GSK3174998 Alone and With Pembrolizumab in Participants With Advanced Solid Tumors (ENGAGE-1)

NCT02528357 | Completed Phase 1 Results

• 2 other identifiers: 2012122015-000152-14
• Study Type: interventional
• Target: 141
• Locations: 4 countries
• Sites: 8

Brief Summary

This is a first time in human (FTIH), open-label, non-randomized, multicenter study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary clinical activity of GSK3174998 administered intravenously to participants with selected advanced or recurrent solid tumors. This dose-escalation study will assess the safety, activity of GSK3174998 as monotherapy (Part 1), in combination with pembrolizumab (Part 2), and potentially in combination with additional therapies. The study will be conducted in 2 parts, each part consisting of starting with a dose-escalation phase followed by a cohort expansion phase. GSK3174998 will first be evaluated as monotherapy in escalating doses. Once a dose of GSK3174998 has been identified that is both tolerable and demonstrates pharmacodynamic activity, enrollment of Part 2 may begin. In Part 2, escalating doses of GSK3174998 will be evaluated with fixed doses of pembrolizumab. The maximum duration of treatment with GSK3174998 and pembrolizumab will be approximately 2 years or 35 cycles, whichever comes first. The follow-up period for safety assessments will be a minimum of 3 months from the date of the last dose. The post-treatment follow-up period will include disease assessments every 12 weeks until documented progressive disease (PD). Approximately 141 participants with selected advanced or recurrent solid tumors will be enrolled.

Conditions

Neoplasms

Keywords

GSK3174998; Non-small Cell Lung Cancer (NSCLC); OX40; Pembrolizumab; Monoclonal Antibody (mAb); Selected Advanced Solid Tumors

Outcome Measures

Primary Outcomes (30)

• Part 1: Number of Participants With Any Serious Adverse Event (SAE) and Non-serious Adverse Event (Non-SAE)

  An adverse event 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. Any untoward medical occurrence that, at any dose: resulting in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly or birth defect or any other situation according to medical or scientific judgment was categorized as SAE.

  Up to maximum 39 weeks

• Part 2A: Number of Participants With Any SAE and Non-SAE

  An adverse event 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. Any untoward medical occurrence that, at any dose: resulting in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly or birth defect or any other situation according to medical or scientific judgment was categorized as SAE.

  Up to maximum 105 weeks

• Part 2B: Number of Participants With Any SAE and Non-SAE

  An adverse event 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. Any untoward medical occurrence that, at any dose: resulting in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly or birth defect or any other situation according to medical or scientific judgment was categorized as SAE.

  Up to maximum 33 weeks

• Part 1: Number of Participants With Dose Limiting Toxicities (DLTs)

  An adverse event was considered as DLT if it was considered by the investigator to be clinically relevant and attributed (definitely, probably or possibly) to study treatment, occurred within the first 28 days of the treatment, and met 1 of the following criteria: Hematologic: Febrile neutropenia, Grade4 neutropenia of \>7days requiring Granulocyte colony-stimulating factor (G-CSF), Grade4 anemia of any duration, Grade4 thrombocytopenia of any duration or Grade3 thrombocytopenia with bleeding as described in National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE version 4). Non-hematologic: Grade4 toxicity, Grade3 toxicity that cannot be controlled within 3days, Ocular toxicity of \>=Grade3 or of Grade2 requiring systemic steroids. Any other event results in permanent discontinuation of treatment during the first 4 weeks of treatment or any other event which in the judgment of the investigator and GlaxoSmithKline medical monitor is considered to be a DLT.

  28 days

• Part 2A: Number of Participants With DLTs

  An adverse event was considered as DLT if it was considered by the investigator to be clinically relevant and attributed (definitely, probably or possibly) to study treatment, occurred within the first 28 days of the treatment, and met 1 of the following criteria: Hematologic: Febrile neutropenia, Grade4 neutropenia of \>7days requiring Granulocyte colony-stimulating factor (G-CSF), Grade4 anemia of any duration, Grade4 thrombocytopenia of any duration or Grade3 thrombocytopenia with bleeding as described in National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE version 4). Non-hematologic: Grade4 toxicity, Grade3 toxicity that cannot be controlled within 3days, Ocular toxicity of \>=Grade3 or of Grade2 requiring systemic steroids. Any other event results in permanent discontinuation of treatment during the first 4 weeks of treatment or any other event which in the judgment of the investigator and GlaxoSmithKline medical monitor is considered to be a DLT.

  28 days

• Part 2B: Number of Participants With DLTs

  An adverse event was considered as DLT if it was considered by the investigator to be clinically relevant and attributed (definitely, probably or possibly) to study treatment, occurred within the first 28 days of the treatment, and met 1 of the following criteria: Hematologic: Febrile neutropenia, Grade4 neutropenia of \>7days requiring Granulocyte colony-stimulating factor (G-CSF), Grade4 anemia of any duration, Grade4 thrombocytopenia of any duration or Grade3 thrombocytopenia with bleeding as described in National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE version 4). Non-hematologic: Grade4 toxicity, Grade3 toxicity that cannot be controlled within 3days, Ocular toxicity of \>=Grade3 or of Grade2 requiring systemic steroids. Any other event results in permanent discontinuation of treatment during the first 4 weeks of treatment or any other event which in the judgment of the investigator and GlaxoSmithKline medical monitor is considered to be a DLT.

  28 days

• Part 1: Number of Participants With Any Adverse Event Leading to Withdrawal (AELD) From the Study

  An adverse event 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. Number of participants with any adverse event leading to withdrawal from the study is presented.

  Up to maximum 39 weeks

• Part 2A: Number of Participants With Any Adverse Event Leading to Withdrawal From the Study

  An adverse event 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. Number of participants with any adverse event leading to withdrawal from the study is presented.

  Up to maximum 105 weeks

• Part 2B: Number of Participants With Any Adverse Event Leading to Withdrawal From the Study

  An adverse event 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. Number of participants with any adverse event leading to withdrawal from the study is presented.

  Up to maximum 33 weeks

• Part 1: Number of Participants With Dose Reductions or Delay

  Number of participants who had any dose reduction or dose delay (GSK3174998) due to any reason have been presented.

  Up to maximum 39 weeks

• Part 2A: Number of Participants With Dose Reductions or Delay

  Number of participants who had any dose reduction or dose delay (GSK3174998) due to any reason have been presented.

  Up to maximum 105 weeks

• Part 2B: Number of Participants With Dose Reductions or Delay

  Number of participants who had any dose reduction or dose delay (GSK3174998) due to any reason have been presented.

  Up to maximum 33 weeks

• Part 1: Number of Participants With Any Grade Change From Baseline in Hematology Parameters

  Blood samples were collected for the analysis of following hematology parameters: hemoglobin (Hb), leukocyte count (leuko.), lymphocyte count (Lymph.), neutrophil count (Neutro.) and platelet count (PC). The laboratory parameters were graded according to NCI-CTCAE version 4. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences. Baseline was defined as the most recent, non-missing value from a central laboratory prior to or on the first study treatment dose date (Day 1). Any grade increase is defined as an increase in NCI-CTCAE grade relative to Baseline grade. Data for worst-case post Baseline is presented. Only those participants with any grade increase have been presented.

  Baseline (Day 1) and up to maximum 39 weeks

• Part 2A: Number of Participants With Any Grade Change From Baseline in Hematology Parameters

  Blood samples were collected for the analysis of following hematology parameters: Hb, leuko., Lymph., Neutro. and PC. The laboratory parameters were graded according to NCI-CTCAE version 4. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences. Baseline was defined as the most recent, non-missing value from a central laboratory prior to or on the first study treatment dose date (Day 1). Any grade increase is defined as an increase in NCI-CTCAE grade relative to Baseline grade. Data for worst-case post Baseline is presented. Only those participants with any grade increase have been presented.

  Baseline (Day 1) and up to maximum 105 weeks

• Part 2B: Number of Participants With Any Grade Change From Baseline in Hematology Parameters

  Blood samples were collected for the analysis of following hematology parameters: Hb, leuko., Lymph., Neutro. and PC. The laboratory parameters were graded according to NCI-CTCAE version 4. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences. Baseline was defined as the most recent, non-missing value from a central laboratory prior to or on the first study treatment dose date (Day 1). Any grade increase is defined as an increase in NCI-CTCAE grade relative to Baseline grade. Data for worst-case post Baseline is presented. Only those participants with any grade increase have been presented.

  Baseline (Day 1) and up to maximum 33 weeks

• Part 1: Number of Participants With Any Grade Change From Baseline in Liver Function Laboratory Parameters

  Blood samples were collected for the analysis of following liver function laboratory parameters: alanine aminotransferase (ALT), alkaline phosphatase (ALP), aspartate aminotransferase (AST) and bilirubin. The laboratory parameters were graded according to NCI-CTCAE version 4. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences. Baseline was defined as the most recent, non-missing value from a central laboratory prior to or on the first study treatment dose date (Day 1). Any grade increase is defined as an increase in NCI-CTCAE grade relative to Baseline grade. Data for worst-case post Baseline is presented. Only those participants with any grade increase have been presented.

  Baseline (Day 1) and up to maximum 39 weeks

• Part 2A: Number of Participants With Any Grade Change From Baseline in Liver Function Laboratory Parameters

  Blood samples were collected for the analysis of following liver function laboratory parameters: ALT, ALP, AST and bilirubin. The laboratory parameters were graded according to NCI-CTCAE version 4. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences. Baseline was defined as the most recent, non-missing value from a central laboratory prior to or on the first study treatment dose date (Day 1). Any grade increase is defined as an increase in NCI-CTCAE grade relative to Baseline grade. Data for worst-case post Baseline is presented. Only those participants with any grade increase have been presented.

  Baseline (Day 1) and up to maximum 105 weeks

• Part 2B: Number of Participants With Any Grade Change From Baseline in Liver Function Laboratory Parameters

  Blood samples were collected for the analysis of following liver function laboratory parameters: ALT, ALP, AST and bilirubin. The laboratory parameters were graded according to NCI-CTCAE version 4. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences. Baseline was defined as the most recent, non-missing value from a central laboratory prior to or on the first study treatment dose date (Day 1). Any grade increase is defined as an increase in NCI-CTCAE grade relative to Baseline grade. Data for worst-case post Baseline is presented. Only those participants with any grade increase have been presented.

  Baseline (Day 1) and up to maximum 33 weeks

• Part 1: Number of Participants With Any Grade Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)

  SBP and DBP were graded using NCI-CTCAE version 4. For SBP: Grade 0: \<120 millimeter mercury (mmHg); Grade 1: 120-139 mmHg; Grade 2: 140-159 mmHg; Grade 3: \>=160 mmHg. For DBP: Grade 0: \<80 mmHg; Grade 1: 80-89 mmHg; Grade 2: 90-99 mmHg; Grade 3: \>=100 mmHg. Baseline was defined as the most recent, non-missing value prior to or on the first study treatment dose date (Day 1). Any grade increase is defined as an increase in NCI-CTCAE grade relative to Baseline grade. Data for worst-case post Baseline is presented. Only those participants with any grade increase have been presented.

  Baseline (Day 1) and up to maximum 39 weeks

• Part 2A: Number of Participants With Any Grade Change From Baseline in SBP and DBP

  SBP and DBP were graded using NCI-CTCAE version 4. For SBP: Grade 0: \<120 mmHg; Grade 1: 120-139 mmHg; Grade 2: 140-159 mmHg; Grade 3: \>=160 mmHg. For DBP: Grade 0: \<80 mmHg; Grade 1: 80-89 mmHg; Grade 2: 90-99 mmHg; Grade 3: \>=100 mmHg. Baseline was defined as the most recent, non-missing value prior to or on the first study treatment dose date (Day 1). Any grade increase is defined as an increase in NCI-CTCAE grade relative to Baseline grade. Data for worst-case post Baseline is presented. Only those participants with any grade increase have been presented.

  Baseline (Day 1) and up to maximum 105 weeks

• Part 2B: Number of Participants With Any Grade Change From Baseline in SBP and DBP

  SBP and DBP were graded using NCI-CTCAE version 4. For SBP: Grade 0: \<120 mmHg; Grade 1: 120-139 mmHg; Grade 2: 140-159 mmHg; Grade 3: \>=160 mmHg. For DBP: Grade 0: \<80 mmHg; Grade 1: 80-89 mmHg; Grade 2: 90-99 mmHg; Grade 3: \>=100 mmHg. Baseline was defined as the most recent, non-missing value prior to or on the first study treatment dose date (Day 1). Any grade increase is defined as an increase in NCI-CTCAE grade relative to Baseline grade. Data for worst-case post Baseline is presented. Only those participants with any grade increase have been presented.

  Baseline (Day 1) and up to maximum 33 weeks

• Part 1: Number of Participants With Worst Case Change From Baseline in Heart Rate (HR)

  Baseline was defined as the most recent, non-missing value prior to or on the first study treatment dose date (Day 1). Change from Baseline was defined as post Baseline value minus Baseline value. Number of participants with worst case change from Baseline in heart rate is presented. Data was categorized as: heart rate 'decrease to low', 'increase to high' and 'change to normal or no change'; where low HR: \<60 beats per minute \[bpm\]', normal HR: 60 to 100 bpm and high HR: \>100 bpm. If values were unchanged (example: increase to \>100 bpm to increase to \>100 bpm), or whose value became normal, were recorded in the 'change to normal or no change' category. Participants were counted twice if the participant had both 'decreased to low' and 'increased to high' during post Baseline, so the percentages might not add to 100%.

  Baseline (Day 1) and up to maximum 39 weeks

• Part 2A: Number of Participants With Worst Case Change From Baseline in HR

  Baseline was defined as the most recent, non-missing value prior to or on the first study treatment dose date (Day 1). Change from Baseline was defined as post Baseline value minus Baseline value. Number of participants with worst case change from Baseline in heart rate is presented. Data was categorized as: heart rate 'decrease to low', 'increase to high' and 'change to normal or no change'; where low HR: \<60 bpm', normal HR: 60 to 100 bpm and high HR: \>100 bpm. If values were unchanged (example: increase to \>100 bpm to increase to \>100 bpm), or whose value became normal, were recorded in the 'change to normal or no change' category. Participants were counted twice if the participant had both 'decreased to low' and 'increased to high' during post Baseline, so the percentages might not add to 100%.

  Baseline (Day 1) and up to maximum 105 weeks

• Part 2B: Number of Participants With Worst Case Change From Baseline in HR

  Baseline was defined as the most recent, non-missing value prior to or on the first study treatment dose date (Day 1). Change from Baseline was defined as post Baseline value minus Baseline value. Number of participants with worst case change from Baseline in heart rate is presented. Data was categorized as: heart rate 'decrease to low', 'increase to high' and 'change to normal or no change'; where low HR: \<60 bpm', normal HR: 60 to 100 bpm and high HR: \>100 bpm. If values were unchanged (example: increase to \>100 bpm to increase to \>100 bpm), or whose value became normal, were recorded in the 'change to normal or no change' category. Participants were counted twice if the participant had both 'decreased to low' and 'increased to high' during post Baseline, so the percentages might not add to 100%.

  Baseline (Day 1) and up to maximum 33 weeks

• Part 1: Number of Participants With Worst Case Change From Baseline in Body Temperature

  Baseline was defined as the most recent, non-missing value prior to or on the first study treatment dose date (Day 1). Change from Baseline was defined as post Baseline value minus Baseline value. Number of participants with worst case change from Baseline in body temperature is presented. Data was categorized as: 'decrease to low', 'increase to high' and 'change to normal or no change'; where low body temperature: \<=35 degrees Celsius, normal body temperature: 35 to 38 degrees Celsius and high body temperature: \>=38 degrees Celsius. If values were unchanged (example: increase to \>=38 degrees Celsius to increase to \>=38 degrees Celsius), or whose value became normal, were recorded in the 'change to normal or no change' category. Participants were counted twice if the participant had both 'decreased to low' and 'increased to high' during post Baseline, so the percentages might not add to 100%.

  Baseline (Day 1) and up to maximum 39 weeks

• Part 2A: Number of Participants With Worst Case Change From Baseline in Body Temperature

  Baseline was defined as the most recent, non-missing value prior to or on the first study treatment dose date (Day 1). Change from Baseline was defined as post Baseline value minus Baseline value. Number of participants with worst case change from Baseline in body temperature is presented. Data was categorized as: 'decrease to low', 'increase to high' and 'change to normal or no change'; where low body temperature: \<=35 degrees Celsius, normal body temperature: 35 to 38 degrees Celsius and high body temperature: \>=38 degrees Celsius. If values were unchanged (example: increase to \>=38 degrees Celsius to increase to \>=38 degrees Celsius), or whose value became normal, were recorded in the 'change to normal or no change' category. Participants were counted twice if the participant had both 'decreased to low' and 'increased to high' during post Baseline, so the percentages might not add to 100%.

  Baseline (Day 1) and up to maximum 105 weeks

• Part 2B: Number of Participants With Worst Case Change From Baseline in Body Temperature

  Baseline was defined as the most recent, non-missing value prior to or on the first study treatment dose date (Day 1). Change from Baseline was defined as post Baseline value minus Baseline value. Number of participants with worst case change from Baseline in body temperature is presented. Data was categorized as: 'decrease to low', 'increase to high' and 'change to normal or no change'; where low body temperature: \<=35 degrees Celsius, normal body temperature: 35 to 38 degrees Celsius and high body temperature: \>=38 degrees Celsius. If values were unchanged (example: increase to \>=38 degrees Celsius to increase to \>=38 degrees Celsius), or whose value became normal, were recorded in the 'change to normal or no change' category. Participants were counted twice if the participant had both 'decreased to low' and 'increased to high' during post Baseline, so the percentages might not add to 100%.

  Baseline (Day 1) and up to maximum 33 weeks

• Part 1: Number of Participants With Worst Case Post-Baseline Abnormal Clinically Significant Electrocardiogram (ECG) Findings

  A 12-lead ECG was obtained after the participant had rested at least 10 minutes in a semi-recumbent or supine position during the study using ECG machine. Clinically significant abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. Number of participants with worst case post Baseline abnormal clinical significant ECG findings are presented.

  Up to maximum 39 weeks

• Part 2A: Number of Participants With Worst Case Post-Baseline Abnormal Clinically Significant ECG Findings

  A 12-lead ECG was obtained after the participant had rested at least 10 minutes in a semi-recumbent or supine position during the study using ECG machine. Clinically significant abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. Number of participants with worst case post Baseline abnormal clinical significant ECG findings are presented.

  Up to maximum 105 weeks

• Part 2B: Number of Participants With Worst Case Post-Baseline Abnormal Clinically Significant ECG Findings

  A 12-lead ECG was obtained after the participant had rested at least 10 minutes in a semi-recumbent or supine position during the study using ECG machine. Clinically significant abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. Number of participants with worst case post Baseline abnormal clinical significant ECG findings are presented.

  Up to maximum 33 weeks

Secondary Outcomes (28)

• Part 1: Objective Response Rate (ORR)

  Up to maximum 39 weeks

• Part 2A: Objective Response Rate (ORR)

  Up to maximum 105 weeks

• Part 2B: Objective Response Rate (ORR)

  Up to maximum 33 weeks

• Part 1: Disease Control Rate (DCR)

  Up to maximum 39 weeks

• Part 2A: Disease Control Rate (DCR)

  Up to maximum 105 weeks

Study Arms (3)

Part 1A: GSK3174998 Monotherapy- Dose escalation

EXPERIMENTAL

Participants will receive GSK3174998 intravenously (IV) (dose range 0.003 to 10.0 milligram per kilogram \[mg/kg\]) every 3 weeks (Q3W) for up to 2 years or 35 cycles, whichever comes first.

Drug: GSK3174998

Part 2A: GSK3174998+ pembrolizumab - Dose escalation

EXPERIMENTAL

Participants will receive GSK3174998 IV (dose range 0.003 to 10.0 mg/kg) Q3W for up to 2 years or 35 cycles, whichever comes first + Pembrolizumab 200 mg IV Q3W for up to 2 years or 35 cycles, whichever comes first.

Drug: GSK3174998; Drug: Pembrolizumab

Part 2B: GSK3174998+ pembrolizumab - Cohort expansion

EXPERIMENTAL

Participants will receive GSK3174998 IV (at one dose level shown to be tolerable in dose escalation of part 2A) Q3W for up to 2 years or 35 cycles, whichever comes first + Pembrolizumab 200 mg IV Q3W for 2 years or 35 cycles, whichever comes first.

Drug: GSK3174998; Drug: Pembrolizumab

Interventions

GSK3174998 DRUG

Lyophilized powder 40 mg reconstituted to get a dose range of 0.003 to \<=10 mg/kg to be given as IV infusion for 30 minutes (min), Q3W

Part 1A: GSK3174998 Monotherapy- Dose escalation; Part 2A: GSK3174998+ pembrolizumab - Dose escalation; Part 2B: GSK3174998+ pembrolizumab - Cohort expansion

Pembrolizumab DRUG

Pembrolizumab as 100 mg/4 milliliter (mL) solution (dose: 200 mg) to be given as IV infusion for 30 min, Q3W

Part 2A: GSK3174998+ pembrolizumab - Dose escalation; Part 2B: GSK3174998+ pembrolizumab - Cohort expansion

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provide signed, written informed consent.
• Male and female participants, age \>=18 years (at the time consent is obtained).
• Histological documentation of locally advanced, recurrent or metastatic solid malignancy that has progressed after standard therapy appropriate for the specific tumor type, or for which standard therapy has proven to be ineffective, intolerable, or is considered inappropriate. Participants should not have received more than 5 prior lines of therapy for advanced disease including both standards of care and investigational therapies. Participants whose cancers harbor molecular alterations for which targeted therapy is standard of care should have received health authority approved appropriate targeted therapy for their tumor types before enrollment.
• Participants with the following solid tumors are eligible for screening: Non-small cell lung cancer (NSCLC), Squamous cell carcinoma of the head and neck (SCCHN), Renal cell carcinoma (RCC), melanoma, bladder, Soft Tissue Sarcoma (STS), Triple-negative breast cancer (TNBC), and Colorectal carcinoma displaying high microsatellite instability (MSI CRC). In Part 2B (Cohort Expansion), specific subgroups of the above solid tumors will be studied. These subgroups may be defined by specific lines of treatment, types of prior treatment, histological subtypes, and may be enriched for selected biomarkers or participant characteristics. Populations to be studied in Amendment 3 include but are not limited to the following. Enrolment of additional populations will be communicated in writing: Participants with dedifferentiated liposarcoma who have not received prior treatment with a Programmed death ligand 1 (PD-L1) inhibitor; Participants with melanoma who have received a prior PD-L1 inhibitor, had a CR, PR or SD and subsequently progressed while on PD-L1 therapy. Participants who have received prior treatment with a PD-L1 inhibitor must have documented disease progression as defined by meeting all of the following criteria: Has received at least 2 doses of an approved PD-L1 inhibitor; has demonstrated disease progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The initial evidence of disease progression is to be confirmed by a second assessment no less than four weeks from the date of the first documented PD , in the absence of rapid clinical progression; Progressive disease has been documented within 18 weeks from the last dose of the PD-L1 inhibitor.
• In Parts 1A and 2A, a biopsy of the tumor tissue obtained at anytime 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.
• Participants enrolled in Part 1A or Part 2A Pharmacodynamic Cohorts or in Part 2B of the study 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. In addition, an archived tumor tissue should be submitted for Participants in Part 2B, if available. The criterion for collection of fresh biopsies may be waived once GlaxoSmithKline (GSK)has determined an appropriate number of viable tissue samples have been analyzed For Part 1B and Part 2B, any archival tumor specimen must have been obtained within 3 months of starting study drug.
• Measurable disease as per RECIST v1.1
• Palpable lesions that are not measurable by radiologic or photographic evaluations may not be utilized as the only measurable lesion.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.
• Life expectancy of at least 12 weeks.
• Adequate organ function as defined by System Laboratory Values; Hematologic (Absolute neutrophil count \[ANC\] \>=1.5x10\^9/ liter \[L\], Lymphocyte count \>=800/cubic millimeter \[mm\^3\], Hemoglobin \>=9 grams/deciliter \[g/dL\], Platelets \>=100x10\^9/L), Hepatic (Total bilirubin \<=1.5x upper limit of normal \[ULN\] \[For participants with Gilbert's Syndrome, only if direct bilirubin \<=35 percent (%), \<=3.0xULN\], for Part 1A and 2A: alanine aminotransferase \[ALT\] \<=1.5xULN), Part 2B: ALT \<=2.5xULN; Renal (Serum Creatinine \<=1.5xULN OR Calculated creatinine clearance \[CrCl \>50 mL/min ) and Endocrine (Thyroid stimulating hormone \[TSH\]) within normal limits. If TSH is not within normal limits at baseline, the participant may still be eligible if total triiodothyronine (T3) or free T3 and free thyroxine (T4) are within the normal limits.
• QT duration corrected for heart rate by Fridericia's formula (QTcF) \<450 milliseconds (msec) or \<480 msec for participants with bundle branch block.
• Female participant: is eligible to participate if she is not pregnant (as confirmed by a negative serum beta-human chorionic gonadotrophin \[beta-hCG\] test), not lactating, and at least one of the following conditions applies: Non-reproductive potential defined as: Pre-menopausal females with one of the following: Documented tubal ligation; Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion ; Hysterectomy; Documented Bilateral Oophorectomy.
• Postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause). Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment.
• Reproductive potential and agrees to follow one of the options listed below in the GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) requirements from 30 days prior to the first dose of study medication and until 120 days after the last dose of study medication and completion of the follow-up visit. GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP).

You may not qualify if:

• Prior treatment with the following agents (from last dose of prior treatment to first dose of GSK3174998): Tumor necrosis factor receptor (TNFR) agonists, including OX40, CD27, CD137 (4-1BB), CD357 (GITR): at any time; Checkpoint inhibitors, including Programmed death receptor-1 (PD-1),
• , and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors: within 4 weeks; other anticancer therapy, including chemotherapy, targeted therapy, and biological therapy: within 4 weeks or 5 half lives of the drug, whichever is shorter. Prior radiation therapy is permissible if at least one unirradiated measurable lesion is available for assessment via RECIST version 1.1. A wash out of at least two weeks before start of study drug for palliative radiation to the extremities for osseous bone metastases and 4 weeks for radiation to the chest, brain, or visceral organs is required; Investigational therapy: if the participant has participated in a clinical trial and has received an investigational product: within 30 days or 5 half-lives of the investigational product (whichever is shorter). At least 14 days must have passed between the last dose of prior investigational agent and the first dose of study drug.
• Prior allogeneic or autologous bone marrow transplantation or other solid organ transplantation.
• Toxicity from previous treatment: Participants with \>=Grade 3 toxicity related to prior immunotherapy leading to study treatment discontinuation are not eligible; participants whose toxicity related to prior treatment has not resolved to \<=Grade 1 (except alopecia, hearing loss, grade \<=2 neuropathy or endocrinopathy managed with replacement therapy) are not eligible.
• Malignancy other than disease under study, except as noted below: any other malignancy from which the participant has been disease-free for more than 2 years and, in the opinion of the principal investigators and GSK Medical Monitor, will not affect the evaluation of the effects of this clinical trial treatment on currently targeted malignancy, can be included in this clinical trial.
• Central nervous system (CNS) metastases, with the following exception: Participants who have previously-treated CNS metastases, are asymptomatic, and have had no requirement for steroids for 2 weeks prior to first dose of study drug.
• Has 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 \[GMCSF\], recombinant erythropoietin) within 2 weeks before the first dose of study drug.
• Major surgery \<=4 weeks before the first dose of study treatment. Participants must have also fully recovered from any surgery (major or minor) and/or its complications before initiating study treatment.
• Active autoimmune disease that has required systemic treatment within the last 2 years (that is with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (example \[e.g.\], thyroxine or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Concurrent medical condition requiring the use of systemic immunosuppressive medications 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 participant is on a stable dose.
• Active infection, known human immunodeficiency virus infection, or positive test for hepatitis B surface antigen or hepatitis C.
• Current active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones, liver metastases, or otherwise stable chronic liver disease per investigator assessment).
• Known, current drug or alcohol abuse.
• Recent history (within the past 6 months) of acute diverticulitis, inflammatory bowel disease, intra-abdominal abscess, or gastrointestinal obstruction.
• Receipt of any live vaccine within 4 weeks.

Sponsors & Collaborators

• GlaxoSmithKline: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (8)

GSK Investigational Site

Boston, Massachusetts, 02215, United States

Location

GSK Investigational Site

New York, New York, 10016, United States

Location

GSK Investigational Site

New York, New York, 10065, United States

Location

GSK Investigational Site

Nashville, Tennessee, 37203, United States

Location

GSK Investigational Site

Houston, Texas, 77030, United States

Location

GSK Investigational Site

Toronto, Ontario, M5G 2M9, Canada

Location

GSK Investigational Site

Villejuif, 94805, France

Location

GSK Investigational Site

Amsterdam, 1066 CX, Netherlands

Location

Related Publications (1)

• Postel-Vinay S, Lam VK, Ros W, Bauer TM, Hansen AR, Cho DC, Stephen Hodi F, Schellens JHM, Litton JK, Aspeslagh S, Autio KA, Opdam FL, McKean M, Somaiah N, Champiat S, Altan M, Spreafico A, Rahma O, Paul EM, Ahlers CM, Zhou H, Struemper H, Gorman SA, Watmuff M, Yablonski KM, Yanamandra N, Chisamore MJ, Schmidt EV, Hoos A, Marabelle A, Weber JS, Heymach JV. First-in-human phase I study of the OX40 agonist GSK3174998 with or without pembrolizumab in patients with selected advanced solid tumors (ENGAGE-1). J Immunother Cancer. 2023 Mar;11(3):e005301. doi: 10.1136/jitc-2022-005301.

  PMID: 36927527 DERIVED

MeSH Terms

Conditions

Neoplasms; Carcinoma, Non-Small-Cell Lung

Interventions

pembrolizumab

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Lung Diseases; Respiratory Tract Diseases

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 17, 2015
• First Posted: August 19, 2015
• Study Start: September 11, 2015
• Primary Completion: April 29, 2020
• Study Completion: April 29, 2020
• Last Updated: May 18, 2021
• Results First Posted: May 18, 2021

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, 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.

Locations

CA (1); US (5); FR (1); NL (1)