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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT03843359


Additional trial details provided through ANZCTR are available at the end of this record.


Registration number
NCT03843359
Ethics application status
Date submitted
14/02/2019
Date registered
18/02/2019
Date last updated
14/08/2019

Titles & IDs
Public title
Phase 1 First Time in Humans (FTIH), Open Label Study of GSK3745417 Administered to Subjects With Advanced Solid Tumors
Scientific title
A Phase I First Time in Human Open Label Study of GSK3745417 Administered With and Without Anticancer Agents in Participants With Advanced Solid Tumors
Secondary ID [1] 0 0
208850
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Neoplasms 0 0
Condition category
Condition code

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - GSK3745417
Treatment: Drugs - Pembrolizumab

Experimental: Part 1A: GSK3745417 Monotherapy, Dose-escalation Cohort - Subjects will receive GSK3745417 IV at every one week intervals (Q1W). Escalating doses of GSK3745417 will be evaluated using NCRM approach.

Experimental: Part 1B: GSK3745417 Monotherapy Dose Expansion Cohort - Subjects will be administered the recommended Phase 2 dose of GSK3745417 IV Q1W established in Part 1A of the study.

Experimental: Part 2A: GSK3745417 + pembrolizumab, Dose escalation Cohort - Subjects will receive GSK3745417 IV Q1W for 2 weeks followed by GSK3745417 along with pembrolizumab 200 mg IV once every 3 weeks (Q3W). Escalating doses of GSK3745417 in combination with 200 mg pembrolizumab will be evaluated.

Experimental: Part 2B: GSK3745417 combination Expansion Cohort - Subjects will receive GSK3745417 IV Q1W for 2 weeks then once every 3 week (Q3W) in combination with pembrolizumab 200 mg IV Q3W.


Treatment: Drugs: GSK3745417
GSK3745417 is available as white to off-white cake or powder for solution for injection at a unit dose strength of 2 mg per vial. GSK3745417 will be administered as IV injection for up to 5 minutes.

Treatment: Drugs: Pembrolizumab
Pembrolizumab is available as solution for infusion or lyophilized powder for reconstitution to be administered at a dose of 200 mg Q3W. It will be administered as an IV infusion for 30 minutes.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
1A: Number of subjects achieving Dose-limiting toxicity (DLT) - DLT is defined as any Grade 3 or 4 cytokine release syndrome; alanine aminotransferase (ALT) >=3 times upper limit of normal (ULN),plus bilirubin >=2 times ULN (>35% direct) or plus international normalized ratio (INR)>1.5 (possible Hy's law);or both ALT >=5 times ULN and >=2 times Baseline value (in subjects with liver metastases/tumor infiltration at Baseline);Grade >=3 non-hematologic toxicity of any duration with exceptions: Transient (<=72 hours) abnormal laboratory value without associated clinically significant signs or symptoms; Nausea, vomiting, or diarrhea adequately controlled with supportive care within 48 hours;Alopecia; Grade >=3 fatigue in subjects with Baseline fatigue of grade <=2. Grade >=3 immune related toxicity;any other event which in judgment of investigator and GlaxoSmithKline Medical Monitor is considered to be a DLT;Grade 4 anemia;Grade 4 neutropenia of >7 days duration or febrile neutropenia;Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding.
Timepoint [1] 0 0
Up to Day 21
Primary outcome [2] 0 0
1A: Number of subjects with adverse events (AEs) and serious adverse events (SAEs) - An AE is any untoward medical occurrence in a clinical study subject, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE 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 requires medical judgement.
Timepoint [2] 0 0
Up to 2 years
Primary outcome [3] 0 0
1A: Severity of AEs - The severity of AEs will be graded utilizing the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0.
Timepoint [3] 0 0
Up to 2 years
Primary outcome [4] 0 0
2A: Number of subjects achieving DLT - DLT is defined as any Grade 3 or 4 cytokine release syndrome; ALT >=3 times ULN,plus bilirubin >=2 times ULN (>35% direct) or plus INR>1.5 (possible Hy's law);or both ALT >=5 times ULN and >=2 times Baseline value (in subjects with liver metastases/tumor infiltration at Baseline);Grade >=3 non-hematologic toxicity of any duration with exceptions: Transient (<=72 hours) abnormal laboratory value without associated clinically significant signs or symptoms; Nausea, vomiting, or diarrhea adequately controlled with supportive care within 48 hours;Alopecia; Grade >=3 fatigue in subjects with Baseline fatigue of grade <=2. Grade >=3 immune related toxicity;any other event which in judgment of investigator and GlaxoSmithKline Medical Monitor is considered to be a DLT;Grade 4 anemia;Grade 4 neutropenia of >7 days duration or febrile neutropenia;Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding.
Timepoint [4] 0 0
Up to Day 29
Primary outcome [5] 0 0
2A: Number of subjects with AEs and SAEs - An AE is any untoward medical occurrence in a clinical study subject, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE 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 requires medical judgement.
Timepoint [5] 0 0
Up to 2 years
Primary outcome [6] 0 0
2A: Severity of AEs - The severity of AEs will be graded utilizing the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0.
Timepoint [6] 0 0
Up to 2 years
Primary outcome [7] 0 0
1B: Objective response rate based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria - Objective response rate is defined as the percentage of subjects with a best overall confirmed complete response (CR) or partial response (PR) at any time as per disease-specific criteria.
Timepoint [7] 0 0
Up to 2 years
Primary outcome [8] 0 0
2B: Objective response rate based on RECIST 1.1 criteria - Objective response rate is defined as the percentage of subjects with a best overall confirmed CR or PR at any time as per disease-specific criteria.
Timepoint [8] 0 0
Up to 2 years
Secondary outcome [1] 0 0
1A: Best objective response based on RECIST 1.1 criteria - Best objective response rate is defined as the percentage of subjects with a best overall confirmed CR or PR at any time as per disease-specific criteria.
Timepoint [1] 0 0
Up to 2 years
Secondary outcome [2] 0 0
1A: GSK3745417 concentrations in plasma following administration of GSK3745417 alone - Blood samples will be collected at indicated time points for plasma pharmacokinetic (PK) analysis of GSK3745417.
Timepoint [2] 0 0
Pre-dose, 1 minute, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours post-injection at Weeks 1, 2, 3, 4, 5, 6, 9 and 12
Secondary outcome [3] 0 0
1A: Maximum observed concentration (Cmax) following administration of GSK3745417 alone - Blood samples will be collected at indicated time points for plasma PK analysis following administration of GSK3745417 monotherapy.
Timepoint [3] 0 0
Pre-dose, 1 minute, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours post-injection at Weeks 1, 2, 3, 4, 5, 6, 9 and 12
Secondary outcome [4] 0 0
1A: Area under the concentration-time curve (AUC) following administration of GSK3745417 alone - Blood samples will be collected at indicated time points for plasma PK analysis following administration of GSK3745417 monotherapy.
Timepoint [4] 0 0
Pre-dose, 1 minute, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours post-injection at Weeks 1, 2, 3, 4, 5, 6, 9 and 12
Secondary outcome [5] 0 0
1A: Apparent terminal phase half-life (t½) following administration of GSK3745417 alone - Blood samples will be collected at indicated time points for plasma PK analysis following administration of GSK3745417 monotherapy.
Timepoint [5] 0 0
Pre-dose, 1 minute, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours post-injection at Weeks 1, 2, 3, 4, 5, 6, 9 and 12
Secondary outcome [6] 0 0
2A: Best objective response based on RECIST 1.1 criteria - Best objective response rate is defined as the percentage of subjects with a best overall confirmed CR or PR at any time as per disease-specific criteria.
Timepoint [6] 0 0
Up to 2 years
Secondary outcome [7] 0 0
2A: GSK3745417 concentrations in plasma following administration of GSK3745417 in combination with pembrolizumab - Blood samples will be collected for plasma PK analysis of GSK3745417 following administration of GSK3745417 in combination with pembrolizumab.
Timepoint [7] 0 0
Pre-dose, 1 minute, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours post injection at Weeks 1, 2, 5, 8, 11, 14 and 17
Secondary outcome [8] 0 0
2A: Cmax following administration of GSK3745417 in combination with pembrolizumab - Blood samples will be collected at indicated time points for plasma PK analysis following administration of GSK3745417 in combination with pembrolizumab.
Timepoint [8] 0 0
Pre-dose, 1 minute, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours post injection at Weeks 1, 2, 5, 8, 11, 14 and 17
Secondary outcome [9] 0 0
2A: AUC following administration of GSK3745417 in combination with pembrolizumab - Blood samples will be collected at indicated time points for plasma PK analysis following administration of GSK3745417 in combination with pembrolizumab.
Timepoint [9] 0 0
Pre-dose, 1 minute, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours post injection at Weeks 1, 2, 5, 8, 11, 14 and 17
Secondary outcome [10] 0 0
2A: t½ following administration of GSK3745417 in combination with pembrolizumab - Blood samples will be collected at indicated time points for plasma PK analysis following administration of GSK3745417 in combination with pembrolizumab.
Timepoint [10] 0 0
Pre-dose, 1 minute, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours post injection at Weeks 1, 2, 5, 8, 11, 14 and 17
Secondary outcome [11] 0 0
1B: Number of subjects achieving DLT - DLT is defined as any Grade 3 or 4 cytokine release syndrome; ALT >=3 times ULN,plus bilirubin >=2 times ULN (>35% direct) or plus INR>1.5 (possible Hy's law);or both ALT >=5 times ULN and >=2 times Baseline value (in subjects with liver metastases/tumor infiltration at Baseline);Grade >=3 non-hematologic toxicity of any duration with exceptions: Transient (<=72 hours) abnormal laboratory value without associated clinically significant signs or symptoms; Nausea, vomiting, or diarrhea adequately controlled with supportive care within 48 hours;Alopecia; Grade >=3 fatigue in subjects with Baseline fatigue of grade <=2. Grade >=3 immune related toxicity;any other event which in judgment of investigator and GlaxoSmithKline Medical Monitor is considered to be a DLT;Grade 4 anemia;Grade 4 neutropenia of >7 days duration or febrile neutropenia;Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding.
Timepoint [11] 0 0
Up to Day 21
Secondary outcome [12] 0 0
1B: Number of subjects with AEs and SAEs - An AE is any untoward medical occurrence in a clinical study subject, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE 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 requires medical judgement.
Timepoint [12] 0 0
Up to 2 years
Secondary outcome [13] 0 0
1B: Severity of AEs - The severity of AEs will be graded utilizing the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0.
Timepoint [13] 0 0
Up to 2 years
Secondary outcome [14] 0 0
1B: GSK3745417 concentrations in plasma following administration of GSK3745417 alone - Blood samples will be collected at indicated time points for plasma PK analysis of GSK3745417.
Timepoint [14] 0 0
Pre-dose, 1 minute, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours post-injection at Weeks 1, 2, 3, 4, 5, 6, 9 and 12
Secondary outcome [15] 0 0
1B: Cmax following administration of GSK3745417 alone - Blood samples will be collected at indicated time points for plasma PK analysis following administration of GSK3745417 alone.
Timepoint [15] 0 0
Pre-dose, 1 minute, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours post-injection at Weeks 1, 2, 3, 4, 5, 6, 9 and 12
Secondary outcome [16] 0 0
1B: AUC following administration of GSK3745417 alone - Blood samples will be collected at indicated time points for plasma PK analysis following administration of GSK3745417 alone.
Timepoint [16] 0 0
Pre-dose, 1 minute, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours post-injection at Weeks 1, 2, 3, 4, 5, 6, 9 and 12
Secondary outcome [17] 0 0
1B: t½ following administration of GSK3745417 alone - Blood samples will be collected at indicated time points for plasma PK analysis following administration of GSK3745417 alone.
Timepoint [17] 0 0
Pre-dose, 1 minute, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours post-injection at Weeks 1, 2, 3, 4, 5, 6, 9 and 12
Secondary outcome [18] 0 0
2B: Number of subjects achieving DLT - DLT is defined as any Grade 3 or 4 cytokine release syndrome; ALT >=3 times ULN,plus bilirubin >=2 times ULN (>35% direct) or plus INR>1.5 (possible Hy's law);or both ALT >=5 times ULN and >=2 times Baseline value (in subjects with liver metastases/tumor infiltration at Baseline);Grade >=3 non-hematologic toxicity of any duration with exceptions: Transient (<=72 hours) abnormal laboratory value without associated clinically significant signs or symptoms; Nausea, vomiting, or diarrhea adequately controlled with supportive care within 48 hours;Alopecia; Grade >=3 fatigue in subjects with Baseline fatigue of grade <=2. Grade >=3 immune related toxicity;any other event which in judgment of investigator and GlaxoSmithKline Medical Monitor is considered to be a DLT;Grade 4 anemia;Grade 4 neutropenia of >7 days duration or febrile neutropenia;Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding.
Timepoint [18] 0 0
Up to Day 29
Secondary outcome [19] 0 0
2B: 2B: Number of subjects with AEs and SAEs - An AE is any untoward medical occurrence in a clinical study subject, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE 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 requires medical judgement.
Timepoint [19] 0 0
Up to 2 years
Secondary outcome [20] 0 0
2B: Severity of AEs - The severity of AEs will be graded utilizing the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0.
Timepoint [20] 0 0
Up to 2 years
Secondary outcome [21] 0 0
2B: GSK3745417 concentrations in plasma following administration of GSK3745417 in combination with pembrolizumab - Blood samples will be collected at indicated time points for plasma PK analysis of GSK3745417.
Timepoint [21] 0 0
Pre-dose, 1 minute, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours post injection at Weeks 1, 2, 5, 8, 11, 14 and 17
Secondary outcome [22] 0 0
2B: Cmax following administration of GSK3745417 in combination with pembrolizumab - Blood samples will be collected at indicated time points for plasma PK analysis following administration of GSK3745417 in combination with pembrolizumab.
Timepoint [22] 0 0
Pre-dose, 1 minute, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours post injection at Weeks 1, 2, 5, 8, 11, 14 and 17
Secondary outcome [23] 0 0
2B: AUC following administration of GSK3745417 in combination with pembrolizumab - Blood samples will be collected at indicated time points for plasma PK analysis following administration of GSK3745417 in combination with pembrolizumab.
Timepoint [23] 0 0
Pre-dose, 1 minute, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours post injection at Weeks 1, 2, 5, 8, 11, 14 and 17
Secondary outcome [24] 0 0
2B: t½ following administration of GSK3745417 in combination with pembrolizumab - Blood samples will be collected at indicated time points for plasma PK analysis following administration of GSK3745417 in combination with pembrolizumab.
Timepoint [24] 0 0
Pre-dose, 1 minute, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours post injection at Weeks 1, 2, 5, 8, 11, 14 and 17

Eligibility
Key inclusion criteria
Inclusion Criteria

- Subject must be >=18 years of age at the time of signing the informed consent.

- Subjects with advanced/recurrent solid tumors, who have progressed on, be intolerant
of, or ineligible for, all available therapies for which clinical benefit has been
established.

- Histological or cytological documentation of an advanced solid tumor.

- A biopsy of the 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 the PK/Pharmacodynamic Cohorts 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.

- Measurable disease per RECIST version 1.1. Palpable lesions that are measurable by
radiologic or photographic evaluations may be utilized as the only measurable lesion.

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.

- Life expectancy of at least 12 weeks.

- 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.

- Adequate organ function (hematologic system: Absolute neutrophil count [ANC]
>=1.5x10^9/Liter, Hemoglobin >=9 grams per deciliter [g/dL], Platelets
>=100x10^9/Liter, prothrombin time [PT]/ INR and partial thromboplastin time [PTT]
[unless subject is receiving anticoagulant] <1.5 times ULN; Hepatic system: Total
bilirubin <=1.5 times ULN and for subjects with Gilbert's Syndrome [only if direct
bilirubin <=35%] total bilirubin <=3.0 times ULN; ALT <=2.5 times ULN, for subjects
with liver metastases/tumor infiltration <=5 times ULN; renal system: Estimated
glomerular filtration rate [eGFR] by Chronic Kidney Disease Epidemiology Collaboration
[CKD-EPI] >60 milliliter per minute [mL/min]; Endocrine system: thyroid stimulating
hormone (TSH) within normal limits; Cardiac system: Ejection fraction >= 50% by
echocardiogram.

