Dose Escalation Study to Investigate the Safety, Pharmacokinetics, and Pharmacodynamics of GSK2849330 in Subjects With Advanced Her3-Positive Solid Tumors

Study Overview
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Brief Summary
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Human Epidermal Growth Factor Receptor 3 (HER3) expression is seen across a wide variety of solid malignancies and is associated with poor prognosis. Up-regulation of HER3 expression and activity is also associated with resistance to multiple pathway inhibitors. GSK2849330, a monoclonal antibody targeting HER3, is a new agent for subjects whose tumors express HER3. This study is a phase I, first time in human, open-label, dose escalation study. The purpose of this study is to investigate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of GSK2849330 in subjects with advanced HER3-positive solid tumors. The study will be conducted in two parts. Part 1 (Dose-Escalation Phase) will include dose escalation and PK/PD cohorts to evaluate safety, PK, and PD to guide selection of dose regimen(s) for Part 2. In Part 2 (Expansion Cohorts), up to 3 cohorts will be enrolled at the dose regimen(s) selected based on Part 1 data, to evaluate safety in a larger cohort of subjects at the recommended dose regimen and also to evaluate preliminary evidence of clinical benefit.

Official Title
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A Phase I, First Time in Human, Open-Label, Dose Escalation Study to Investigate the Safety, Pharmacokinetics, and Pharmacodynamics of Anti-Her3 Monoclonal Antibody GSK2849330 in Subjects With Advanced Her3-Positive Solid Tumors

Conditions
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Cancer, Neoplasms

Intervention / Treatment
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* Biological: GSK2849330


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females >=18 years of age (at the time consent is obtained). Written informed consent provided. Performance Status score of 0 or 1 according to the Eastern Cooperative Oncology Group (ECOG) scale. Sufficient archival tumor specimen is available for HER3 immunohistochemistry (IHC) analysis, or subject is willing to undergo a fresh tumor biopsy for HER3 IHC analysis. Histologically or cytologically confirmed diagnosis of one of the following solid tumor malignancies for which no standard therapeutic alternatives exist: bladder cancer, breast cancer, castrate-resistant prostate cancer, cervical cancer, colorectal cancer (CRC), gastric cancer, hepatocellular carcinoma (HCC), melanoma, non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, squamous cancers of the head and neck region (including parotid and nasopharynx). Exclusion Criteria: Subjects with leptomeningeal or brain metastases or spinal cord compression. Prior HER3- directed treatment (HER2- or EGFR-directed treatment is acceptable). Concurrent medical condition that would jeopardize compliance. Receiving chronic immunosuppressive therapies (includes daily steroid doses in excess of 20 milligrams [mg]/day of prednisone).

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: GSK2849330 Part 1<br>1 hour infusion administered intravenously at intervals of one week or more (escalating doses). | Biological: GSK2849330<br>* Solution containing 100 mg/millilter (mL) GSK2849330 for intravenous infusion<br>|
| Experimental: GSK2849330 Part 2<br>Intravenous infusion administered at the dose and schedule established in Part 1 | Biological: GSK2849330<br>* Solution containing 100 mg/millilter (mL) GSK2849330 for intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)-Parts 1 and 2 | An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; is a congenital anomaly/birth defect; important medical events that may require medical or surgical intervention to prevent one of the outcomes mentioned; events of possible study treatment-induced liver injury with hyperbilirubinemia; and left ventricular ejection fraction (LVEF) meeting stopping criteria. AEs were collected in All Treated Population which comprised of all participants who received at least one dose of GSK2849330. Treatment groups with same dose and administration frequency were combined as pre-specified in reporting and analysis plan. | Median of 6.143 weeks of drug exposure | 
