Clinical trial NCT01966445: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Cancer
Neoplasms
Keywords: GSK2849330
Oncology
First Time in Human
HER3
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2013-10-21
Enrollment: 29
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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).

Primary outcomes:
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)-Parts 1 and 2
timeFrame: Median of 6.143 weeks of drug exposure
measure: Number of Participants With Dose-limiting Toxicities (DLTs)-Parts 1 and 2
timeFrame: Up to 28 days
measure: Number of Participants With Grade Change From Baseline in Clinical Chemistry Data-Parts 1 and 2
timeFrame: Baseline and median of 6.143 weeks of drug exposure
measure: Number of Participants With Change From Baseline in Clinical Chemistry Data With Respect to Normal Range-Parts 1 and 2
timeFrame: Baseline and median of 6.143 weeks of drug exposure
measure: Number of Participants With Grade Change From Baseline in Hematology Data-Parts 1 and 2
timeFrame: Baseline and median of 6.143 weeks of drug exposure
measure: Number of Participants With Change From Baseline in Hematology Data With Respect to Normal Range-Parts 1 and 2
timeFrame: Baseline and median of 6.143 weeks of drug exposure
measure: Number of Participants With Change From Baseline in Urinalysis Data With Respect to Normal Range-Parts 1 and 2
timeFrame: Baseline and median of 6.143 weeks of drug exposure
measure: Number of Participants With Change From Baseline in Vital Signs-Parts 1 and 2
timeFrame: Baseline and median of 6.143 weeks of drug exposure
measure: Number of Participants With Abnormal Electrocardiogram (ECG) Findings-Parts 1 and 2
timeFrame: Median of 6.143 weeks of drug exposure
Secondary outcomes:
measure: Maximum Observed Plasma Concentration (Cmax) of GSK2849330-Part 1
timeFrame: Day 1 (pre-dose, 1 and 6 hours post-dose), Day 8, Day 15, Day 29, and every 12 weeks from first dose
measure: Cmax of GSK2849330-Part 2
timeFrame: Day 1 (pre-dose, 1 and 6 hours post-dose), Day 8, Day 15, Day 29, and every 12 weeks from first dose
measure: Time of Occurrence of Cmax (Tmax) for GSK2849330-Part 1
timeFrame: Day 1 (pre-dose, 1 and 6 hours post-dose), Day 8, Day 15, Day 29, and every 12 weeks from first dose
measure: Tmax for GSK2849330-Part 2
timeFrame: Day 1 (pre-dose, 1 and 6 hours post-dose), Day 8, Day 15, Day 29, and every 12 weeks from first dose
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
timeFrame: Day 1 (pre-dose, 1 and 6 hours post-dose), Day 8, Day 15, Day 29, and every 12 weeks from first dose
measure: AUC(0 to 168) and AUC(0 to 336) for GSK2849330-Part 2
timeFrame: Day 1 (pre-dose, 1 and 6 hours post-dose), Day 8, Day 15, Day 29, and every 12 weeks from first dose
measure: Serum HER3 From Tumor Tissue-Parts 1 and 2
timeFrame: Day 1 (pre-dose, 1 hour, 6 hours), Day 2, Day 8, Day 15, Day 29 and follow-up (28 days post last dose)
measure: Overall Response Rate (ORR)-Parts 1 and 2
timeFrame: Median of 6.143 weeks of drug exposure
measure: Number of Participants With Antibodies to GSK2849330 in Serum
timeFrame: Median of 6.143 weeks of drug exposure
measure: Percentage of Cluster of Differentiation (CD) Marker
timeFrame: Median of 6.143 weeks of drug exposure
Other outcomes:
Locations:
city: Aurora
country: United States
facility: GSK Investigational Site
state: Colorado
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: Salt Lake City
country: United States
facility: GSK Investigational Site
state: Utah
city: Heidelberg
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Melbourne
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Nedlands
country: Australia
facility: GSK Investigational Site
state: Western Australia
city: Amsterdam
country: Netherlands
facility: GSK Investigational Site
city: Amsterdam
country: Netherlands
facility: GSK Investigational Site
city: Groningen
country: Netherlands
facility: GSK Investigational Site
city: Groningen
country: Netherlands
facility: GSK Investigational Site
city: Nijmegen
country: Netherlands
facility: GSK Investigational Site
city: Nijmegen
country: Netherlands
facility: GSK Investigational Site
city: Rotterdam
country: Netherlands
facility: GSK Investigational Site
city: Rotterdam
country: Netherlands
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
affiliation: GlaxoSmithKline (for GlaxoSmithKline; Human Genome Sciences Inc., a GSK Company; Sirtris, a GSK Company; Stiefel, a GSK Company; ViiV Healthcare)
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.