Clinical trial NCT00972686: Dose-Escalation Study of GSK2126458
Official title: A Phase I Open-Label, Dose-Escalation Study of the Phosphoinositide 3-Kinase Inhibitor GSK2126458 in Subjects With Solid Tumors or Lymphoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Tumours
Keywords: solid tumors
lymphoma
Phosphoinositide 3-kinase inhibitor
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2009-09-07
Enrollment: 79
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: P3K112826 is a Phase I, first-time-in-human dose escalation study in subjects with refractory malignancy. The primary objective of this study is to determine the recommended Phase II dose of GSK2126458 based on safety and tolerability, pharmacokinetics, pharmacodynamics and preliminary evidence of clinical activity. Secondary objectives are to characterize the pharmacokinetics of GSK2126458; and to explore relationships between GSK2126458 pharmacokinetics, pharmacodynamics, response prediction biomarkers and clinical endpoints.

Detailed description: This study is a Phase I, first-time-in-human dose escalation study in subjects with refractory solid tumors or lymphoma. The primary objective of this study is to determine the recommended Phase II dose of GSK2126458 based on safety and tolerability, pharmacokinetics, pharmacodynamics and preliminary evidence of clinical activity. Secondary objectives are to characterize the pharmacokinetics of GSK2126458; and to explore relationships between GSK2126458 pharmacokinetics, pharmacodynamics, response prediction biomarkers and clinical endpoints.

Subjects with solid tumors or lymphoma will initially receive oral GSK2126458 daily for 28 consecutive days in each 28 day cycle. Subjects may be dosed once or twice a day or may be dosed on an intermittent schedule depending on the safety, pharmacokinetic and pharmacodynamic results that become available as the study progresses. The starting dose will be 0.1 mg once a day. Expansion of some cohorts will be conducted to test tumor pharmacodynamics, further explore the toxicity profile and to look for preliminary evidence of activity in subjects with tumors with PIK3CA mutations. The recommended Phase II dose will be the lowest dose explored (at or below MTD) that maintains biologic activity with an acceptable tolerability profile.

Eligibility criteria: Inclusion Criteria:

* Histologically- or cytologically- confirmed diagnosis of solid tumor malignancy, or lymphoma
* Performance Status score of 0 or 1 according to the Eastern Cooperative Oncology Group (ECOG) scale.
* Female or male that is willing to take measures to avoid pregnancy in self or a partner, including abstinence, or double barrier method.
* Adequate organ system function

Exclusion Criteria:

* Use of an investigational anti-cancer medication within 28 days or 5 half-lives preceding the first dose of GSK2126458.
* Chemotherapy within the last 3 weeks (6 weeks for prior nitrosourea or mitomycin C
* Any major surgery, radiotherapy, or immunotherapy within the last 4 weeks.
* Prior use of any PI3K inhibitor.
* Current use of a prohibited medication or requires any of these medications during treatment with GSK2126458.
* Presence of an active gastrointestinal disease or other condition known to interfere significantly with the absorption, distribution, metabolism, or excretion of drugs.
* Unresolved toxicity greater than Grade 1 from previous anti-cancer therapy except alopecia.
* QTc interval ≥ 480 msecs.
* History of acute coronary syndromes; Class II, III, or IV heart failure; stroke or subarachnoid hemorrhage.
* Systolic blood pressure (SBP) of ≥140 mmHg or diastolic blood pressure (DBP) of ≥ 90mmHg.
* Previously diagnosed Type 1 diabetes mellitus. Subjects with Type 2 diabetes are prohibited in the dose escalation part of the study.
* Symptomatic or untreated leptomeningeal or brain metastases.
* Primary malignancy of the central nervous system.

Primary outcomes:
measure: Adverse events (AEs) and changes in laboratory values and vital signs. Pharmacokinetic parameter values for GSK2126458, Change from baseline in protein markers in tumor and/or blood. Blood glucose and insulin levels. Tumor response, RECIST defined
timeFrame: Subjects continue on study until disease progression or consent withdrawal
Secondary outcomes:
measure: Metabolic profile in plasma at the maximum tolerated dose
timeFrame: Subjects continue on study until disease progression or consent withdrawal
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: GSK Investigational Site
state: California
city: New Brunswick
country: United States
facility: GSK Investigational Site
state: New Jersey
city: Chapel Hill
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Dallas
country: United States
facility: GSK Investigational Site
state: Texas
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: Salt Lake City
country: United States
facility: GSK Investigational Site
state: Utah
city: Seattle
country: United States
facility: GSK Investigational Site
state: Washington
city: Amsterdam
country: Netherlands
facility: GSK Investigational Site
city: Utrecht
country: Netherlands
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: