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Antibodies, Monoclonal

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1 hour infusion administered intravenously at intervals of one week or more (escalating doses).

Intravenous infusion administered at the dose and schedule established in Part 1

Solution containing 100 mg/millilter (mL) GSK2849330 for intravenous infusion

GSK2849330

GSK Clinical Trials

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.

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

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

GlaxoSmithKline

AEs and SAEs were collected in the 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.

Participants were administered a weekly dose of 1.4 mg/kg GSK2849330 as intravenous infusion for 28 days

GSK2849330 1.4 mg/kg Weekly

Participants were administered 3 mg/kg GSK2849330 as an intravenous infusion every 2 weeks for 28 days.

GSK2849330 3 mg/kg Every 2 Weeks

Participants were administered a weekly dose of 3 mg/kg GSK2849330 as intravenous infusion for 28 days.

GSK2849330 3 mg/kg Weekly

Participants were administered 10 mg/kg GSK2849330 as an intravenous infusion every 2 weeks for 28 days.

GSK2849330 10 mg/kg Every 2 Weeks

Participants were administered 30 mg/kg GSK2849330 as an intravenous infusion every 2 weeks for 28 days

GSK2849330 30 mg/kg Every 2 Weeks

Participants were administered a weekly dose of 30 mg/kg GSK2849330 as intravenous infusion for 28 days. The arm included participants receiving 30 mg/kg weekly from both Part 1 (dose-escalation cohort) and Part 2 (dose expansion cohort).

GSK2849330 30 mg/kg Weekly

Total

Age, Continuous

Sex: Female, Male

Race customized

Race/Ethnicity, Customized

Treatment groups with same dose and administration frequency were combined as pre-specified in reporting and analysis plan.

