PI3Kβ Selective Inhibitor With Paclitaxel, Advanced Gastric Adenocarcinoma

Study Overview
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Brief Summary
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This is a Phase Ib/IIa, open-label, non-randomized, dose-escalation, multi-center study to evaluate the safety, tolerability, pharmacokinetics (PK), and clinical activity of oral GSK2636771 in combination with intravenous (IV) paclitaxel in two independent subject populations: subjects with PTEN-deficient, advanced gastric adenocarcinoma. This study will be conducted in two phases: the Dose Escalation Phase and the Dose Expansion Phase. The Dose Escalation Phase (Phase Ib) is designed to determine the maximum tolerated dose (MTD) and the recommended Phase II dose (RP2D) of GSK2636771 administered in combination with paclitaxel. The Dose Expansion Phase (Phase IIa) will further evaluate the safety and clinical activity of the RP2D as determined in the Dose Escalation Phase.

Official Title
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A Phase Ib/IIa, Open-Label, Dose Finding Study to Evaluate the Safety, Pharmacokinetics and Clinical Activity of PI3Kβ Selective Inhibitor (GSK2636771) Administered in Combination With Paclitaxel in Advanced Gastric Adenocarcinoma Having Alterations in PI3K Pathway Genes

Conditions
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Advanced Gastric Adenocarcinoma

Intervention / Treatment
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* Drug: GSK2636771
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: histologically or cytologically confirmed diagnosis of advanced gastric adenocarcinoma Has a PTEN-deficient tumor as documented from archival or fresh (from biopsy) tumor tissue or has shown genomic alterations in PI3K pathway genes (PIK3CB, PI3KR1, PTEN, etc.) as assessed in a local laboratory. Has had no prior taxane exposure (preferred) or at least 6 months since last taxane exposure. Eastern Cooperative Oncology Group performance status of 0 or 1 measurable or evaluable disease as determined by RECIST 1.1. Is able to swallow and retain orally administered medication adequate baseline organ function Exclusion criteria prior treatment with any AKT, mammalian target of rapamycin (mTOR) inhibitors or PI3K pathway inhibitors Has any unresolved Grade 2 (per CTCAE v4.0) toxicity from previous anti-cancer therapy at the time of enrollment such as neuropathy, except alopecia or Grade 2 anemia (if hemoglobin is ≥9.0 g/dL) Has CNS metastases Has a QTc interval >450 msec or QTc >480 msec for subjects with bundle branch block (BBB) Has a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to GSK2636771 or hypersensitivity to drug formulated in polyoxyl 35 castor oil, NF such as paclitaxel.

Ages Eligible for Study
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Minimum Age: 19 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Paclitaxel & GSK2636771<br>Increasing dose levels of GSK2636771 (300 mg or 400 mg once daily) in combination with a fixed dose of paclitaxel (80 mg/m2 on Days 1, 8 and 15 of a 28-day treatment cycle) | Drug: GSK2636771<br>* Increasing dose levels of GSK2636771 (300 mg or 400 mg once daily)<br>Drug: Paclitaxel<br>* fixed dose of paclitaxel (80 mg/m2 on Days 1, 8 and 15 of a 28-day treatment cycle)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended Phase II dose for phase 1 |  | 4 weeks | 
| Progression-free survival for phase 2 |  | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose limiting toxicity for phase 1 |  | 28 days |