A Phase I Study to Investigate the Safety, Pharmacokinetics, and Pharmacodynamics of GSK2118436 in Subjects With Solid Tumors

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT00880321
First received: April 9, 2009
Last updated: April 10, 2014
Last verified: June 2013
  Purpose

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.


Condition Intervention Phase
Cancer
Drug: GSK2118436
Drug: Midazolam
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • PK data, AEs, changes in laboratory values and vital signs, physical exam, clinical testing and PD data [ Time Frame: 21 days ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • GSK2118436 and its metabolite, PK parameters per protocol following single- and repeat-dose administration of GSK2118436 [ Time Frame: 15 days ] [ Designated as safety issue: No ]
  • Change in PD markers including IL-8 in blood, pERK and other markers in tumor biopsies. [ Time Frame: 15 days ] [ Designated as safety issue: No ]
  • Correlation between PK, PD, and clinical endpoints. [ Time Frame: 15 days ] [ Designated as safety issue: No ]
  • Tumor response as defined by Response Evaluation Criteria in Solid Tumors (RECIST v1.0) [ Time Frame: approximately once every 2 months until the end of participation ] [ Designated as safety issue: No ]
  • Urinary ratio of 6-beta-hydroxycortisol to cortisol ratio [ Time Frame: 15 days ] [ Designated as safety issue: No ]
  • GSK2118436 PK parameters per protocol with and without food [ Time Frame: 15 days ] [ Designated as safety issue: No ]
  • Metabolic profiling in plasma and urine [ Time Frame: 15 days ] [ Designated as safety issue: No ]
  • Midazolam PK parameters per protocol [ Time Frame: 15 days ] [ Designated as safety issue: No ]

Enrollment: 184
Study Start Date: June 2009
Study Completion Date: March 2012
Primary Completion Date: March 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Drug: GSK2118436
Dose escalation with GSK2118436 may proceed until either a maximum tolerated dose is established, or the toxicokinetic safety limit is reached.
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.
Drug: 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.
Drug: 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00880321

Locations
United States, California
GSK Investigational Site
Los Angeles, California, United States, 90025
United States, New York
GSK Investigational Site
New York, New York, United States, 10016
United States, Tennessee
GSK Investigational Site
Nashville, Tennessee, United States, 37203
United States, Texas
GSK Investigational Site
Houston, Texas, United States, 77030
Australia, New South Wales
GSK Investigational Site
Randwick, New South Wales, Australia, 2031
GSK Investigational Site
Westmead, New South Wales, Australia, 2145
Australia, South Australia
GSK Investigational Site
Adelaide, South Australia, Australia, 5000
Australia, Western Australia
GSK Investigational Site
Nedlands, Western Australia, Australia, 6009
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

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.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT00880321     History of Changes
Other Study ID Numbers: 112680
Study First Received: April 9, 2009
Last Updated: April 10, 2014
Health Authority: Australia: Department of Health and Ageing Therapeutic Goods Administration
United States: Food and Drug Administration

Keywords provided by GlaxoSmithKline:
first time in human
BRAF inhibitor
dose escalation

Additional relevant MeSH terms:
Midazolam
Dabrafenib
Adjuvants, Anesthesia
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on October 19, 2014