Study of GSK1363089 in Metastatic Gastric Cancer

Study Overview
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Brief Summary
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This clinical study is being conducted at multiple sites to determine the best confirmed response rate, safety, and tolerability of GSK1363089 treatment in metastatic gastric carcinoma.

Official Title
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A Phase 2 Study of GSK1363089 (XL880) Administered Orally to Subjects With Metastatic Gastric Cancer

Conditions
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Neoplasms, Gastrointestinal Tract

Intervention / Treatment
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* Drug: GSK1363089 (formerly XL880)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: histologically confirmed diagnosis of advanced or metastatic gastric carcinoma, or adenocarcinoma of the gastroesophageal junction or of the distal esophagus. Subjects with tumors of the gastroesophageal junction or of the distal esophagus may be eligible provided that the tumor is not of squamous or sarcomatous histology Measurable disease The subject consents to provide paired tumor biopsies, directly prior to commencing study treatment and then between Days 5 and 8. The subject has an ECOG performance status ≤2. The subject is able to ingest the GSK1363089 capsules. In the adrenocorticotropic hormone (ACTH) stimulation test, the subject has a serum cortisol level ≥20 μg/dL (552 nmol/L) 30-90 minutes after injection of ACTH. The subject has liver, kidney and marrow function. The subject is capable of understanding and complying with the protocol and has signed the informed consent document. Sexually active subjects (male and female) must use a medically-accepted method of contraception during the course of the study. Female subjects of childbearing potential must have a negative serum pregnancy test at screening. The subject has had no other diagnosis of malignancy (unless non-melanoma skin cancer or a malignancy diagnosed ≥5 years ago, and has no evidence of disease for 5 years prior to the screening for this study). QTc < 470 msec. Exclusion Criteria: The subject has received more than two lines of prior cytotoxic chemotherapy for locally advanced or metastatic disease. For the purpose of this protocol, neoadjuvant therapy would not be considered to be prior cytotoxic chemotherapy. In addition, potential subjects who have received prior treatment with c-MET signaling inhibitor are excluded. The subject has received an investigational drug within 14 days of the first dose of study drug. The subject has received chemotherapy, immunotherapy, or radiation therapy (to ≥25% of his or her bone marrow) within 14 days or has received nitrosoureas or mitomycin C within 6 weeks prior to the scheduled first dose of GSK1363089. The subject has AEs due to investigational drugs or other medications administered more than 21 days prior to enrollment that have not recovered to Grade ≤1 using NCI CTCAE v3.0, with the exception of alopecia greater than grade 1. The subject has known brain metastases. The subject has uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. The subject is pregnant or breastfeeding. The subject is known to be positive for the human immunodeficiency virus (HIV). The subject has a previously identified allergy or hypersensitivity to components of the GSK1363089 formulation. The subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee.

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: 5-days on/9-days off<br>Dosing for first 5 days in every 14-day period. | Drug: GSK1363089 (formerly XL880)<br>* c-MET tyrosine kinase inhibitor<br>* Other names: foretinib;|
| Experimental: daily dosing<br>dosed every day | Drug: GSK1363089 (formerly XL880)<br>* c-MET tyrosine kinase inhibitor<br>* Other names: foretinib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Objective Response Rate (ORR), of GSK1363089, Per- Response Evaluation Criteria in Solid Tumors (RECIST) Criteria Version 1.0 | ORR is defined as the percentage of participants achieving best overall response of confirmed complete response (CR) or partial response (PR). Tumor response for participants with measurable lesions was assessed routinely (after 8 weeks of treatment and approximately every 8 weeks thereafter) using RECIST (version 1.0) criteria. The CR for target lesions was defined as disappearance of all target lesions (TLs) and the non-target lesions (NTLs). PR defined as at least 30% decrease in sum of the longest diameter (LD) of TLs, taking as reference baseline sum LD. The safety population included all participants who passed the screening criteria, enrolled in the study, and received at least 1 dose of study drug. Progressive disease will be used as PD. | At every 8 Weeks upto 31 months | 
| Number of Participants With Adverse Event (AE) and Serious Adverse Event (SAE) | An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product whether or not it is considered drug related. This would include any side effect, injury, toxicity, sensitivity reaction, abnormal or worsening of a laboratory value, concurrent illness or sudden death. Pre-existing conditions that worsen during a study will be reported as AEs. SAE is an AE that results in death, is life-threatening, requires inpatient hospitalization or extends a current hospital stay, results in an ongoing or significant incapacity or interferes substantially with normal life functions, or causes a congenital anomaly or birth defect. Medical events that do not result in death, are not life-threatening, or do not require hospitalization may be considered SAEs if they put the participant in danger or require medical or surgical intervention to prevent one of the results listed above. | Up to 31 months | 
| Change From Baseline in Vital Signs-Systolic and Diastolic Blood Pressure | Participants systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured in mm of mercury (mmHg). These were collected after the participant sat quietly for at least five minutes. The change from baseline was calculated by subtracting the baseline values from the individual post-randomization values. The data for minimum (min) and maximum (max) post-baseline has been reported. Baseline is defined as the last non-missing record on or before first dose. | Baseline (pre-dose, Day 1) and before 30-day follow- up (up to 2 years) | 
| Change From Baseline in Vital Signs-Pulse Rate | The pulse rate or heart rate (HR) for the participant's, were collected after the participant sat quietly for at least five minutes. Baseline evaluations were performed within 72 hours before the first dose. If performed within 24 hours of the first dose, baseline evaluations may serve as the pre-dose Day 1 visit evaluations. The change from baseline was calculated by subtracting the baseline values from the individual post-randomization values. Baseline was defined as pre-dose, Day 1. The HR was measured in beats per minute (bpm). The min and max values have been reported. | Baseline (pre-dose, Day 1) and before 30-day follow- up (up to 2 years) | 
| Change From Baseline in Temperature | The body temperature for the participants was assessed. These were collected after the participant sat quietly for at least five minutes. The change from baseline was calculated by subtracting the baseline values from the individual post-randomization values. Baseline is defined as the last non-missing record on or before first dose. | Baseline (pre-dose, Day 1) and before 30-day follow- up (up to 2 years) | 
| Change From Baseline in Respiratory Rate (RR) | The RR for the participant's, were collected after the participant sat quietly for at least five minutes. Baseline evaluations should be performed within 72 hours before the first dose. If performed within 24 hours of the first dose, baseline evaluations may serve as the pre-dose Day 1 visit evaluations. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Baseline was defined as pre-dose, Day 1 . The RR was measured in breaths per minute. Min and max post-baseline values are reported. | Baseline (pre-dose, Day 1) and before 30-day follow- up (up to 2 years) | 
| Number of Participants With Shift From Baseline in by High/Low Flag for Serum Chemistry- Ungraded | The data for serum chemistry parameters like albumin, alanine aminotransferase (ALT), alkaline phosphatase (ALP), amylase, aspartate amino transferase (AST), calcium, carbon dioxide, creatinine, gamma glutamyl transferase (GGT), glucose, blood urea nitrogen (BUN), chloride, free thyroxine, free triiodothyronine, lipase, phosphorous, potassium, sodium, total bilirubin, lactate dehydrogenase, total protein. The abnormal values have been reported wherein data for normal to low and normal to high has been reported. | From Day 1 and before 30-day follow- up (up to 2 years) | 
| Number of Participants With Shift From Baseline in Serum Chemistry- Graded | The worst overall common terminology criteria for adverse events version 3.0 (CTCAE) grade (G) shift post baseline for each parameter was mentioned. Only worst case scenarios are presented. CTCAE grading is done as per intensity namely mild moderate severe life-threatening or Death. Analysis was done for Alanine aminotransferases, aspartate aminotransferases, Albumin, alkaline phosphatase, calcium, sodium, potassium, glucose, amylase, amylase, bilirubin, creatinine, phosphate, gamma glutamyl transferases (GGT), and triglycerol lipase. Worst Overall defined as worst post baseline out of normal range flag in the order of (high, low, normal) before 30 day follow up. Data for G3 and G4 is reported. | From Day 1 to up to 30-day follow-up visit (up to 2 years) | 
| Number of Participants With Shift From Baseline by High/Low Flag for Hematology Paramaters | The hematology parameters worst case overall CTCAE grade shift post Baseline for each parameter was mentioned. CTCAE grading for version 3.0 was used and done as per intensity namely mild moderate severe life-threatening or Death. Participants were analyzed for basophils, eosinophils, erythrocytes, hematocrit, and monocytes were analyzed. Only the abnormal values were reported where normal to high and normal to low changes were reported. Worst Overall was defined as highest post baseline CTCAE grade before 30 day follow up. | From Day 1 and before 30-day follow- up (up to 2 years) | 
| Number of Participants With Grade Shift for Urinalysis Parameters | The urinalysis parameters by worst case overall CTCAE grade shift post Baseline for each parameter were mentioned as per the CTCAE grading for version 3.0 and done as per intensity namely mild moderate severe life-threatening or Death. Participants were analyzed for abnormal values for bilirubin, ketones, nitrites, occult blood, pH, protein, specific gravity, and urobilinogen. | From Day 1 and before 30-day follow- up (up to 2 years) | 
| Number of Participants With Shift From Baseline by Grade for Hematology Parameters | The worst overall grading by CTCAE version 3.0, was used to report the shift from baseline for hematology parameters namely hemoglobin, platelets and lymphocytes. The grades were namely G0, G1, G2, G3 and G4. The data for shifts from G2 to G3 and G0 to G4, mainly the shifts to higher grades G3 and G4 have been reported. | Baseline (pre-dose) and before 30-day follow- up (up to 2 years) | 
| Number of Participants Who Required Concomitant Medications | The number of participants who received concomitant medication during the study were reported. The data has been reported for the participants who have received subsequent chemotherapy, subsequent radiation therapy or other therapy. | Baseline (pre-dose) and before 30-day follow- up (up to 2 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression Free Survival (PFS) of GSK1363089 | Duration of PFS in months is defined as (Date of Disease Progression/Death - Date of First Dose + 1)/30.44. For participants who did not reach an event (disease progression or death) at the time of data cut-off, duration of PFS is censored at date of last available tumor assessment that is not 'Unable to Evaluate'. For participants who did not have any post-baseline tumor assessments, PFS was censored at Day 1. For any participants who received subsequent anti-cancer therapy, PFS will be right censored at the date of last adequate tumor assessment on or prior to the date of anti-cancer therapy initiation. For any participants who died or progressed after an extended lost-to-follow-up time (greater than 17 weeks), PFS was censored at the date of last adequate assessment prior to extended lost-to follow-up. | At every 8 Weeks upto 31 months | 
| Duration of Stable Disease of GSK1363089 | Duration of stable disease, was defined as the time between the date of first dose and death or disease progression, in participants whose best overall response was not progressive disease | At every 8 Weeks upto 31 months | 
| Disease Stabilization Rate of GSK 1363089 | It is defined as the number of participants achieving best overall response of confirmed CR or PR or stable disease (SD). It was assessed using RECIST criteria 1.0. The CR for target lesions was defined as disappearance of all TLs and the NTLs. PR is at least 30% decrease in sum of the LD of TLs, taking as reference baseline sum LD. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as a reference, the smallest sum LD since the treatment started. | At every 8 Weeks upto 31 months | 
| Median Duration of Overall Survival (OS)of GSK1363089 | Duration of OS is defined as (Date of Death [due to any cause]) minus Date of first dose. For the participants who were alive at the time of data cut-off, duration of overall survival was censored at the date of last contact. The upper value of the full range was censored observation. | At every 8 Weeks upto 31 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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c-Met, Metastatic Gastric Carcinoma, adenocarcinoma, Gastric cancer, GSK1363089, XL880, MET inhibitor