Study of a Combination of GSK1795091 and Immunotherapies in Subjects With Advanced Solid Tumors

• ClinicalTrials.gov Identifier: NCT03447314
• Recruitment Status: Completed
• First Posted: February 27, 2018
• Results First Posted: July 20, 2021
• Last Update Posted: May 3, 2023
• Sponsor: GlaxoSmithKline
• Collaborator: Iqvia Pty Ltd
• Information provided by (Responsible Party): GlaxoSmithKline

Study Description

Brief Summary:

GSK1795091 is being developed for administration in combination with other immune system modulators for the treatment of cancers. The study will be conducted in two parts. In Part 1, dose escalation will be performed to identify combination dose levels comprising GSK1795091 with either 24 milligrams (mg) GSK3174998 (Part 1a), 80 mg GSK3359609 (Part 1b), or 200 mg pembrolizumab (Part 1c). One dose level of GSK3174998, GSK3359609, or pembrolizumab with up to 5 dose levels of GSK1795091 are planned for evaluation. In Part 2 (dose-expansion), subjects will receive a single dose level of GSK1795091 as identified based on data from Part 1, in combination with either GSK3174998, GSK3359609, or pembrolizumab.

Condition or disease	Intervention/treatment	Phase
Neoplasms	Drug: GSK1795091; Drug: GSK3174998; Drug: GSK3359609; Drug: Pembrolizumab	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 54 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: In Part 1, one dose level of GSK3174998, GSK3359609, or pembrolizumab with up to 5 dose levels of GSK1795091 are planned for evaluation. Sequential cohorts will be enrolled and dose escalation (or de-escalation) will proceed according to Neuenschwander-Continual Reassessment Method (N-CRM design). In Part 2, subjects will be administered GSK1795091 in combination with either 24 mg GSK3174998, 80 mg GSK3359609, or 200 mg pembrolizumab at a dose identified in Part 1.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I, Open-Label Study of GSK1795091 Administered in Combination With Immunotherapies in Participants With Advanced Solid Tumors
• Actual Study Start Date: March 26, 2018
• Actual Primary Completion Date: July 1, 2020
• Actual Study Completion Date: March 11, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part 1a: 50ng GSK1795091 + 24mg GSK3174998; Participants will be administered GSK1795091 50 nanogram (ng) intravenously (IV) on Days 1 and 8 followed by once weekly administration of GSK1795091 50 ng IV in combination with GSK3174998 24 milligram (mg) administered at 3-week intervals (Q3W) via the IV route until Week 12. From Week 12 onwards, GSK1795091 50 ng IV will be administered in combination with GSK3174998 24 mg at Q3W interval.	Drug: GSK1795091; GSK1795091 will be available as solution for injection; Drug: GSK3174998; GSK3174998 will be available as lyophilized powder to be reconstituted for infusion.
Experimental: Part 1a: 100ng GSK1795091 + 24mg GSK3174998; Participants will be administered GSK1795091 100 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 100 ng IV in combination with GSK3174998 24 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 100 ng IV will be administered in combination with GSK3174998 24 mg at Q3W interval.	Drug: GSK1795091; GSK1795091 will be available as solution for injection; Drug: GSK3174998; GSK3174998 will be available as lyophilized powder to be reconstituted for infusion.
Experimental: Part 1a: 150ng GSK1795091 + 24mg GSK3174998; Participants will be administered GSK1795091 150 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 150 ng IV in combination with GSK3174998 24 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 150 ng IV will be administered in combination with GSK3174998 24 mg at Q3W interval.	Drug: GSK1795091; GSK1795091 will be available as solution for injection; Drug: GSK3174998; GSK3174998 will be available as lyophilized powder to be reconstituted for infusion.
Experimental: Part 1a: 200ng GSK1795091 + 24mg GSK3174998; Participants will be administered GSK1795091 200 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 200 ng IV in combination with GSK3174998 24 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 200 ng IV will be administered in combination with GSK3174998 24 mg at Q3W interval.	Drug: GSK1795091; GSK1795091 will be available as solution for injection; Drug: GSK3174998; GSK3174998 will be available as lyophilized powder to be reconstituted for infusion.
Experimental: Part 1a: 250ng GSK1795091 + 24mg GSK3174998; Participants will be administered GSK1795091 250 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 250 ng IV in combination with GSK3174998 24 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 250 ng IV will be administered in combination with GSK3174998 24 mg at Q3W interval.	Drug: GSK1795091; GSK1795091 will be available as solution for injection; Drug: GSK3174998; GSK3174998 will be available as lyophilized powder to be reconstituted for infusion.
Experimental: Part 1b: 50ng GSK1795091 + 80mg GSK3359609; Participants will be administered GSK1795091 50 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 50 ng IV in combination with GSK3359609 80 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 50 ng IV will be administered in combination with GSK3359609 80 mg at Q3W interval.	Drug: GSK1795091; GSK1795091 will be available as solution for injection; Drug: GSK3359609; GSK3359609 will be available as solution for infusion.
