Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01966445
Recruitment Status : Completed
First Posted : October 21, 2013
Results First Posted : July 1, 2019
Last Update Posted : July 1, 2019
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Tracking Information
First Submitted Date  ICMJE October 17, 2013
First Posted Date  ICMJE October 21, 2013
Results First Submitted Date  ICMJE August 30, 2018
Results First Posted Date  ICMJE July 1, 2019
Last Update Posted Date July 1, 2019
Actual Study Start Date  ICMJE November 26, 2013
Actual Primary Completion Date September 18, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 4, 2019)
  • Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)-Parts 1 and 2 [ Time Frame: Median of 6.143 weeks of drug exposure ]
    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.
  • Number of Participants With Dose-limiting Toxicities (DLTs)-Parts 1 and 2 [ Time Frame: Up to 28 days ]
    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.
  • Number of Participants With Grade Change From Baseline in Clinical Chemistry Data-Parts 1 and 2 [ Time Frame: Baseline and median of 6.143 weeks of drug exposure ]
    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.
  • Number of Participants With Change From Baseline in Clinical Chemistry Data With Respect to Normal Range-Parts 1 and 2 [ Time Frame: Baseline and median of 6.143 weeks of drug exposure ]
    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.
  • Number of Participants With Grade Change From Baseline in Hematology Data-Parts 1 and 2 [ Time Frame: Baseline and median of 6.143 weeks of drug exposure ]
    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.
  • Number of Participants With Change From Baseline in Hematology Data With Respect to Normal Range-Parts 1 and 2 [ Time Frame: Baseline and median of 6.143 weeks of drug exposure ]
    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.
  • Number of Participants With Change From Baseline in Urinalysis Data With Respect to Normal Range-Parts 1 and 2 [ Time Frame: Baseline and median of 6.143 weeks of drug exposure ]
    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.
  • Number of Participants With Change From Baseline in Vital Signs-Parts 1 and 2 [ Time Frame: Baseline and median of 6.143 weeks of drug exposure ]
    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.
  • Number of Participants With Abnormal Electrocardiogram (ECG) Findings-Parts 1 and 2 [ Time Frame: Median of 6.143 weeks of drug exposure ]
    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.
Original Primary Outcome Measures  ICMJE
 (submitted: October 17, 2013)
  • Number of subjects with adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: Part 1 and Part 2: From Day 1 up to 45 days or 5 half lives (whichever is longer) after last dose of study treatment ]
    SAEs assessed as related to study participation , study treatment or GSK concomitant medication must be recorded from the time a subject consents to participate in the study up to and including any follow-up contact
  • Dose-limiting toxicities (DLTs) [ Time Frame: Part 1 and Part 2: From Day 1 up to Day 29 ]
    An event will be considered a DLT if it occurs within the first 4 weeks (28 days) of treatment, and meets one of the protocol defined criteria unless it can be clearly established that the event is unrelated to treatment
  • Change in laboratory values [ Time Frame: Part 1 and Part 2: From Screening up to approximately 28 days after the last dose of study treatment ]
    Laboratory tests will include hematology, clinical chemistry and urinalysis parameters
  • Change in electrocardiograms (ECGs) [ Time Frame: Part 1 and Part 2: From Screening up to approximately 28 days after the last dose of study treatment ]
    Single 12-lead ECGs will be obtained at scheduled time points
  • Changes in vital signs [ Time Frame: Part 1 and Part 2: From Screening up to approximately 28 days after the last dose of study treatment ]
    Vital sign measurements will include systolic and diastolic blood pressure and pulse rate
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 4, 2019)
  • Maximum Observed Plasma Concentration (Cmax) of GSK2849330-Part 1 [ Time Frame: Day 1 (pre-dose, 1 and 6 hours post-dose), Day 8, Day 15, Day 29, and every 12 weeks from first dose ]
    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.
  • Cmax of GSK2849330-Part 2 [ Time Frame: Day 1 (pre-dose, 1 and 6 hours post-dose), Day 8, Day 15, Day 29, and every 12 weeks from first dose ]
    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.
  • Time of Occurrence of Cmax (Tmax) for GSK2849330-Part 1 [ Time Frame: Day 1 (pre-dose, 1 and 6 hours post-dose), Day 8, Day 15, Day 29, and every 12 weeks from first dose ]
    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.
  • Tmax for GSK2849330-Part 2 [ Time Frame: Day 1 (pre-dose, 1 and 6 hours post-dose), Day 8, Day 15, Day 29, and every 12 weeks from first dose ]
    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.
  • 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 [ Time Frame: Day 1 (pre-dose, 1 and 6 hours post-dose), Day 8, Day 15, Day 29, and every 12 weeks from first dose ]
    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.
  • AUC(0 to 168) and AUC(0 to 336) for GSK2849330-Part 2 [ Time Frame: Day 1 (pre-dose, 1 and 6 hours post-dose), Day 8, Day 15, Day 29, and every 12 weeks from first dose ]
    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.
  • Serum HER3 From Tumor Tissue-Parts 1 and 2 [ Time Frame: Day 1 (pre-dose, 1 hour, 6 hours), Day 2, Day 8, Day 15, Day 29 and follow-up (28 days post last dose) ]
    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.
  • Overall Response Rate (ORR)-Parts 1 and 2 [ Time Frame: Median of 6.143 weeks of drug exposure ]
    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.
  • Number of Participants With Antibodies to GSK2849330 in Serum [ Time Frame: Median of 6.143 weeks of drug exposure ]
    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.
  • Percentage of Cluster of Differentiation (CD) Marker [ Time Frame: Median of 6.143 weeks of drug exposure ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: October 17, 2013)
  • PK parameter values for GSK2849330 [ Time Frame: Part 1 and Part 2: Scheduled timepoints from Day 1 until 45 days or 5 half lives (whichever is longer) after last dose of study treatment ]
  • Total and phospho-HER3 from tumor tissue [ Time Frame: Part 1 and Part 2: Screening (pre-treatment) and either Day 15 or Day 22 depending on dosing schedule ]
    Tumor biopsies will be obtained and analyzed for total and phospho-HER3
  • Antibodies to GSK2849330 assessed in serum [ Time Frame: Part 1 and Part 2: Scheduled timepoints from Day 1 until 45 days or 5 half lives (whichever is longer) after last dose of study treatment ]
  • Overall response rate [ Time Frame: Part 2: Screening and Every 8 or 9 weeks from the first dose ]
    Response evaluations (either complete response [CR] or partial response [PR]) will be determined according to the definitions established in the Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
  • Tumor markers [ Time Frame: Part 2: Day 1 and Every 8 or 9 weeks from the first dose. ]
    Tumor markers will be collected as applicable to the subject's primary tumor type
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Dose Escalation Study to Investigate the Safety, Pharmacokinetics, and Pharmacodynamics of GSK2849330 in Subjects With Advanced Her3-Positive Solid Tumors
Official Title  ICMJE 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
Brief Summary 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Cancer
  • Neoplasms
Intervention  ICMJE Biological: GSK2849330
Solution containing 100 mg/millilter (mL) GSK2849330 for intravenous infusion
Study Arms  ICMJE
  • Experimental: GSK2849330 Part 1
    1 hour infusion administered intravenously at intervals of one week or more (escalating doses).
    Intervention: Biological: GSK2849330
  • Experimental: GSK2849330 Part 2
    Intravenous infusion administered at the dose and schedule established in Part 1
    Intervention: Biological: GSK2849330
Publications * Drilon A, Somwar R, Mangatt BP, Edgren H, Desmeules P, Ruusulehto A, Smith RS, Delasos L, Vojnic M, Plodkowski AJ, Sabari J, Ng K, Montecalvo J, Chang J, Tai H, Lockwood WW, Martinez V, Riely GJ, Rudin CM, Kris MG, Arcila ME, Matheny C, Benayed R, Rekhtman N, Ladanyi M, Ganji G. Response to ERBB3-Directed Targeted Therapy in NRG1-Rearranged Cancers. Cancer Discov. 2018 Jun;8(6):686-695. doi: 10.1158/2159-8290.CD-17-1004. Epub 2018 Apr 2.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: October 17, 2017)
29
Original Estimated Enrollment  ICMJE
 (submitted: October 17, 2013)
155
Actual Study Completion Date  ICMJE September 18, 2017
Actual Primary Completion Date September 18, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Netherlands,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01966445
Other Study ID Numbers  ICMJE 117158
2013-001699-39 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party GlaxoSmithKline
Study Sponsor  ICMJE GlaxoSmithKline
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: GSK Clinical Trials GlaxoSmithKline
Study Director: GSK Clinical Trials GlaxoSmithKline (for GlaxoSmithKline; Human Genome Sciences Inc., a GSK Company; Sirtris, a GSK Company; Stiefel, a GSK Company; ViiV Healthcare)
PRS Account GlaxoSmithKline
Verification Date April 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP