Last updated: 11/03/2018 13:25:21
A Phase I Study to Investigate the Safety, Pharmacokinetics, and Pharmacodynamics of GSK2118436 in Subjects with Solid Tumors
Clinicaltrials.gov ID
EudraCT ID
Not applicable
EU CT Number
Not applicable
Trial status
Completed
Completed
Trial overview
Official 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
Trial description: 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.
Primary purpose:
Treatment
Trial design:
Single Group Assignment
Masking:
None (Open Label)
Allocation:
Non-randomized
Primary outcomes:
PK data, AEs, changes in laboratory values and vital signs, physical exam, clinical testing and PD data
Timeframe: 21 days
Secondary outcomes:
GSK2118436 and its metabolite, PK parameters per protocol following single- and repeat-dose administration of GSK2118436
Timeframe: 15 days
Change in PD markers including IL-8 in blood, pERK and other markers in tumor biopsies.
Timeframe: 15 days
Correlation between PK, PD, and clinical endpoints.
Timeframe: 15 days
Tumor response as defined by Response Evaluation Criteria in Solid Tumors (RECIST v1.0)
Timeframe: approximately once every 2 months until the end of participation
Urinary ratio of 6-beta-hydroxycortisol to cortisol ratio
Timeframe: 15 days
GSK2118436 PK parameters per protocol with and without food
Timeframe: 15 days
Metabolic profiling in plasma and urine
Timeframe: 15 days
Midazolam PK parameters per protocol
Timeframe: 15 days
Interventions:
Drug: GSK2118436
Drug: Midazolam
Enrollment:
170
Observational study model:
Not applicable
Primary completion date:
2011-25-03
Time perspective:
Not applicable
Clinical publications:
David S. Hong, Luis Vence, Gerald Falchook, Laszlo Radvanyi, Chengwen Liu, Vicki Goodman, Antonio Scarmadio, Razelle Kurzrock, Gregory Lizee and Patrick Hwu. BRAF(V600E) inhibitor therapy in cancer patients does not impair overall immune competency . [Clin. Cancer Res]. 2012;18:2326-2335.
Falchook G.S., Long G.V., Kurzrock R., Kim K.B., Arkenau H.T., Brown M.P., Hamid O., Infante J., Millward M., Pavlick A., O'Day S., Blackman S.C., Curtis C.M., Lebowitz P., Ma B., Ouellet D., Kefford R.F.. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial . [Lancet]. 2012;379(9829):1893 - 1901.
KL Nathanson, A-M Martin, B Wubbenhorst, J Greshock, R Letrero, K D'Andrea, S O'Day, JR Infante, GS Falchook, H-T Arkenau, M Millward, MP Brown, A Pavlick, MA Davies, B Ma, R Gagnon, M Curtis, PF Lebowitz, R Kefford, GV Long. Tumor genetic analyses of patients with metastatic melanoma treated with the BRAF inhibitor Dabrafenib (GSK2118436) . Clin. Cancer Res. 2013;
Daniele Ouellet, Ekaterina Gibiansky, Cathrine L Denton, Anne O’Hagan, Pat Haney, Julie Switzky, Vicki Goodman.Population Pharmacokinetics of Dabrafenib: Effect of Dose, Time, Covariates and Relationship with its Metabolites .J Clin Pharmacol.2014;54(6):696-706
David S. Hong, Luis Vence, Gerald Falchook, Laszlo Radvanyi, Chengwen Liu, Vicki Goodman, Antonio Scarmadio, Razelle Kurzrock, Gregory Lizee and Patrick Hwu. BRAF(V600E) inhibitor therapy in cancer patients does not impair overall immune competency . Clin. Cancer Res. 2012;18:2326-2335.
Falchook G.S., Long G.V., Kurzrock R., Kim K.B., Arkenau H.T., Brown M.P., Hamid O., Infante J., Millward M., Pavlick A., O'Day S., Blackman S.C., Curtis C.M., Lebowitz P., Ma B., Ouellet D., Kefford R.F.. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial . Lancet. 2012;379(9829):1893 - 1901.
G Falchook, G Long, R Kurzrock, K Kim, M Chin, M Brown, O Hamid, J Infante, M Millward, A Pavlick, S Blackman, CM Curtis, P Lebowitz, B Ma, D Ouellet, R Kefford .Pharmacokinetics, pharmacodynamics, and dose selection in the First-In-Human Phase I dose-escalation trial of RAF inhibitor Dabrafenib (GSK2118436).Clin. Cancer Res.2014;20:4449-4458
KL Nathanson, A-M Martin, B Wubbenhorst, J Greshock, R Letrero, K D'Andrea, S O'Day, JR Infante, GS Falchook, H-T Arkenau, M Millward, MP Brown, A Pavlick, MA Davies, B Ma, R Gagnon, M Curtis, PF Lebowitz, R Kefford, GV Long. Tumor genetic analyses of patients with metastatic melanoma treated with the BRAF inhibitor Dabrafenib (GSK2118436) . Clin Cancer Res. 2013;19(17):4868–78.
Medical condition
Cancer
Product
dabrafenib
Collaborators
Not applicable
Study date(s)
June 2009 to March 2012
Type
Interventional
Phase
1
Participation criteria
Sex
Female & Male
Age
18+ years
Accepts healthy volunteers
No
- Written informed consent provided.
- 18 years old or older. Subjects enrolled in the midazolam cohort need to be younger than 65 years old.
- 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.
Inclusion and exclusion criteria
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.
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.
Trial location(s)
Location
GSK Investigational Site
Randwick, New South Wales, Australia, 2031
Status
Study Complete
Location
GSK Investigational Site
New York, New York, United States, 10016
Status
Study Complete
Location
GSK Investigational Site
Nedlands, Western Australia, Australia, 6009
Status
Study Complete
Location
GSK Investigational Site
Westmead, New South Wales, Australia, 2145
Status
Study Complete
Location
GSK Investigational Site
Nashville, Tennessee, United States, 37203
Status
Study Complete
Location
GSK Investigational Site
Los Angeles, California, United States, 90025
Status
Study Complete
Location
GSK Investigational Site
Adelaide, South Australia, Australia, 5000
Status
Study Complete
Study documents
Clinical study report
Available language(s): English
Scientific result summary
Available language(s): English
If you wish to request for full study report, please contact - [email protected]
Results overview
Refer to study documents
Recruitment status
Completed
Actual primary completion date
2011-25-03
Actual study completion date
2012-20-03
Plain language summaries
Plain language summaries of clinical trial results for Phase 2-4 clinical trials that were initiated on or after January 2022 will be posted by GSK within one year following study completion.
Additional information about the trial
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Additional information
Results for study 112680 can be found on the GSK Clinical Study Register.
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