Experimental: Part 1b: 100ng GSK1795091 + 80mg GSK3359609; Participants will be administered GSK1795091 100 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 100 ng IV in combination with GSK3359609 80 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 100 ng IV will be administered in combination with GSK3359609 80 mg at Q3W interval.	Drug: GSK1795091; GSK1795091 will be available as solution for injection; Drug: GSK3359609; GSK3359609 will be available as solution for infusion.; Drug: Pembrolizumab; Pembrolizumab will be available as solution for infusion or lyophilized powder for reconstitution.
Experimental: Part 1b: 150ng GSK1795091 + 80mg GSK3359609; Participants will be administered GSK1795091 150 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 150 ng IV in combination with GSK3359609 80 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 150 ng IV will be administered in combination with GSK3359609 80 mg at Q3W interval.	Drug: GSK1795091; GSK1795091 will be available as solution for injection; Drug: GSK3359609; GSK3359609 will be available as solution for infusion.
Experimental: Part 1b: 200ng GSK1795091 + 80mg GSK3359609; Participants will be administered GSK1795091 200 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 200 ng IV in combination with GSK3359609 80 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 200 ng IV will be administered in combination with GSK3359609 80 mg at Q3W interval.	Drug: GSK1795091; GSK1795091 will be available as solution for injection; Drug: GSK3359609; GSK3359609 will be available as solution for infusion.
Experimental: Part 1b: 250ng GSK1795091 + 80mg GSK3359609; Participants will be administered GSK1795091 250 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 250 ng IV in combination with GSK3359609 80 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 250 ng IV will be administered in combination with GSK3359609 80 mg at Q3W interval.	Drug: GSK1795091; GSK1795091 will be available as solution for injection; Drug: GSK3359609; GSK3359609 will be available as solution for infusion.
Experimental: Part 1c: 50ng GSK1795091 + 200mg Pembrolizumab; Participants will be administered GSK1795091 50 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 50 ng IV in combination with pembrolizumab 200 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 50 ng IV will be administered in combination with pembrolizumab 200 mg at Q3W interval.	Drug: GSK1795091; GSK1795091 will be available as solution for injection; Drug: Pembrolizumab; Pembrolizumab will be available as solution for infusion or lyophilized powder for reconstitution.
Experimental: Part 1c: 100ng GSK1795091 + 200mg Pembrolizumab; Participants will be administered GSK1795091 100 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 100 ng IV in combination with pembrolizumab 200 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 100 ng IV will be administered in combination with pembrolizumab 200 mg at Q3W interval.	Drug: GSK1795091; GSK1795091 will be available as solution for injection; Drug: Pembrolizumab; Pembrolizumab will be available as solution for infusion or lyophilized powder for reconstitution.
Experimental: Part 1c: 150ng GSK1795091 + 200mg Pembrolizumab; Participants will be administered GSK1795091 150 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 150 ng IV in combination with pembrolizumab 200 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 150 ng IV will be administered in combination with pembrolizumab 200 mg at Q3W interval.	Drug: GSK1795091; GSK1795091 will be available as solution for injection; Drug: Pembrolizumab; Pembrolizumab will be available as solution for infusion or lyophilized powder for reconstitution.
Experimental: Part 1c: 200ng GSK1795091 + 200mg Pembrolizumab; Participants will be administered GSK1795091 200 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 200 ng IV in combination with pembrolizumab 200 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 200 ng IV will be administered in combination with pembrolizumab 200 mg at Q3W interval.	Drug: GSK1795091; GSK1795091 will be available as solution for injection; Drug: Pembrolizumab; Pembrolizumab will be available as solution for infusion or lyophilized powder for reconstitution.
Experimental: Part 1c: 250ng GSK1795091 + 200mg Pembrolizumab; Participants will be administered GSK1795091 250 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 250 ng IV in combination with pembrolizumab 200 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 250 ng IV will be administered in combination with pembrolizumab 200 mg at Q3W interval.	Drug: GSK1795091; GSK1795091 will be available as solution for injection; Drug: Pembrolizumab; Pembrolizumab will be available as solution for infusion or lyophilized powder for reconstitution.
Experimental: Part 2a: GSK1795091 + 24 mg GSK3174998; Participants will be administered GSK1795091 at a dose identified in Part 1 along with GSK3174998 24 mg.	Drug: GSK1795091; GSK1795091 will be available as solution for injection; Drug: GSK3174998; GSK3174998 will be available as lyophilized powder to be reconstituted for infusion.
Experimental: Part 2b: GSK1795091 + 80 mg GSK3359609; Participants will be administered GSK1795091 at a dose identified in Part 1 along with GSK3359609 80 mg.	Drug: GSK1795091; GSK1795091 will be available as solution for injection; Drug: GSK3359609; GSK3359609 will be available as solution for infusion.
Experimental: Part 2c: GSK1795091 + 200 mg Pembrolizumab; Participants will be administered GSK1795091 at a dose identified in Part 1 along with pembrolizumab 200 mg.	Drug: GSK1795091; GSK1795091 will be available as solution for injection; Drug: Pembrolizumab; Pembrolizumab will be available as solution for infusion or lyophilized powder for reconstitution.

Outcome Measures

Primary Outcome Measures :

1. Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs (STEAEs) [ Time Frame: Up to 27 months ]
   An adverse event is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. A serious adverse event is defined as any untoward medical occurrence that, at any dose; results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgement or associated with liver injury and impaired liver function. TEAEs are defined as adverse events that started or worsened in severity on or after the first dose of study medication. All Treated Population consisted of all participants who received at least 1 dose of GSK1795091, GSK3174998, GSK3359609, or pembrolizumab.
2. Part 2: Number of Participants With TEAEs and STEAEs [ Time Frame: Up to 27 months ]
   An adverse event is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. A serious adverse event is defined as any untoward medical occurrence that, at any dose; results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgement or associated with liver injury and impaired liver function. TEAEs are defined as adverse events that started or worsened in severity on or after the first dose of study medication.
3. Part 1: Number of Participants With Dose-limiting Toxicity (DLT) [ Time Frame: 42 days ]
   An adverse event was considered to be a DLT if it was considered by investigator to be clinically relevant and attributed (definitely, probably or possibly) to study treatment and met one of the criteria: hematologic toxicity-Grade4 neutropenia of >7 days duration or febrile neutropenia, Grade 4 anemia, Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding as described in Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, non-hematologic toxicity-Grade 4 toxicity, Grade 3 toxicity that does not resolve to <=Grade 1 or Baseline within 14 days despite optimal supportive care, alanine aminotransferase (ALT) >=5 times upper limit of normal (ULN), ALT >=3 times ULN persists for >=4 weeks, ALT >=3 times ULN and bilirubin >=2 times ULN (>35 percent [%] direct bilirubin), ALT >=3 times ULN and international normalized ratio (INR) >1.5, ALT >=3 times ULN associated with symptoms (new or worsening) believed to be related to liver injury or hypersensitivity.
4. Part 1: Number of Participants With TEAEs Leading to Discontinuation [ Time Frame: Up to 2 years ]
   An adverse event is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. TEAEs are defined as adverse events that started or worsened in severity on or after the first dose of study medication.
5. Part 2: Number of Participants With TEAEs Leading to Discontinuation [ Time Frame: Up to 2 years ]
   An adverse event is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. TEAEs are defined as adverse events that started or worsened in severity on or after the first dose of study medication.
6. Part 1: Number of Participants With TEAEs Leading to Dose Reductions or Dose Delays [ Time Frame: Up to 2 years ]
   An adverse event is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. TEAEs are defined as adverse events that started or worsened in severity on or after the first dose of study medication.
7. Part 2: Number of Participants With TEAEs Leading to Dose Reductions or Dose Delays [ Time Frame: Up to 2 years ]
   An adverse event is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. TEAEs are defined as adverse events that started or worsened in severity on or after the first dose of study medication.
8. Part 1: Number of Participants With Change From Baseline in Hematology Parameters With Respect to the Normal Range [ Time Frame: Baseline (Day 1: Pre-dose) and up to 2 years ]
   Blood samples were collected for the analysis of following hematology parameters: neutrophils (Neutro), lymphocytes (lympho), monocytes (Mono), eosinophils (Eosino), basophils (Baso), hemoglobin (Hb), hematocrit (Hct), erythrocytes (Erythro), erythrocyte mean corpuscular volume (EMCV), erythrocyte mean corpuscular hemoglobin (EMCH) and platelet count (PC). Baseline value was the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Data was categorized as decrease to low (D to L) (value below lower limit of normal range [LNR]) and increase to high (I to H) (value above upper LNR). Participants were counted twice if participant had both decreased to low and increased to high within an assessment. Data for worst-case on therapy for categories decrease to low and increase to high is presented.
9. Part 2: Number of Participants With Change From Baseline in Hematology Parameters With Respect to the Normal Range [ Time Frame: Baseline (Day 1: Pre-dose) and up to 2 years ]
   Blood samples were planned to be collected for the analysis of following hematology parameters: neutrophils, lymphocytes, monocytes, eosinophils, basophils, hemoglobin, hematocrit, erythrocytes, erythrocyte mean corpuscular volume, erythrocyte mean corpuscular hemoglobin and platelet count.
10. Part 1: Number of Participants With Change From Baseline in Chemistry Parameters With Respect to the Normal Range [ Time Frame: Baseline (Day 1: Pre-dose) and up to 2 years ]
