Phase 2 Study of GSK1363089 (Formerly XL880) in Adults With Squamous Cell Cancer of the Head and Neck

Study Overview
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Brief Summary
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This study is being conducted to determine the best confirmed response rate, safety, and tolerability of GSK1363089 treatment in adult subjects with squamous cell carcinoma of the head and neck (SCCHN). GSK1363089 is a new chemical entity that inhibits multiple receptor tyrosine kinases (RTKs) with growth-promoting and angiogenic properties. The primary targets of GSK1363089 are the HGF and vascular endothelial growth factor (VEGF) RTK families (eg, MET, VEGFR2/kinase insert domain receptor [KDR]). Since MET overexpression has been associated with poorer prognosis and MET tyrosine kinase mutations have been reported in SCCHN, inhibition of MET receptor and VEGFR2/KDR activation by agents such as GSK1363089 may be of therapeutic benefit in this patient population.

Official Title
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A Phase 2 Study of the MET RTK Inhibitor GSK1363089 (Formerly XL880) in Subjects With Recurrent or Metastatic Squamous Cell Cancer of the Head and Neck

Conditions
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Neoplasms, Head and Neck

Intervention / Treatment
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* Drug: GSK1363089 (foretinib)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The subject has a histologically or cytologically confirmed diagnosis of SCCHN and has recurrent and/or metastatic disease is not eligible for curative intent surgery or radiotherapy has no history of uncontrolled tumor bleeding including hemoptysis in patients with documented pulmonary metastasis. The subject has measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as =20 mm with conventional techniques, or as =10 mm with spiral computerized tomography (CT) scan. Subject is capable of swallowing capsules. Fifteen unstained slides of tumor tissue, archival or fresh, or paraffin block are available, and there - confirmation that samples have been sent for analysis at the central laboratory. The subject is at least 18 years old. The subject has an Eastern Cooperative Oncology Group (ECOG) performance status =1. 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 organ and marrow function as follows: absolute neutrophil count (ANC) =1500/mm3, platelets =100,000/mm3, hemoglobin =9 g/dL, bilirubin =1.5 mg/dL, serum creatinine =1.5 mg/dL and/or calculated creatinine clearance =60 mL/min, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =2.5 times the upper limit of normal if no liver involvement or =5 times the upper limit of normal with liver involvement. The subject has signed the informed consent document. Sexually active subjects must use a medically accepted method of contraception during the course of the study. Female patients of childbearing potential must have a negative pregnancy test at enrollment. The subject has had no other diagnosis of malignancy (unless non-melanoma skin cancer, in situ carcinoma of the cervix, or a malignancy diagnosed =5 years ago, and has had no evidence of disease for 5 years prior to screening for this study). Exclusion Criteria: The subject has received radiation to >25% of his or her bone marrow within 30 days of GSK1363089 treatment. The subject has received an investigational drug within 30 days (or <5.5 half lives) of the first dose of study drug. The subject has received more than one regimen of systemic anticancer therapy for disease that has recurred or is metastatic. This may include either single-agent or combination cytotoxic chemotherapy with radiotherapy or anti-EGFR treatment (eg, cetuximab). Adjuvant or neoadjuvant systemic chemotherapy does not count as a regimen for recurrent or metastatic disease. The subject has progressed within 6 months after completion of curative intent (definitive) treatment for localized/locoregionally advanced disease. The subject has not recovered to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0 Grade =1 from adverse events (AEs) due to investigational drugs or other medications that were administered more than 30 days before study enrollment with the sole exception of persistent Grade 2 peripheral neuropathy in patients who have previously received platinum-based therapy. 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, active alcoholism, or psychiatric illness 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 an allergy or hypersensitivity to components of the GSK1363089 formulation.