GSK Response Center

SAEs

Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)-Parts 1 and 2

Number of Participants With Dose-limiting Toxicities (DLTs)-Parts 1 and 2

Albumin; any Grade increase; n=1,3,2,5,4,14

Albumin; increase to Grade 3; n=1,3,2,5,4,14

Albumin; increase to Grade 4; n=1,3,2,5,4,14

ALP; any grade increase; n=1,3,2,5,4,14

ALP; increase to Grade 3; n=1,3,2,5,4,14

ALP; increase to Grade 4; n=1,3,2,5,4,14

ALT; any Grade increase; n=1,3,2,5,4,14

ALT; increase to Grade 3; n=1,3,2,5,4,14

ALT; increase to Grade 4; n=1,3,2,5,4,14

AST; any Grade increase; n=1,3,2,5,4,14

AST; increase to Grade 3; n=1,3,2,5,4,14

AST; increase to Grade 4; n=1,3,2,5,4,14

Total bil; any Grade increase; n=1,3,2,5,4,14

Total bil; increase to Grade 3; n=1,3,2,5,4,14

Total bil; increase to Grade 4; n=1,3,2,5,4,14

Calcium; any Grade increase; n=1,3,2,5,4,14

Calcium; increase to Grade 3; n=1,3,2,5,4,14

Calcium; increase to Grade 4; n=1,3,2,5,4,14

Creatinine; any Grade increase; n=1,3,2,5,4,14

Creatinine; increase to Grade 3; n=1,3,2,5,4,14

Creatinine; increase to Grade 4; n=1,3,2,5,4,14

GGT; any Grade increase; n=1,3,2,5,4,14

GGT; increase to Grade 3; n=1,3,2,5,4,14

GGT; increase to Grade 4; n=1,3,2,5,4,14

Glucose; any Grade increase; n=1,3,2,5,4,14

Glucose; increase to Grade 3; n=1,3,2,5,4,14

Glucose; increase to Grade 4; n=1,3,2,5,4,14

Potassium; any Grade increase; n=1,3,2,5,4,14

Potassium; increase to Grade 3; n=1,3,2,5,4,14

Potassium; increase to Grade 4; n=1,3,2,5,4,14

Magnesium; any Grade increase; n=1,3,2,5,4,14

Magnesium; increase to Grade 3; n=1,3,2,5,4,14

Magnesium; increase to Grade 4; n=1,3,2,5,4,14

Sodium; any Grade increase; n=1,3,2,5,4,14

Sodium; increase to Grade 3; n=1,3,2,5,4,14

Sodium; increase to Grade 4; n=1,3,2,5,4,14

Phosphorus; any Grade increase; n=1,3,2,5,4,14

Phosphorus; increase to Grade 3; n=1,3,2,5,4,14

Phosphorus; increase to Grade 4; n=1,3,2,5,4,14

Uric acid; any Grade increase; n=0,0,0,0,0,1

Uric acid; increase to Grade 3; n=0,0,0,0,0,1

Uric acid; increase to Grade 4; n=0,0,0,0,0,1

All Treated Population. Only those participants with data available at specified time points were analyzed (represented by n=X in category titles).

Number of Participants With Grade Change From Baseline in Clinical Chemistry Data-Parts 1 and 2

D.Bil.; Decrease to Low; n=1,3,2,5,3,14

D.Bil.; increase to high; n=1,3,2,5,3,14

CA-125; Decrease to Low; n=1,3,0,5,4, 0

CA-125; increase to high; n=1,3,0,5,4, 0

CA 15.3; Decrease to Low; n=0, 0, 0, 0, 4, 0

CA 15.3; increase to high; n=0, 0, 0, 0, 4, 0

CA 19-9.; Decrease to Low; n=1,0,0,0,2,0

CA 19-9; increase to high; n=1,0,0,0,2,0

Chloride; Decrease to Low; n=1,3,2,5,4,14

Chloride; increase to high; n=1,3,2,5,4,14

CO2/HCO3.; Decrease to Low; n=1,3,2,5,4,14

CO2/HCO3; increase to high; n=1,3,2,5,4,14

LH; Decrease to Low; n=1,0,2,3,2,7

LH; increase to high; n=1,0,2,3,2,7

Total Protein; Decrease to Low; n=1,3,2,5,4,14

Total Protein; increase to high; n=1,3,2,5,4,14

Urea/BUN; Decrease to Low; n=1,3,2,5,4,14

Urea/BUN; increase to high; n=1,3,2,5,4,14

Number of Participants With Change From Baseline in Clinical Chemistry Data With Respect to Normal Range-Parts 1 and 2

Hemoglobin; any Grade increase

Hemoglobin; increase to Grade 3

Hemoglobin; increase to Grade 4

Lymphocytes; any grade increase

Lymphocytes; increase to Grade 3

Lymphocytes; increase to Grade 4

Total neutrophils; any Grade increase

Total neutrophils; increase to Grade 3

Total neutrophils; increase to Grade 4

Platelet; any Grade increase

Platelet; increase to Grade 3

Platelet; increase to Grade 4

WBC; any Grade increase

WBC; increase to Grade 3

WBC; increase to Grade 4

Number of Participants With Grade Change From Baseline in Hematology Data-Parts 1 and 2

Basophils: decrease to low

Basophils: increase to high

Eosinophils: decrease to low

Eosinophils: increase to high

Hematocrit: decrease to low

Hematocrit: increase to high

MCHC: decrease to low

MCHC: increase to high

MCH: decrease to low

MCH: increase to high

MCV: decrease to low

MCV: increase to high

Monocytes: decrease to low

Monocytes: increase to high

RBC: decrease to low

RBC: increase to high

Reticulocytes: decrease to low

Reticulocytes: increase to high

Number of Participants With Change From Baseline in Hematology Data With Respect to Normal Range-Parts 1 and 2

Urine pH; decrease to low; n=1, 3, 1, 5, 4, 7

Urine pH; increase to high; n=1, 3, 1, 5, 4, 7

Specific gravity; decrease to low; n=1,3,1,4,4,8

Specific gravity; increase to high; n=1,3,1,4,4,8

Number of Participants With Change From Baseline in Urinalysis Data With Respect to Normal Range-Parts 1 and 2

HR; decrease to <60 beats per minute

HR; increase to >100 beats per minute

Temp; decrease to <=35 degree Celsius

Temp; increase to >=38 degree Celsius

SBP; increase to Grade 1 (120-139 mmHg)

SBP; increase to Grade 2 (140-159 mmHg)

SBP; increase to Grade 3 (>=160 mmHg)

DBP; increase to Grade 1 (80-89 mmHg)

DBP; increase to Grade 2 (90-99 mmHg)

DBP; increase to Grade 3 (>=100 mmHg)

Number of Participants With Change From Baseline in Vital Signs-Parts 1 and 2

Abnormal-not clinically significant

Abnormal-clinically significant

Number of Participants With Abnormal Electrocardiogram (ECG) Findings-Parts 1 and 2

Participants were administered a weekly dose of 30 mg/kg GSK2849330 as intravenous infusion for 28 days. The arm included participants receiving 30 mg/kg weekly from Part 1 (dose-escalation cohort).

Maximum Observed Plasma Concentration (Cmax) of GSK2849330-Part 1

Participants were administered a weekly dose of 30 mg/kg GSK2849330 as intravenous infusion for 28 days. The arm included participants receiving 30 mg/kg weekly in Part 2 (dose expansion cohort).

PK Parameter Population. PK parameters for Part 2 were not analyzed due to sparse sampling.

Cmax of GSK2849330-Part 2

Time of Occurrence of Cmax (Tmax) for GSK2849330-Part 1

Tmax for GSK2849330-Part 2

AUC(0 to 168); n=1, 3, 2, 3, 3, 5

AUC(0 to 336); 0, 3, 0, 3, 3, 0

PK Parameter Population. Only those participants with data available at specified time points were analyzed (indicated by n=X in category titles).

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

AUC(0 to 168) and AUC(0 to 336) for GSK2849330-Part 2

Day 1; pre-dose; n=1, 3, 1, 5, 4, 12

Day 1; 1 hour; n=1, 3, 1, 5, 4, 11

Day 1; 6 hours; n=1, 3, 1, 5, 4, 10

Day 2; n=0, 0, 1, 1, 1, 2

Day 8; n=1, 3, 1, 5, 4, 11

Day 15; n=0, 2, 1, 3, 4, 10

Day 29; n=1, 3, 1, 4, 4, 8

Follow-up; n=1, 2, 1, 3, 2, 5

PD Population. Only those participants with data available at specified time points were analyzed (indicated by n=X in category titles).

Serum HER3 From Tumor Tissue-Parts 1 and 2

Overall Response Rate (ORR)-Parts 1 and 2

Day1; n=1, 3, 2, 5, 4, 13

Any time post-Baseline; n=1, 3, 1, 5, 4, 7

All Treated Population. Only those participants with data available at specified time points were analyzed (indicated by n=X in category titles)

Number of Participants With Antibodies to GSK2849330 in Serum

CD45+; D1; pre; n=1, 3, 1, 5, 4, 9

CD45+; D1; 1 h; n=1, 3, 1, 5, 4, 9

CD45+; D1; 6 h; n=1, 3, 1, 5, 4, 11

PD Population. Only those participants with data available at specified time points were analyzed (indicated by n=X in category titles)

Percentage of Cluster of Differentiation (CD) Marker

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Dose Escalation Study to Investigate the Safety, Pharmacokinetics, and Pharmacodynamics of GSK2849330 in Subjects With Advanced Her3-Positive Solid Tumors	NCT01966445	Cancer Neoplasms	GSK2849330	18 Years -	GlaxoSmithKline
Immuno Positron Emission Tomography Study of GSK2849330 in Subjects With Human Epidermal Growth Factor Receptor 3-Positive Solid Tumors	NCT02345174	Cancer Neoplasms	GSK2849330 89Zr-GSK2849330	18 Years -	GlaxoSmithKline
Dose Escalation Study to Investigate the Safety, Pharmacokinetics, and Pharmacodynamics of GSK2849330 in Subjects With Advanced Her3-Positive Solid Tumors	NCT01966445	Cancer Neoplasms	GSK2849330	18 Years -	GlaxoSmithKline

Spots Global Cancer Trial Database for gsk2849330

Every month we try and update this database with for gsk2849330 cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for gsk2849330

Every month we try and update this database with for gsk2849330 cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for gsk2849330 cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.