| Number of Participants With Dose-limiting Toxicities (DLTs)-Parts 1 and 2 | An event was considered a DLT if it occured within the first 4 weeks (28 days) of treatment, and met one of the following criteria unless it could be established that the event was unrelated to treatment: Grade 3 or greater non-hematologic toxicity; Grade 4 neutropenia lasting >5 days; Febrile neutropenia, of any grade or duration; Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia associated with bleeding; Alanine aminotransferase (ALT) >3 times upper limit of normal (ULN) with bilirubin >2 times ULN; Any Grade 2 or greater toxicity that in the judgment of the investigator and GlaxoSmithKline (GSK) Medical Monitor, would be considered dose-limiting; Grade 3 or greater decrease in LVEF. Treatment groups with same dose and administration frequency were combined as pre-specified in reporting and analysis plan. | Up to 28 days | 
| Number of Participants With Grade Change From Baseline in Clinical Chemistry Data-Parts 1 and 2 | Blood samples were collected for the analysis of following clinical chemistry parameters: albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (Total bil), calcium, creatinine, gamma glutamyl transferase (GGT), glucose, potassium, magnesium, sodium, phosphorus, uric acid. Laboratory parameters were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences; Grade 5: death related to AE. Baseline is the most recent, non-missing value from a central laboratory prior to or on the first study treatment dose date. Change from Baseline was calculated as visit value minus Baseline value. Data for worst-case post Baseline is presented. Treatment groups with same dose and administration frequency were combined as pre-specified in reporting and analysis plan. | Baseline and median of 6.143 weeks of drug exposure | 
| Number of Participants With Change From Baseline in Clinical Chemistry Data With Respect to Normal Range-Parts 1 and 2 | Blood samples were collected for the analysis of following clinical chemistry parameters: direct bilirubin (D.Bil.), cancer antigen (CA)-125, CA-15.3, CA19-9, chloride, carbon dioxide (CO2)/bicarbonate (HCO3), luteinizing hormone (LH), total protein and urea or blood urea nitrogen (BUN). Baseline was defined as the most recent, non-missing value from a central laboratory prior to or on the first study treatment dose date. Change from Baseline was calculated as visit value minus Baseline value. A laboratory value that is outside the reference range was considered either high abnormal (value above the upper limit of the reference range) or low abnormal (value below the lower limit of the reference range). Number of participants with change from Baseline in clinical chemistry data at worst-case post Baseline is presented. Treatment groups with same dose and administration frequency were combined as pre-specified in reporting and analysis plan. | Baseline and median of 6.143 weeks of drug exposure | 
| Number of Participants With Grade Change From Baseline in Hematology Data-Parts 1 and 2 | Blood samples were collected for the analysis of following hematology parameters: hemoglobin, lymphocytes, total neutrophils, platelet count, and white blood cell (WBC). The laboratory parameters were graded according to NCI-CTCAE version 4.0. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences; Grade 5: death related to AE. Baseline was defined as the most recent, non-missing value from a central laboratory prior to or on the first study treatment dose date. Change from Baseline was calculated as visit value minus Baseline value. Number of participants with any grade increase, increase to Grade 3 and increase to Grade 4 in hematology data at worst-case post Baseline is presented. Treatment groups with same dose and administration frequency were combined as pre-specified in reporting and analysis plan. | Baseline and median of 6.143 weeks of drug exposure | 
| Number of Participants With Change From Baseline in Hematology Data With Respect to Normal Range-Parts 1 and 2 | Blood samples were collected for the analysis of following hematology parameters: basophils, eosinophils, hematocrit, mean corpuscle hemoglobin concentration (MCHC), mean corpuscle hemoglobin (MCH), mean corpuscle volume (MCV), monocytes, red blood cell count (RBC) and reticulocytes. A laboratory value that was outside the reference range was considered either high abnormal (value above the upper limit of the reference range) or low abnormal (value below the lower limit of the reference range). Baseline was defined as the most recent, non-missing value from a central laboratory prior to or on the first study treatment dose date. Change from Baseline was calculated as value at visit minus Baseline value. Number of participants with change from Baseline in hematology data at worst-case post Baseline is presented. Treatment groups with same dose and administration frequency were combined as pre-specified in reporting and analysis plan. | Baseline and median of 6.143 weeks of drug exposure | 
| Number of Participants With Change From Baseline in Urinalysis Data With Respect to Normal Range-Parts 1 and 2 | Urine samples were collected for the analysis of urine potential of hydrogen (pH) and urine specific gravity. A laboratory value that was outside the reference range was considered either high abnormal (value above the upper limit of the reference range) or low abnormal (value below the lower limit of the reference range). Baseline was defined as the most recent, non-missing value from a central laboratory prior to or on the first study treatment dose date. Change from Baseline was calculated as visit value minus Baseline value. The data for worst-case post Baseline is presented. Treatment groups with same dose and administration frequency were combined as pre-specified in reporting and analysis plan. | Baseline and median of 6.143 weeks of drug exposure | 
| Number of Participants With Change From Baseline in Vital Signs-Parts 1 and 2 | Vital sign measurements included systolic blood pressure (SBP), diastolic blood pressure (DBP), temperature (Temp) and heart rate (HR). Vital signs were graded according to NCI-CTCAE version 4.0. The following criteria was used to flag vital signs of potential clinical importance: change from Baseline in HR (decrease to <60 beats per minute and increase to >100 beats per minute); increase in SBP from Baseline (>=120 to <140 millimeters of mercury [mmHg] Grade 1; >=140 to <160 mmHg [Grade 2]; >=160 [Grade 3]); increase in DBP from Baseline (>=80 to <90 [Grade 1]; >=90 to <100 [Grade 2]; >=100 mmHg [Grade 3]) and change in temperature from Baseline (increase to >=38 or decrease to <=35 degree Centigrade). Baseline was defined as the most recent, non-missing value prior to or on the first study treatment dose date. Change from Baseline was calculated as visit value minus Baseline value. The data for worst-case post Baseline is presented. | Baseline and median of 6.143 weeks of drug exposure | 
| Number of Participants With Abnormal Electrocardiogram (ECG) Findings-Parts 1 and 2 | A 12-lead ECG was measured using an automated ECG machine after at least 5 minutes of rest for the participant in a semi-recumbent or supine position. Number of participants with abnormal ECG findings at any time post-Baseline is presented. Treatment groups with same dose and administration frequency were combined as pre-specified in reporting and analysis plan. | Median of 6.143 weeks of drug exposure | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) of GSK2849330-Part 1 | The first occurrence of the maximum observed plasma concentration determined directly from the raw concentration-time data is defined as Cmax. Blood samples were collected at indicated time points. The analysis was performed on pharmacokinetic (PK) parameter population which comprised of all participants from the PK concentration population (participants who received at least one dose of GSK2849330 and for whom at least one post-dose PK sample was obtained and analyzed) for whom valid and valuable PK parameters were derived. | Day 1 (pre-dose, 1 and 6 hours post-dose), Day 8, Day 15, Day 29, and every 12 weeks from first dose | 
| Cmax of GSK2849330-Part 2 | PK parameters for Part 2 were not analyzed due to sparse sampling. The protocol was written in a flexible way to either pursue or not pursue additional analyses in Part 2. | Day 1 (pre-dose, 1 and 6 hours post-dose), Day 8, Day 15, Day 29, and every 12 weeks from first dose | 
| Time of Occurrence of Cmax (Tmax) for GSK2849330-Part 1 | The time at which Cmax is observed was determined directly from the raw concentration-time data is defined as Tmax. Blood samples were collected at indicated time points for evaluation of pharmacokinetic parameters. | Day 1 (pre-dose, 1 and 6 hours post-dose), Day 8, Day 15, Day 29, and every 12 weeks from first dose | 
| Tmax for GSK2849330-Part 2 | PK parameters for Part 2 were not analyzed due to sparse sampling. The protocol was written in a flexible way to either pursue or not pursue additional analyses in Part 2. | Day 1 (pre-dose, 1 and 6 hours post-dose), Day 8, Day 15, Day 29, and every 12 weeks from first dose | 
| Area Under the Concentration Time Curve (AUC) to a Fixed Nominal Time (AUC[0 to 168]) and AUC(0 to 336) for GSK2849330-Part 1 | The AUC to a fixed nominal time AUC(0-168) and AUC(0-336) were calculated using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations. Blood samples were collected at indicated time points for determination of PK parameters. | Day 1 (pre-dose, 1 and 6 hours post-dose), Day 8, Day 15, Day 29, and every 12 weeks from first dose | 
| AUC(0 to 168) and AUC(0 to 336) for GSK2849330-Part 2 | PK parameters for Part 2 were not analyzed due to sparse sampling. The protocol was written in a flexible way to either pursue or not pursue additional analyses in Part 2. | Day 1 (pre-dose, 1 and 6 hours post-dose), Day 8, Day 15, Day 29, and every 12 weeks from first dose | 
| Serum HER3 From Tumor Tissue-Parts 1 and 2 | Pre-treatment and on-treatment biopsy tissues (tumor and normal skin) were analyzed for markers of HER3 pathway such as HER3 that may indicate a pharmacodynamic (PD) response to GSK2849330. Serum HER3 (soluble HER3) analyses was performed. The analysis was performed on PD population which comprised of all participants who received at least one dose of GSK2849330 and for whom at least one evaluable paired pre-treatment PD sample and on-treatment PD sample were obtained and analyzed. Mean and standard deviation for serum HER3 is presented. Treatment groups with same dose and administration frequency were combined as pre-specified in reporting and analysis plan. | Day 1 (pre-dose, 1 hour, 6 hours), Day 2, Day 8, Day 15, Day 29 and follow-up (28 days post last dose) | 
| Overall Response Rate (ORR)-Parts 1 and 2 | ORR was determined by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST v 1.1). ORR was calculated as the number of participants with best overall response of complete response (CR) and partial response (PR). CR=Disappearance of all target lesions. Any pathological lymph nodes must be <10 millimeter (mm) in the short axis and PR=At least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters (e.g., percent change from Baseline). An estimate to the true response rate for the number of participants analyzed is given. The 95% confidence interval was the exact confidence interval based on binomial proportion for ORR. Treatment groups with same dose and administration frequency were combined as pre-specified in reporting and analysis plan. | Median of 6.143 weeks of drug exposure | 
| Number of Participants With Antibodies to GSK2849330 in Serum | Serum samples were collected for the determination of anti-GSK2849330 antibodies using a validated immunoelectrochemiluminescent (ECL) assay. The assay involved screening, confirmation and titration steps (tiered-testing approach). If serum samples contained anti-GSK2849330 antibodies, they were further analyzed for the specificity of antibodies by a confirmation assay. Confirmed positive samples were titrated to obtain the titers of antibodies. The number of participants who tested positive for anti-GSK2849330 antibody in confirmatory testing on Day 1 and at any time post-Baseline is presented. Treatment groups with same dose and administration frequency were combined as pre-specified in reporting and analysis plan. | Median of 6.143 weeks of drug exposure | 
| Percentage of Cluster of Differentiation (CD) Marker | Blood samples were collected on Day (D) 1 at pre-dose (pre) and at 1 hour (h) and 6 h post infusion for the analysis of markers to evaluate biological activity of GSK2849330. A pre-dose blood sample was collected on D8, D15 and D29 with additional blood sample collected at progression of disease. CDX241 represent CD45+CD3-CD56+CD16+CD69+CD107+, CDX243=CD45+CD3-CD56+CD16+CD69+CD107-; CDX244=CD45+CD3-CD56+CD16+CD69-CD107+ and CDX245=CD45+CD3-CD56+CD16+CD69-CD107-. For participants in GSK2849330 3 mg/kg weekly arm, two samples (S1 and S2) were collected for D15 analysis. Treatment groups with same dose and administration frequency were combined as pre-specified in reporting and analysis plan. | Median of 6.143 weeks of drug exposure | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HER3, GSK2849330, Oncology, First Time in Human