Dose-Escalation Study of GSK2126458

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase I Open-Label, Dose-Escalation Study of the Phosphoinositide 3-Kinase Inhibitor GSK2126458 in Subjects With Solid Tumors or Lymphoma

Conditions
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Solid Tumours

Intervention / Treatment
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* Drug: GSK2126458


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GSK2126458<br>GSK2126458 will be dosed continuously (every day) for the duration a 28 day cycle. The 28 day cycles will continue until the subjects withdraw from the study. | Drug: GSK2126458<br>* GSK2126458 is an experimental treatment for patients with cancer.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 |  | Subjects continue on study until disease progression or consent withdrawal | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metabolic profile in plasma at the maximum tolerated dose |  | Subjects continue on study until disease progression or consent withdrawal | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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lymphoma, solid tumors, Phosphoinositide 3-kinase inhibitor