part 2 will use the recommended Part 2 dose of GSK2118436 identified during Part 1 of the study. Biologically active doses will be identified by measurement of pharmacodynamic markers in tumor tissue and blood across a range of doses and these doses may be explored in Part 2.

Treatment: Drugs: Midazolam
Midazolam will be administered alone and with GSK2118436 in a sub-set of subjects in Part 2 to study the effect of GSK2118436 on CYP3A using midazolam as a probe.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
PK data, AEs, changes in laboratory values and vital signs, physical exam, clinical testing and PD data
Timepoint [1] 0 0
21 days
Primary outcome [2] 0 0
PK data, AEs, changes in laboratory values and vital signs, physical exam, clinical testing and PD data
Timepoint [2] 0 0
21 days
Secondary outcome [1] 0 0
GSK2118436 and its metabolite, PK parameters per protocol following single- and repeat-dose administration of GSK2118436
Timepoint [1] 0 0
15 days
Secondary outcome [2] 0 0
Change in PD markers including IL-8 in blood, pERK and other markers in tumor biopsies.
Timepoint [2] 0 0
15 days
Secondary outcome [3] 0 0
Correlation between PK, PD, and clinical endpoints.
Timepoint [3] 0 0
15 days
Secondary outcome [4] 0 0
Tumor response as defined by Response Evaluation Criteria in Solid Tumors (RECIST v1.0)
Timepoint [4] 0 0
approximately once every 2 months until the end of participation
Secondary outcome [5] 0 0
Urinary ratio of 6-beta-hydroxycortisol to cortisol ratio
Timepoint [5] 0 0
15 days
Secondary outcome [6] 0 0
GSK2118436 PK parameters per protocol with and without food
Timepoint [6] 0 0
15 days
Secondary outcome [7] 0 0
Metabolic profiling in plasma and urine
Timepoint [7] 0 0
15 days
Secondary outcome [8] 0 0
Midazolam PK parameters per protocol
Timepoint [8] 0 0
15 days
Secondary outcome [9] 0 0
GSK2118436 and its metabolite, PK parameters per protocol following single- and repeat-dose administration of GSK2118436
Timepoint [9] 0 0
15 days
Secondary outcome [10] 0 0
Change in PD markers including IL-8 in blood, pERK and other markers in tumor biopsies.
Timepoint [10] 0 0
15 days
Secondary outcome [11] 0 0
Correlation between PK, PD, and clinical endpoints.
Timepoint [11] 0 0
15 days
Secondary outcome [12] 0 0
Tumor response as defined by Response Evaluation Criteria in Solid Tumors (RECIST v1.0)
Timepoint [12] 0 0
approximately once every 2 months until the end of participation
Secondary outcome [13] 0 0
Urinary ratio of 6-beta-hydroxycortisol to cortisol ratio
Timepoint [13] 0 0
15 days
Secondary outcome [14] 0 0
GSK2118436 PK parameters per protocol with and without food
Timepoint [14] 0 0
15 days
Secondary outcome [15] 0 0
Metabolic profiling in plasma and urine
Timepoint [15] 0 0
15 days
Secondary outcome [16] 0 0
Midazolam PK parameters per protocol
Timepoint [16] 0 0
15 days

Eligibility
Key inclusion criteria
- Written informed consent provided.

- 18 years old or older. Subjects enrolled in the midazolam cohort need to be younger
than 65 years old.

- Histologically or cytologically confirmed diagnosis of a solid tumor that is not
responsive to standard therapies or for which there is no approved or curative
therapy. Subjects must have BRAF mutant positive tumors.

- Performance Status score of 0 or 1 according to the Eastern Cooperative Oncology Group
(ECOG) scale.

- Able to swallow and retain oral medication.

- Male subjects must agree to use one of the contraception methods listed in the
protocol. The criterion must be followed from the time of the first dose of study
medication until 16 weeks after the last dose of study medication.

- A female subject is eligible to participate if she is of non-childbearing potential or
postmenopausal as defined in the protocol. A female of child-bearing potential may
participate if she agrees to use one of the contraception methods listed in the
protocol.

- Adequate organ system function as defined in the protocol.

- Part 2/Cohorts A, B and C: Must have radiologically and/or clinically documented
disease with at least one measurable lesion as defined by RECIST criteria.

- Part 2/Cohort C only: Must have BRAF positive melanoma with the V600E mutation.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Currently receiving cancer therapy (chemotherapy, radiation therapy, immuno-therapy,
biologic therapy, hormonal therapy, surgery and/or tumor embolization).

- Use of an investigational anti-cancer drug within 28 days preceding the first dose of
GSK2118436.

- Current use of a prohibited medication as defined in the protocol or requires any of
these medications during treatment with GSK2118436.

- Current use of therapeutic warfarin.

- Any major surgery, radiotherapy, or immunotherapy within 4 weeks prior to first dose.
Limited radiotherapy within 2 weeks prior to first dose.

- Chemotherapy regimens with delayed toxicity within four weeks prior to first dose (6
weeks for prior nitrosourea or mitomycin C). Chemotherapy regimens given continuously
or on a weekly basis with limited potential for delayed toxicity within 2 weeks prior
to first dose.

- Unresolved toxicity greater than National Cancer Institute Common Terminology Criteria
for Adverse Events, version 3.0 Grade 1 from previous anti-cancer therapy except
alopecia unless agreed to by a GSK Medical Monitor and the investigator.

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

- A history of known HIV infection.

- Primary malignancy of the central nervous system.

- Symptomatic or untreated leptomeningeal or brain metastases or spinal cord
compression. Subjects previously treated for these conditions that are asymptomatic
and off corticosteroids for at least two weeks are permitted. Brain metastases must be
stable for at least 3 months with verification by imaging (brain MRI completed at
screening). Subjects are not permitted to receive enzyme inducing anti-epileptic drugs
(EIAEDs). In Part 2 of the study, subjects with asymptomatic, untreated brain
metastases that have not been stable for 3 months may be enrolled with approval of the
GSK medical monitor. These subjects can be on a stable dose of corticosteroids.

- History of alcohol or drug abuse within 6 months prior to the screen visit.

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

- Concurrent condition that in the investigator's opinion would jeopardize compliance
with the protocol.

- QTc interval greater than or equal to 480 msecs.

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

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

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

- Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to the study drug, or excipients as described in the protocol (to
date there are no known FDA approved drugs chemically related to GSK2118436).

- Pregnant or lactating female.

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

- Subjects with known glucose 6 phosphate dehydrogenase (G6PD) deficiency.

- Patients positive for HPV. Entry on study allowed only at the discretion of subject
and investigator after informed consent regarding discussion of the risk of
papillomavirus infection. If enrolled, these subjects must use condoms for sexual
activity, regardless of the use of other contraceptive measures and childbearing
status.

- Prior treatment with a BRAF or MEK inhibitor unless approved by the GSK medical
monitor.

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
Single group
Other design features
Phase
Phase 1
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
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,SA,WA
Recruitment hospital [1] 0 0
GSK Investigational Site - Randwick
Recruitment hospital [2] 0 0
GSK Investigational Site - Westmead
Recruitment hospital [3] 0 0
GSK Investigational Site - Adelaide
Recruitment hospital [4] 0 0
GSK Investigational Site - Nedlands
Recruitment postcode(s) [1] 0 0
2031 - Randwick
Recruitment postcode(s) [2] 0 0
2145 - Westmead
Recruitment postcode(s) [3] 0 0
5000 - Adelaide
Recruitment postcode(s) [4] 0 0
6009 - Nedlands
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
New York
Country [3] 0 0
United States of America
State/province [3] 0 0
Tennessee
Country [4] 0 0
United States of America
State/province [4] 0 0
Texas