- Male or female: Female subjects are eligible to participate if they are not either
pregnant or breastfeeding, and at least one of the following conditions applies: Is
not a woman of childbearing potential (WOCBP) OR Is a WOCBP and using a contraceptive
method that is highly effective (with a failure rate of <1% per year), with low user
dependency, during the study treatment period and for at least 7 days (subjects
receiving monotherapy) or 120 days (subjects receiving pembrolizumab) after the last
dose of study treatment and agrees not to donate eggs (ova, oocytes) for the purpose
of reproduction during this period. The investigator should evaluate the effectiveness
of the contraceptive method in relationship to the first dose of study treatment. A
WOCBP must have a negative highly sensitive pregnancy test (urine or serum) as
required by local regulations) within 7 days before the first dose of study
intervention. If a urine test cannot be confirmed as negative (e.g., an ambiguous
result), a serum pregnancy test is required. In such cases, the subject must be
excluded from participation if the serum pregnancy result is positive. Additional
requirements for pregnancy testing during and after study treatment. The investigator
is responsible for review of medical history, menstrual history, and recent sexual
activity to decrease the risk for inclusion of a woman with an early undetected
pregnancy.

- Capable of giving signed informed consent.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
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. Curatively treated non-melanoma
skin cancer is permitted.

- Symptomatic central nervous system (CNS) metastases or asymptomatic CNS metastases
that have required steroids within 2 weeks prior to first dose of study treatment.
Subjects with carcinomatous meningitis or leptomeningeal spread are excluded
regardless of clinical stability.

- Active autoimmune disease that has required systemic disease modifying or
immunosuppressive treatment within the last 2 years. Replacement therapy (e.g.,
thyroxine or physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency, etc.) is permitted.

- Concurrent medical condition requiring the use of systemic immunosuppressive treatment
within 28 days before the first dose of study treatment. Physiologic doses of
corticosteroids for treatment of endocrinopathies or steroids with minimal systemic
absorption, including topical, inhaled, or intranasal corticosteroids may be continued
if the subject is on a stable dose.

- 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. Stable chronic liver disease
(including Gilbert's syndrome or asymptomatic gallstones) or hepatobiliary involvement
of malignancy is acceptable if subject otherwise meets entry criteria.

- History of vasculitis at any time prior to study treatment.

- Evidence or history of significant active bleeding or coagulation disorder.

- Active infection requiring systemic treatment, known human immunodeficiency virus
infection, or positive test for hepatitis B surface antigen or hepatitis C.

- QTcF >450 milliseconds (msec) or QTcF >480 msec for subjects with bundle branch block.
QTcF is the QT interval corrected for heart rate according to Fridericia's formula,
machine-read or manually over-read.

- 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 or evidence of cardiovascular (CV) risk including any of the following: 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; Cardiomyopathy, myocardial infarction, acute coronary
syndromes (including unstable angina pectoris), coronary angioplasty, stenting, or
bypass grafting within the past 6 months before enrolment; Congestive heart failure
(Class II, III, or IV) as defined by the New York Heart Association functional
classification system (NYHA).

- Recent (within the past 6 months) history of symptomatic pericarditis.

- History of idiopathic pulmonary fibrosis, interstitial lung disease, or organizing
pneumonia, or evidence of active, non-infectious pneumonitis. Note: post-radiation
changes in the lung related to prior radiotherapy and/or asymptomatic
radiation-induced pneumonitis not requiring treatment may be permitted if agreed by
the investigator and Sponsor.

- History of (non-infectious) pneumonitis that required steroids or current 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 (e.g., 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: Stimulator of Interferon Genes (STING)
agonist at any time. Subjects treated in Part 1/monotherapy with GSK3745417 may be
enrolled into Part 2/combination with pembrolizumab upon disease progression and upon
discussion and approval from the GSK Medical Monitor; Anticancer therapy or
investigational therapy within 28 days or 5 half-lives of the drug, whichever is
shorter; Checkpoint inhibitors, including Programmed death receptor-1 (PD-1), PD-L1
and Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors within 28 days;
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 28
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. Palliative radiation is permissible at any time before or
during the study.

- Receipt of any live vaccine within 30 days of the start of study treatment.

- Prior allogeneic or autologous bone marrow transplantation or other solid organ
transplantation.

- Toxicity from previous treatment including: Toxicity Grade >=3 related to prior
immunotherapy and that led to study treatment discontinuation; Toxicity related to
prior treatment that has not resolved to Grade <=1 (except alopecia, hearing loss or
grade <=2 neuropathy 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 14 days before the first dose of study treatment.

- Concomitant administration of drugs that are sensitive substrates or narrow
therapeutic range substrates for cytochrome p450 (CYP) 3A4, 1A2, 2C19 enzymes and
OATP1B1 transporter, and moderate to strong inducers and inhibitors of CYP 3A4 should
be excluded during the study and for 7 days prior to and following treatment with
GSK3745417 (14 days for itraconazole).

- Major surgery <=28 days 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Phase
Phase 1
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
GSK Investigational Site - Melbourne
Recruitment postcode(s) [1] 0 0
3000 - Melbourne
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Texas
Country [2] 0 0
Canada
State/province [2] 0 0
Ontario

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
GlaxoSmithKline
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
This is a Phase I, FTIH, open-label, repeat-dose, non-randomized, multicenter, multi-country
study to evaluate the safety, tolerability, and preliminary clinical activity and establish a
recommended dose of GSK3745417 administered intravenously (IV) alone (Part 1) or
co-administered (Part 2) with pembrolizumab in subjects with refractory/relapsed solid
tumors. Each part consists of a dose escalation phase and a cohort expansion phase. In Part
1A, escalating doses of GSK3745417 will be evaluated as guided by the
Neuenschwander-continuous reassessment method (N-CRM) approach. In Part 2A, escalating doses
of GSK3745417 in combination with 200 milligrams (mg) pembrolizumab will be evaluated as
guided by the N-CRM approach. In Part 1B and 2B, subjects will receive a single dose level of
GSK3745417 as identified based on data from Part 1, either alone or in combination with
pembrolizumab. A total of approximately 300 subjects will be enrolled in this study,
approximately 120 for dose escalation cohorts, and approximately 180 in the expansion
cohorts.
Trial website
https://clinicaltrials.gov/show/NCT03843359
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
GSK Clinical Trials
Address 0 0
GlaxoSmithKline
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
US GSK Clinical Trials Call Center
Address 0 0
Country 0 0
Phone 0 0
877-379-3718
Fax 0 0
Email 0 0
GSKClinicalSupportHD@gsk.com
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT03843359

Additional trial details provided through ANZCTR
Accrual to date
Recruiting in Australia
Recruitment state(s)
VIC
Funding & Sponsors
Primary sponsor
Commercial sector/Industry
Primary sponsor name
GlaxoSmithKline
Primary sponsor address
Primary sponsor country
Ethics approval
Ethics application status
Approved
 
Public notes

Contacts
Principal investigator
Title 57 0
A/Prof
Name 57 0
Jayesh Desai
Address 57 0
Peter MacCallum Cancer Centre Melbourne VIC 3000
Country 57 0
Australia
Phone 57 0
Fax 57 0
Email 57 0
Contact person for public queries
Title 58 0
Name 58 0
Address 58 0
Country 58 0
Phone 58 0
Fax 58 0
Email 58 0
GSKClinicalSupportHD@gsk.com
Contact person for scientific queries
Title 59 0
Name 59 0
Address 59 0
Country 59 0
Phone 59 0
Fax 59 0
Email 59 0
GSKClinicalSupportHD@gsk.com