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm<br>Participants who qualified for study entry received 240 mg of GSK1363089 (foretinib) on a 5-day on 9-day off schedule every 2 weeks. | Drug: GSK1363089 (foretinib)<br>* Multitargeted tyrosine kinase inhibitor<br>* Other names: GSK1363089 (formerly XL880);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Achieving Best Overall Response | Best overall response was assessed by the investigator per response evaluation criteria in solid tumors (RECIST). Per RECIST v1.0 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Tumor size was recorded at Baseline, and tumor response were recorded approximately every 8 weeks. Tumor response were classified by the investigator using RECIST criteria participant's best response whether observed in the study treatment period or the treatment extension period was considered. The best overall response was the best response recorded from the start of treatment until disease progression/recurrence. Number of participants who achieved best overall response were recorded. | Approximately up to 1 year | 
| Percentage of Participants With Objective Response Rate (ORR) | ORR was defined as the proportion of participants achieving best overall response of confirmed CR or PR divided by the total number of participants who received treatment. Per RECIST v1.0 for target lesions and assessed by MRI: CR, Disappearance of all target lesions; Partial Response PR, >=30% decrease in the sum of the longest diameter of target lesions; OR = CR + PR. Participants were evaluated for tumor response per RECIST. Percentage of participants with ORR were reported. | Approximately up to 1 year | 
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Data for number of participants who presented one or more adverse events (serious or non serious) was reported. An AE was defined as any untoward medical occurrence (MO) in a participant temporally associated with the use of a medicinal product (MP), whether or not considered related to the MP and can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with its use. The SAE was any untoward MO that, at any dose, results in death, life threatening, persistent or significant disability/incapacity, results in or prolongs inpatient hospitalization, congenital abnormality or birth defect, that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition. | Up to 20 months | 
| Number of Participants With Abnormalities of Common Toxicity Criteria for Adverse Events (CTCAE) Grade 3 in Laboratory Parameters (Clinical Chemistry and Hematology) | The National Cancer Institute -CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each toxicity based on the following general guideline: Grade 1: Mild AE, Grade 2: Moderate AE, Grade 3: Severe AE, Grade 4: Life-threatening or disabling AE and Grade 5: Death related to AE. Number of participants with abnormalities of CTCAE grade 3 in clinical chemistry parameters: alanine aminotransferase (ALT), γ-glutamyl transferase (GGT), phosphate, low sodium and hematology parameters: Leukocyte and Lymphocytes were presented. | Up to 20 months | 
| Number of Participants With Abnormalities in Urinalysis | Urinalysis parameters like appearance, color, pH, specific gravity, ketones, protein, glucose, bilirubin, nitrite, urobilinogen, and occult blood were performed. Number of participants with abnormalities are reported. In case of no abnormalities observed then it is reported as zero. | Week 5 [Day 29] | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Progression-free Survival | Progression-free survival was defined as the duration from the date of first dose to the date of disease progression or date of death without documented progression or date of study termination + 1. The start of confounding anticancer therapy was not treated as a censoring event. Time to progression or death was censored at the study termination date or at the analysis cutoff date, if earlier. | Approximately up to 1 year | 
| Duration of Overall Survival | Overall survival was defined as the duration from the date of the first dose to the date of death. The start of a confounding anticancer therapy was treated as a censoring event. Every effort made to follow participant's until death. Time to death was censored at the date of the latest participant contact or at the analysis cutoff date, if earlier. Kaplan-Meier method was used to estimate the overall survival distribution. | Approximately up to 1 year | 
| Duration of Stable Disease | Per RECIST v1.0 for target lesions and assessed by MRI: CR, Disappearance of all target lesions; Partial Response PR, >=30% decrease in the sum of the longest diameter of target lesions; OR = CR + PR. Duration of stable disease was defined as the time between the date of first dose of study drug and the first occurrence of 1 of the events: Tumor progression per RECIST as assessed by the investigator, Termination of study drug because of disease progression, Death due to disease progression, Disease progression as documented on the participant follow-up status form, Initiation of subsequent anticancer therapy. | Approximately up to 1 year | 
| Percentage Participants With Disease Stabilization Rate | Disease stabilization rate was defined as the proportion of participants for whom the best overall response was a PR, CR, or stable disease. percentage participants with disease stabilization rate were presented. | Approximately up to 1 year | 
| Maximum Plasma Concentration (Cmax) of Foretinib in Participants With Squamous Cell Carcinoma of the Head and Neck (SCCHN) | Plasma samples for pharmacokinetic analysis were planned to be drawn at time points: Day 1, 5, 19, 33, 43, 47 (approximately 15 minutes before dosing, and at 4 hours (±30 minutes) after dosing) of each treatment cycle, however these analyses were not completed. Cmax was defined as maximal measured plasma concentration over the time span specified. Data was not collected for this endpoint. | Day 1, 5, 19, 33, 43, 47 (pre-dose15 min) and 4 h (± 30 min) post-dose | 
| Time to Maximum Plasma Concentration (Tmax) of Foretinib in Participants With SCCHN | tmax was defined as the time to the maximum or peak concentration of a drug observed after multiple administration. Blood samples were planned to be obtained during the time points: Day 1, 5, 19, 33, 43, 47 (approximately 15 minutes before dosing, and at 4 hours (±30 minutes) after dosing). However these analyses were not completed. Data was not collected for this endpoint. | Day 1, 5, 19, 33, 43, 47 (pre-dose15 min) and 4 h (± 30 min) post-dose | 
| Area Under the Concentration-time Curve (AUC) of Foretinib in Participants With SCCHN | AUC was defined as area under the plasma concentration vs. time curve. Blood samples were planned to be collected on time points: Day 1, 5, 19, 33, 43, 47 (approximately 15 minutes before dosing, and at 4 hours (±30 minutes) after dosing). However these analyses were not completed. Data was not collected for this endpoint. | Day 1, 5, 19, 33, 43, 47 (pre-dose15 min) and 4 h (± 30 min) post-dose | 
| Elimination Half-life (t1/2) of Foretinib in Participants With SCCHN | t1/2 was defined as the time to when half of the total amount of a particular substance is eliminated from the body. Blood samples were planned to be obtained during indicated time points: Day 1, 5, 19, 33, 43, 47 (approximately 15 minutes before dosing, and at 4 hours (±30 minutes) after dosing). However these analyses were not completed. Data was not collected for this endpoint. | Day 1, 5, 19, 33, 43, 47 (pre-dose15 min) and 4 h (± 30 min) post-dose | 
| Apparent Oral Clearance | Blood samples were planned to be obtained during indicated time points: Day 1, 5, 19, 33, 43, 47 (approximately 15 minutes before dosing, and at 4 hours (±30 minutes) after dosing). Data for apparent oral clearance was not derived as pharmacokinetic analysis was not completed. Data was not collected for this endpoint. | Day 1, 5, 19, 33, 43, 47 (pre-dose15 min) and 4 h (± 30 min) post-dose | 
| Apparent Volume of Distribution | Blood samples were planned to be obtained during indicated time points: Day 1, 5, 19, 33, 43, 47 (approximately 15 minutes before dosing, and at 4 hours (±30 minutes) after dosing). Data for apparent volume of distribution was not derived as pharmacokinetic analysis was not completed. Data was not collected for PK analysis. | Day 1, 5, 19, 33, 43, 47 (pre-dose15 min) and 4 h (± 30 min) post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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VEGFR2, XL880, foretinib, Squamous Cell Cancer of the Head and Neck, MET, GSK1363089