    Blood samples were collected for the analysis of following chemistry parameters: urea, creatinine (Cr), glucose (Glu), potassium (Pot), sodium (Sod), calcium (Cal), aspartate aminotransferase (AST), ALT, alkaline phosphatase (ALP), bilirubin (Bil), direct bilirubin (D.Bil), protein, albumin (Alb), C-reactive protein (CRP) and Creatinine Clearance (CrCl). Baseline value was the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Data was categorized as decrease to low (value below the lower LNR), and increase to high (value above the upper LNR). Participants were counted twice if the participant had both decreased to low and increased to high within an assessment. Data for worst case on therapy for categories decrease to low and increase to high is presented.
11. Part 2: Number of Participants With Change From Baseline in Chemistry Parameters With Respect to the Normal Range [ Time Frame: Baseline (Day 1: Pre-dose) and up to 2 years ]
    Blood samples were planned to be collected for the analysis of following chemistry parameters: urea, creatinine, glucose, potassium, sodium, calcium, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, bilirubin, direct bilirubin, protein, albumin, C-reactive protein and Creatinine Clearance.
12. Part 1: Number of Participants With Worst Case Urinalysis Results Relative to Normal Range Criteria [ Time Frame: Up to 2 years ]
    Urine samples were collected for the analysis of following urinalysis parameters: glucose (Glu), protein (Pro), occult blood (OB), ketones, potential of hydrogen (pH) and specific gravity (SpGr) by dipstick method. The dipstick test gives results in a semi-quantitative manner. Urine specific gravity is a measure of the concentration of solutes in the urine and provides information on the kidney's ability to concentrate urine. The reference range is 1.002-1.030. Urine pH is an acid-base measurement. Normal urine has a slightly acid pH (5.0 - 6.0). Data was categorized as decrease to low (value below the lower LNR) and increase to high (value above the upper LNR). Participants were counted twice if the participant had both decreased to low and increased to high within an assessment. Data for worst-case on therapy for categories decrease to low and increase to high is presented.
13. Part 2: Number of Participants With Worst Case Urinalysis Results Relative to Normal Range Criteria [ Time Frame: Up to 2 years ]
    Urine samples were planned to be collected for the analysis of following urine parameters: glucose, protein, occult blood, ketones, potential of hydrogen and specific gravity by dipstick method.
14. Part 1: Number of Participants With Increase From Baseline in Vital Signs According to Markedly Abnormal Criteria [ Time Frame: Up to 2 years ]
    Vital signs including systolic blood pressure (SBP), diastolic BP (DBP), pulse rate (PR) and body temperature (BT) were measured in a semi-supine position after 5 minutes rest for the participants. SBP: Category1 (>140 and <161 millimeter of mercury[mmHg]), Category 2 (>=161 and <181 mmHg), Category3 (>=181 mmHg); DBP: Category1 (>90 and <101 mmHg), Category 2 (>=101 and <111 mmHg), Category 3 (>=111 mmHg); PR: Category 1 (>101 and <116 beats per minutes[bpm]), Category 2 (>=116 and <131 bpm), Category 3 (>=131 bpm); BT: Category 1 (>38.0 and <38.6 degrees Celsius), Category 2 (>=38.6 and <39.1 degrees Celsius), Category 3 (>=39.1 degrees Celsius). Data for any increase in category at worst case on therapy is presented.
15. Part 2: Number of Participants With Vital Signs Any Increases From Baseline According to Markedly Abnormal Criteria [ Time Frame: Up to 2 years ]
    Vital signs including SBP, DBP, pulse rate and body temperature were planned to be measured in a semi-supine position after 5 minutes rest for the participants.
16. Part 1: Number of Participants With Any Decrease From Baseline in Vital Sign According to Markedly Abnormal Criteria [ Time Frame: Up to 2 years ]
    Vital signs including SBP, DBP and pulse rate were measured in a semi-supine position after 5 minutes rest for the participants. For SBP: a decrease in Category was defined as <80 mmHg decrease from Baseline; DBP: decrease defined as Category (<50 mmHg decrease from Baseline); pulse rate: decrease defined as Category (<45 bpm decrease from Baseline). Data for decrease in category at worst case on therapy is presented.
17. Part 2: Number of Participants With Vital Signs Any Decreases From Baseline According to Markedly Abnormal Criteria [ Time Frame: Up to 2 years ]
    Vital signs including SBP, DBP and pulse rate were planned to be measured in a semi-supine position after 5 minutes rest for the participants.
18. Part 1: Number of Participants With Any Increase From Baseline in Corrected QT Interval Using Fredericia's Formula (QTcF) According to Markedly Abnormal Criteria [ Time Frame: Up to 2 years ]
    12-lead electrocardiogram (ECG) was obtained at indicated time point using an automated ECG machine that measured QTcF interval. QTc parameters were graded according to National Cancer Institute - CTCAE version 4.0. Grade 1 (>450 milliseconds [msec]), Grade 2 (>480 msec), Grade 3 (>500 msec). An increase is defined as an increase in CTCAE grade relative to Baseline grade. Data for any grade increase at worst case on therapy is presented.
19. Part 2: Number of Participants With Any QTcF Interval Increases From Baseline According to Markedly Abnormal Criteria [ Time Frame: Up to 2 years ]
    12-lead ECG was planned to be performed to measure QTcF interval.

Secondary Outcome Measures :

1. Part 1: Objective Response Rate [ Time Frame: Up to 47 months and 13 days ]
   Objective response rate is defined as the percentage of participants achieving a confirmed best overall response of complete response (CR) or partial response (PR) evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1, where CR=Disappearance of all target lesions. Any pathological lymph nodes must be <10 millimeters (mm) in the short axis. 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.
2. Part 2: Objective Response Rate [ Time Frame: Up to 47 months and 13 days ]
   Objective response rate is defined as the percentage of participants achieving a confirmed best overall response of CR or PR evaluated using RECIST v 1.1, where CR=Disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis. 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.
3. Part 1: Disease Control Rate [ Time Frame: Up to 47 months and 13 days ]
   Disease control rate is defined as the percentage of participants with a confirmed best overall response of CR or PR or at least 12 weeks of stable disease per RECIST v 1.1.
4. Part 2: Disease Control Rate [ Time Frame: Up to 47 months and 13 days ]
   Disease control rate is defined as the percentage of participants with a confirmed best overall response of CR or PR or at least 12 weeks of stable disease per RECIST v 1.1.
5. Part 1: Time to Response [ Time Frame: Up to 47 months and 13 days ]
   Time to response is defined as the time from the date of first dose to the date of the first documented evidence of response (PR or CR).
6. Part 2: Time to Response [ Time Frame: Up to 47 months and 13 days ]
   Time to response is defined as the time from the date of first dose to the date of the first documented evidence of response (PR or CR).
7. Part 1: Duration of Response [ Time Frame: Up to 47 months and 13 days ]
   Duration of response is defined as the time from first documented evidence of CR or PR until disease progression or death due to any cause among participants who achieve an overall response (that is., a confirmed best overall response of CR or PR) by RECIST v 1.1.
8. Part 2: Duration of Response [ Time Frame: Up to 47 months and 13 days ]
   Duration of response is defined as the time from first documented evidence of CR or PR until disease progression or death due to any cause among participants who achieve an overall response (that is., a confirmed best overall response of CR or PR) by RECIST v 1.1.
9. Part 1: Progression-free Survival [ Time Frame: Up to 47 months and 13 days ]
   Progression-free survival is defined as the interval of time (in months) between the date of first dose to the date of disease progression according to clinical or radiological assessment or death due to any causes, whichever occurs earliest. PFS was determined according to RECIST version 1.1. Progressive disease is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started.
10. Part 2: Progression-free Survival [ Time Frame: Up to 47 months and 13 days ]
    Progression-free survival is defined as the interval of time (in months) between the date of first dose to the date of disease progression according to clinical or radiological assessment or death due to any causes, whichever occurs earliest by RECIST v 1.1. Progressive disease is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started.
11. Part 1: Overall Survival [ Time Frame: Up to 47 months and 13 days ]
    Overall survival is defined as time from the date of first dose of study treatment (whichever investigational drug administered first) to the date of death due to any cause.
12. Part 2: Overall Survival [ Time Frame: Up to 47 months and 13 days ]
    Overall survival is defined as time from the date of first dose of study treatment (whichever investigational drug administered first) to the date of death due to any cause.
13. Part 1a: Plasma Concentration of GSK1795091 [ Time Frame: Day 1: Pre-dose, 10 minutes, 2, 4, 6, 24 hours; Day 8: Pre-dose, 10 minutes, 4 hours; Days 15 and 57: Pre-dose, 10 minutes, 4, 24 hours; Day 22: Pre-dose; Day 64: Pre-dose, 10 minutes; Days 78, 162, 246, 414 and 498: 10 minutes post-dose ]
    Blood samples were collected at indicated time points for the determination of plasma concentration of GSK1795091. Pharmacokinetic (PK) Population consisted of all participants from the All Treated population for whom a PK sample was obtained, analyzed, measurable, and valid.
14. Part 1b: Plasma Concentration of GSK1795091 [ Time Frame: Day 1: Pre-dose, 10 minutes, 2, 4, 6, 24 hours; Day 8: Pre-dose, 10 minutes, 4 hours; Days 15 and 57: Pre-dose, 10 minutes, 4, 24 hours; Day 22: Pre-dose; Day 64: Pre-dose, 10 minutes; Day 78: 10 minutes post-dose ]
    Blood samples were collected at indicated time points for the determination of plasma concentration of GSK1795091.
15. Part 1c: Plasma Concentration of GSK1795091 [ Time Frame: Day 1: Pre-dose, 10 minutes, 2, 4, 6, 24 hours; Day 8: Pre-dose, 10 minutes, 4 hours; Days 15 and 57: Pre-dose, 10 minutes, 4, 24 hours; Day 22: Pre-dose; Day 64: Pre-dose, 10 minutes; Day 78: 10 minutes post-dose ]
    Blood samples were collected at indicated time points for the determination of plasma concentration of GSK1795091.
16. Part 1a: Maximum Plasma Concentration (Cmax) of GSK1795091 [ Time Frame: Day 1: Pre-dose, 10 minutes, 2, 4, 6, 24 hours; Day 8: Pre-dose, 10 minutes, 4 hours; Days 15 and 57: Pre-dose, 10 minutes, 4, 24 hours; Day 22: Pre-dose; Day 64: Pre-dose, 10 minutes; Days 78, 162, 246, 414 and 498: 10 minutes post-dose ]
    Blood samples were collected at indicated time points for the determination of Cmax of GSK1795091.
17. Part 1b: Cmax of GSK1795091 [ Time Frame: Day 1: Pre-dose, 10 minutes, 2, 4, 6, 24 hours; Day 8: Pre-dose, 10 minutes, 4 hours; Days 15 and 57: Pre-dose, 10 minutes, 4, 24 hours; Day 22: Pre-dose; Day 64: Pre-dose, 10 minutes; Day 78: 10 minutes post-dose ]
    Blood samples were collected at indicated time points for the determination of Cmax of GSK1795091.
18. Part 1c: Cmax of GSK1795091 [ Time Frame: Day 1: Pre-dose, 10 minutes, 2, 4, 6, 24 hours; Day 8: Pre-dose, 10 minutes, 4 hours; Days 15 and 57: Pre-dose, 10 minutes, 4, 24 hours; Day 22: Pre-dose; Day 64: Pre-dose, 10 minutes; Day 78: 10 minutes post-dose ]
    Blood samples were collected at indicated time points for the determination of Cmax of GSK1795091.
19. Part 1a: Area Under the Concentration-time Curve Over the Dosing Interval (AUC[0-tau]) GSK1795091 [ Time Frame: Day 1: Pre-dose, 10 minutes, 2, 4, 6, 24 hours; Day 8: Pre-dose, 10 minutes, 4 hours; Days 15 and 57: Pre-dose, 10 minutes, 4, 24 hours; Day 22: Pre-dose; Day 64: Pre-dose, 10 minutes; Days 78, 162, 246, 414 and 498: 10 minutes post-dose ]
    Blood samples were collected at indicated time points for the determination of AUC(0-tau) of GSK1795091.
20. Part 1b: AUC(0-tau) GSK1795091 [ Time Frame: Day 1: Pre-dose, 10 minutes, 2, 4, 6, 24 hours; Day 8: Pre-dose, 10 minutes, 4 hours; Days 15 and 57: Pre-dose, 10 minutes, 4, 24 hours; Day 22: Pre-dose; Day 64: Pre-dose, 10 minutes; Day 78: 10 minutes post-dose ]
    Blood samples were collected at indicated time points for the determination of AUC(0-tau) of GSK1795091.
21. Part 1c: AUC(0-tau) GSK1795091 [ Time Frame: Day 1: Pre-dose, 10 minutes, 2, 4, 6, 24 hours; Day 8: Pre-dose, 10 minutes, 4 hours; Days 15 and 57: Pre-dose, 10 minutes, 4, 24 hours; Day 22: Pre-dose; Day 64: Pre-dose, 10 minutes; Day 78: 10 minutes post-dose ]
    Blood samples were collected at indicated time points for the determination of AUC(0-tau) of GSK1795091.
22. Part 1a: Predose Concentration (Cpre) of GSK1795091 [ Time Frame: Days 1, 8, 15, 22, 57, 64, 78, 162, 246, 414 and 498: Pre-dose ]
    Blood samples were collected at indicated time points for the determination of Cpre of GSK1795091.
23. Part 1b: Cpre of GSK1795091 [ Time Frame: Days 1, 8, 15, 22, 57, 64 and 78: Pre-dose ]
    Blood samples were collected at indicated time points for the determination of Cpre of GSK1795091.
24. Part 1c: Cpre of GSK1795091 [ Time Frame: Days 1, 8, 15, 22, 57, 64 and 78: Pre-dose ]
    Blood samples were collected at indicated time points for the determination of Cpre of GSK1795091.
25. Part 1a: Number of Participants With Present Antidrug Antibody (ADA) Against GSK3174998 [ Time Frame: Up to 27 months ]
    Serum samples were collected at indicated time points and tested for the presence of antibodies that bind to GSK3174998. The presence of anti-GSK3174998 antibodies were assessed using a titered approach using validated immunoassays (that is, screening, confirmation, titer, and neutralizing antibody assay).
26. Part 1b: Number of Participants With the Present ADA Against GSK3359609 [ Time Frame: Up to 27 months ]
    Serum samples were collected at indicated time points and tested for the presence of antibodies that bind to GSK3359609. The presence of anti-GSK3359609 antibodies were assessed using a titered approach using validated immunoassays (that is, screening, confirmation, titer, and neutralizing antibody assay).
27. Part 1c: Number of Participants With the Present ADA Against Pembrolizumab [ Time Frame: Up to 27 months ]
    Serum samples were collected at indicated time points for the presence of antibodies that bind to pembrolizumab. The presence of anti-pembrolizumab antibodies were planned to be assessed using a titered approach using validated immunoassays (that is, screening, confirmation, titer, and neutralizing antibody assay).
28. Part 2a: Number of Participants With the Present ADA Against GSK3174998 [ Time Frame: Up to 2 years ]
    Serum samples were planned to be collected at indicated time points and tested for the presence of antibodies that bind to GSK3174998. The presence of anti-GSK3174998 antibodies were were planeed to be assessed using a titered approach using validated immunoassays (that is, screening, confirmation, titer, and neutralizing antibody assay).
29. Part 2b: Number of Participants With the Present ADA Against GSK3359609 [ Time Frame: Up to 2 years ]
    Serum samples were planned to be collected at indicated time points and tested for the presence of antibodies that bind to GSK3359609. The presence of anti-GSK3359609 antibodies were were planeed to be assessed using a titered approach using validated immunoassays (that is, screening, confirmation, titer, and neutralizing antibody assay).
30. Part 2c: Number of Participants With the Present ADA Against Pembrolizumab [ Time Frame: Up to 2 years ]
    Serum samples were planned to be collected at indicated time points and tested for the presence of antibodies that bind to pembrolizumab. The presence of anti-pembrolizumab antibodies were were planeed to be assessed using a titered approach using validated immunoassays (that is, screening, confirmation, titer, and neutralizing antibody assay).

Other Outcome Measures:

1. Part 1: Number of Participants With TEAEs and STEAEs Until End of the Study [ Time Frame: Up to 47 months and 13 days ]
   An adverse event is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. A serious adverse event is defined as any untoward medical occurrence that, at any dose; results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgement or associated with liver injury and impaired liver function. TEAEs are defined as adverse events that started or worsened in severity on or after the first dose of study medication.
2. Part 2: Number of Participants With TEAEs and STEAEs Until End of the Study [ Time Frame: Up to 47 months and 13 days ]
   An adverse event is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. A serious adverse event is defined as any untoward medical occurrence that, at any dose; results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgement or associated with liver injury and impaired liver function. TEAEs are defined as adverse events that started or worsened in severity on or after the first dose of study medication.
3. Part 1: Number of Participants With Worst-case Grade Change From Baseline in Hematology Parameters [ Time Frame: Up to 2 years ]
   Blood samples were collected for the analysis of following hematology parameters: neutrophils (Neutro), lymphocytes (lympho) (Low), hemoglobin (Hb) (Low) and platelet count (PC). The 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. Higher grade indicates greater severity and an increase in CTCAE grade was defined relative to the Baseline grade. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Data for any worst-case on therapy any grade increase has been presented.
4. Part 2: Number of Participants With Worst-case Grade Change From Baseline in Hematology Parameters [ Time Frame: Up to 2 years ]
   Blood samples were planned to be collected for the analysis of following hematology parameters: neutrophils (Neutro), lymphocytes (lympho), hemoglobin (Hb) and platelet count (PC).
5. Part 1: Number of Participants With Worst-case Grade Change From Baseline in Chemistry Parameters [ Time Frame: Up to 2 years ]
   Blood samples were collected for the analysis of following chemistry parameters: albumin (Hypo), ALP, ALT, AST, bilirubin, calcium (Hyper and Hypo), creatinine, glucose (Hyper and Hypo), potassium (Hyper and Hypo) and sodium (Hyper and Hypo). 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. Higher grade indicates greater severity and an increase in CTCAE grade was defined relative to the Baseline grade. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Data for any worst-case on therapy any grade increase has been presented.
6. Part 2: Number of Participants With Worst-case Grade Change From Baseline in Chemistry Parameters [ Time Frame: Up to 2 years ]
   Blood samples were planned to be collected for the analysis of following chemistry parameters: albumin, ALP, ALT, AST, bilirubin, calcium, creatinine, glucose, potassium and sodium.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Subject must be >=18 years of at the time of signing the informed consent.
• Histological documentation of advanced solid tumor.
• Archival tumor tissue obtained at any time from the initial diagnosis to study entry. Although a fresh biopsy obtained during screening is preferred, archival tumor specimen is acceptable if it is not feasible to obtain a fresh biopsy. Subjects enrolled in a PK/Pharmacodynamic Cohort must provide a fresh biopsy of a tumor lesion not previously irradiated during the screening period and must agree to provide at least one additional on-treatment biopsy.
• Disease that has progressed after standard therapies or for which standard therapy is otherwise unsuitable (example, intolerance).
• Measurable disease, that is, presenting with at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST version 1.1).
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.
• Life expectancy of at least 12 weeks.
• Adequate organ function.
• In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.
• Male or female subjects will be included. A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies: a) Not a woman of childbearing potential (WOCBP) OR b). A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 120 days after the last dose of study treatment.
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions specified.

Additional Inclusion criteria for Subjects in Part 2a (GSK3174998 expansion) and Part 2b (GSK3359609 expansion):

• Histological or cytological documentation of squamous cell carcinoma of the head and neck (SCCHN) (oral cavity, oropharynx, hypopharynx, or larynx) that is recurrent, locally advanced, or metastatic and is not amenable to curative treatment options, surgery or definitive chemoradiation therapy.
• Received, ineligible for, or otherwise unsuitable for platinum-based therapy and anti-Programmed death receptor-1 (PD-1)/programmed death-ligand 1 (PD-L1) therapy
• Received no more than 3 prior lines of systemic therapy for metastatic disease.

Additional Inclusion Criteria for Subjects in Part 2c (pembrolizumab expansion):

• Histological or cytological documentation of SCCHN (oral cavity, oropharynx, hypopharynx, or larynx) that is recurrent, locally advanced, or metastatic and is not amenable to curative treatment options, surgery or definitive chemoradiation therapy.
• Received no more than 2 prior lines of systemic therapy for metastatic disease.

Exclusion Criteria:

• Malignancy other than disease under study with the exception of those from which the subject has been disease-free for more than 2 years and not expected to affect the safety of the subject or the endpoints of the trial.
• Symptomatic central nervous system (CNS) metastases or asymptomatic CNS metastases that have required steroids within 2 weeks prior to first dose of study treatment.
• Active autoimmune disease that has required systemic disease modifying or immunosuppressive treatment within the last 2 years. Replacement therapy (example, thyroxine or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is permitted.
• Concurrent medical condition requiring the use of systemic immunosuppressive treatment within 28 days before the first dose of study treatment.
• Known human immunodeficiency virus infection.
• Current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis.
• Presence of Hepatitis B surface antigen (HBsAg) at screening or within 3 months prior to first dose of study treatment.
• Positive Hepatitis C test result at screening or within 3 months prior to first dose of study treatment.
• QT interval corrected for heart rate according to Fridericia's formula (QTcF) >450 milliseconds (msec) or QTcF >480 msec for subjects with bundle branch block
• Recent history (within the past 6 months) of acute diverticulitis, inflammatory bowel disease, intra-abdominal abscess, or gastrointestinal obstruction.
• Recent history of allergen desensitization therapy within 4 weeks of starting study treatment.
• History of severe hypersensitivity to monoclonal antibodies (mAbs).
• History or evidence of cardiovascular (CV) risk including any of the following: a) Recent (within the past 6 months) history of serious uncontrolled cardiac arrhythmia or clinically significant ECG abnormalities including second degree (Type II) or third degree atrioventricular block. b) Cardiomyopathy, myocardial infarction, acute coronary syndromes (including unstable angina pectoris), coronary angioplasty, stenting, or bypass grafting within the past 6 months before enrollment. c) Congestive heart failure (Class II, III, or IV) as defined by the New York Heart Association (NYHA) functional classification system. d) Recent (within the past 6 months) history of symptomatic pericarditis.
• History of idiopathic pulmonary fibrosis, pneumonitis, interstitial lung disease, or organizing pneumonia, or evidence of active, non-infectious pneumonitis.
• Recent history (within 6 months) of uncontrolled symptomatic ascites or pleural effusions.
• Any serious and/or unstable pre-existing medical, psychiatric disorder, or other condition that could interfere with the subject's safety, obtaining informed consent, or compliance to the study procedures.
• Is or has an immediate family member (example, spouse, parent/legal guardian, sibling or child) who is investigational site or sponsor staff directly involved with this trial, unless prospective Institutional Review Board (IRB) approval (by chair or designee) is given allowing exception to this criterion for a specific subject.
• Prior treatment with the following agents: a) OX40, inducible T-cell co-stimulator (ICOS) agonist at any time. b) Prior systemic or intratumoral therapy with TLR agonist. c) Anticancer therapy or investigational therapy within 30 days or 5 half-lives of the drug, whichever is shorter. d) Prior radiation therapy: permissible if at least 1 non-irradiated measurable lesion is available for assessment according to RECIST version 1.1 or if a solitary measurable lesion was irradiated, objective progression is documented. A wash out of at least 14 days before start of study treatment for radiation of any intended use to the extremities for bone metastases and 28 days for radiation to the chest, brain, or visceral organs is required.
• Prior allogeneic or autologous bone marrow transplantation or other solid organ transplantation.
• Toxicity from previous treatment including: a) Toxicity Grade >=3 related to prior immunotherapy and that lead to study treatment discontinuation. b) Toxicity related to prior treatment has not resolved to Grade <=1 (except alopecia, or endocrinopathy managed with replacement therapy).
• Received transfusion of blood products (including platelets or red blood cells) or administration of colony stimulating factors (including granulocyte colony-stimulating factor [G-CSF], granulocyte macrophage colony-stimulating factor, and recombinant erythropoietin) within 2 weeks before the first dose of study treatment.
• Major surgery <=4 weeks before the first dose of study treatment. Subjects must have also fully recovered from any surgery (major or minor) and/or its complications before initiating study treatment.
• Known drug or alcohol abuse.
• Receipt of any live vaccine within 4 weeks.

Additional Exclusion Criteria for Subjects in Part 2c

• Received prior anti-PD-1/PD-L1 therapy.

Contacts and Locations

Locations

United States, Massachusetts

GSK Investigational Site

Boston, Massachusetts, United States, 02215

United States, Missouri

GSK Investigational Site

Saint Louis, Missouri, United States, 63110

United States, Texas

GSK Investigational Site

Dallas, Texas, United States, 75230

GSK Investigational Site

Houston, Texas, United States, 77030

United States, Washington

GSK Investigational Site

Tacoma, Washington, United States, 98405

Canada, Ontario

GSK Investigational Site

Toronto, Ontario, Canada, M5G 2M9

Netherlands

GSK Investigational Site

Amsterdam, Netherlands, 1066 CX

Spain

GSK Investigational Site

Barcelona, Spain, 08035

Sponsors and Collaborators

GlaxoSmithKline

Iqvia Pty Ltd

Investigators

• Study Director: GSK Clinical Trials; GlaxoSmithKline

  Study Documents (Full-Text)

Documents provided by GlaxoSmithKline:

Study Protocol  [PDF] September 8, 2020

Statistical Analysis Plan  [PDF] December 23, 2020

More Information

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT03447314
• Other Study ID Numbers: 204686; 2017-003545-23 ( EudraCT Number )
• First Posted: February 27, 2018
• Results First Posted: July 20, 2021
• Last Update Posted: May 3, 2023
• Last Verified: April 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)
• Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints, key secondary endpoints and safety data of the study.
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
• URL: http://clinicalstudydatarequest.com

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by GlaxoSmithKline:

pembrolizumab; GSK1795091; Dose-escalation; 204686; Immunotherapies; GSK3359609; Phase I; anticancer agent; OX40; 201212; 204691; ICOS; TLR4; GSK3174998; Advanced Solid Tumors

Additional relevant MeSH terms:

Pembrolizumab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action