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
GlaxoSmithKline
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
BRF112680 is a first-time-in-human study to establish the recommended dose and schedule of
the orally administered GSK2118436. The recommended dose and regimen will be selected based
on the safety, pharmacokinetic, and pharmacodynamic profiles observed after the treatment of
subjects with solid tumors. This is a two-part study. Part 1 will identify the recommended
Part 2 dose using a dose-escalation procedure. Escalation may proceed until either a maximum
tolerated dose is established, or the toxicokinetic safety limit is reached. The recommended
Part 2 dose will be expanded to up to 12 patients. Part 2 will explore further the safety,
tolerability, and clinical activity of GSK2118436 in subjects with BRAF mutation-positive
tumors. In addition, the effect of GSK2118436 on midazolam will be assessed in a subset of
patients in Part 2. Biologically active doses will be identified by measurement of
pharmacodynamic markers in tumor tissue and blood across a range of doses and these doses may
be explored in Part 2.
Trial website
https://clinicaltrials.gov/show/NCT00880321
Trial related presentations / publications
Hong DS, Vence L, Falchook G, Radvanyi LG, Liu C, Goodman V, Legos JJ, Blackman S, Scarmadio A, Kurzrock R, Lizee G, Hwu P. BRAF(V600) inhibitor GSK2118436 targeted inhibition of mutant BRAF in cancer patients does not impair overall immune competency. Clin Cancer Res. 2012 Apr 15;18(8):2326-35. doi: 10.1158/1078-0432.CCR-11-2515. Epub 2012 Feb 21. Erratum in: Clin Cancer Res. 2012 Jul 1;18(13):3715.
Falchook GS, Long GV, Kurzrock R, Kim KB, Arkenau TH, Brown MP, Hamid O, Infante JR, Millward M, Pavlick AC, O'Day SJ, Blackman SC, Curtis CM, Lebowitz P, Ma B, Ouellet D, Kefford RF. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet. 2012 May 19;379(9829):1893-901. doi: 10.1016/S0140-6736(12)60398-5.
Nathanson KL, Martin AM, Wubbenhorst B, Greshock J, Letrero R, D'Andrea K, O'Day S, Infante JR, Falchook GS, Arkenau HT, Millward M, Brown MP, Pavlick A, Davies MA, Ma B, Gagnon R, Curtis M, Lebowitz PF, Kefford R, Long GV. Tumor genetic analyses of patients with metastatic melanoma treated with the BRAF inhibitor dabrafenib (GSK2118436). Clin Cancer Res. 2013 Sep 1;19(17):4868-78. doi: 10.1158/1078-0432.CCR-13-0827. Epub 2013 Jul 5.
Hong DS, Vence L, Falchook G, Radvanyi LG, Liu C, Goodman V, Legos JJ, Blackman S, Scarmadio A, Kurzrock R, Lizee G, Hwu P. BRAF(V600) inhibitor GSK2118436 targeted inhibition of mutant BRAF in cancer patients does not impair overall immune competency. Clin Cancer Res. 2012 Apr 15;18(8):2326-35. doi: 10.1158/1078-0432.CCR-11-2515. Epub 2012 Feb 21. Erratum in: Clin Cancer Res. 2012 Jul 1;18(13):3715.
Falchook GS, Long GV, Kurzrock R, Kim KB, Arkenau TH, Brown MP, Hamid O, Infante JR, Millward M, Pavlick AC, O'Day SJ, Blackman SC, Curtis CM, Lebowitz P, Ma B, Ouellet D, Kefford RF. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet. 2012 May 19;379(9829):1893-901. doi: 10.1016/S0140-6736(12)60398-5.
Nathanson KL, Martin AM, Wubbenhorst B, Greshock J, Letrero R, D'Andrea K, O'Day S, Infante JR, Falchook GS, Arkenau HT, Millward M, Brown MP, Pavlick A, Davies MA, Ma B, Gagnon R, Curtis M, Lebowitz PF, Kefford R, Long GV. Tumor genetic analyses of patients with metastatic melanoma treated with the BRAF inhibitor dabrafenib (GSK2118436). Clin Cancer Res. 2013 Sep 1;19(17):4868-78. doi: 10.1158/1078-0432.CCR-13-0827. Epub 2013 Jul 5.
Public notes

Contacts
Principal investigator
Name 0 0
GSK Clinical Trials
Address 0 0
GlaxoSmithKline
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications