Description:
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.
Title
- Brief Title: Dose Escalation Study to Investigate the Safety, Pharmacokinetics, and Pharmacodynamics of GSK2849330 in Subjects With Advanced Her3-Positive Solid Tumors
- Official Title: 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
Clinical Trial IDs
- ORG STUDY ID:
117158
- SECONDARY ID:
2013-001699-39
- NCT ID:
NCT01966445
Conditions
Interventions
| Drug | Synonyms | Arms |
|---|
| GSK2849330 | | GSK2849330 Part 1 |
Purpose
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.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| GSK2849330 Part 1 | Experimental | 1 hour infusion administered intravenously at intervals of one week or more (escalating doses). | |
| GSK2849330 Part 2 | Experimental | Intravenous infusion administered at the dose and schedule established in Part 1 | |
Eligibility Criteria
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).
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | 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 |
| Safety Issue: | |
| Description: | 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. |
Secondary Outcome Measures
| Measure: | 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 |
| Safety Issue: | |
| Description: | 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. |
| Measure: | 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 |
| Safety Issue: | |
| Description: | 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. |
| Measure: | 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 |
| Safety Issue: | |
| Description: | 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. |
| Measure: | 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 |
| Safety Issue: | |
| Description: | 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. |
| Measure: | 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 |
| Safety Issue: | |
| Description: | 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. |
| Measure: | 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 |
| Safety Issue: | |
| Description: | 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. |
| Measure: | 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) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Overall Response Rate (ORR)-Parts 1 and 2 |
| Time Frame: | Median of 6.143 weeks of drug exposure |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Number of Participants With Antibodies to GSK2849330 in Serum |
| Time Frame: | Median of 6.143 weeks of drug exposure |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Percentage of Cluster of Differentiation (CD) Marker |
| Time Frame: | Median of 6.143 weeks of drug exposure |
| Safety Issue: | |
| Description: | 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. |
Details
| Phase: | Phase 1 |
| Primary Purpose: | Interventional |
| Overall Status: | Completed |
| Lead Sponsor: | GlaxoSmithKline |
Trial Keywords
- GSK2849330
- Oncology
- First Time in Human
- HER3
Last Updated
July 1, 2019
