Dose Escalation and Expansion Study of GSK3359609 in Participants With Selected Advanced Solid Tumors (INDUCE-1)

GlaxoSmithKline829 enrolled

Overview

GSK3359609 is an anti-Inducible T cell Co-Stimulator (ICOS) receptor agonist antibody intended for the treatment of cancers of different histology. This is a first-time-in-human (FTIH), open-label, multicenter study designed to investigate the safety, pharmacology, and preliminary antitumor activity in participants with selected, advanced or recurrent solid tumors with the aim to establish recommended dose(s) of GSK3359609 for further exploration as monotherapy and in combination with pembrolizumab or chemotherapy regimens. The study is comprised of two primary parts, each composed of two phases: Part 1: GSK3359609 monotherapy with Part 1A as dose escalation phase and Part 1B as cohort expansion phase; Part 2: GSK3359609 combination therapy with Part 2A pembrolizumab or GSK3174998 or chemotherapy or pembrolizumab plus chemotherapy or dostarlimab plus cobolimab or Bintrafusp alfa combination dose escalation phase and Part 2B expansion phase with pembrolizumab. The primary objective of the study is to determine the safety, tolerability, maximum tolerated dose or the maximum administered dose of GSK3359609 alone or in combination.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

829

Conditions

Neoplasms

Interventions

Eligibility

Sex: ALLMin age: 18 YearsMax age: 93 Years

Medical Language ↔ Plain English

Inclusion Criteria * Capable of giving signed, written informed consent. * Male or female, age 18 to 93 years (at the time consent is obtained). * Histological or cytological documentation of an invasive malignancy that was diagnosed as locally advanced/metastatic or relapsed/refractory and is of one of the following tumor types: bladder/urothelial cancer of the upper and lower urinary tract; cervical; colorectal (includes appendix); esophagus, squamous cell; head and neck carcinoma; melanoma; malignant pleural mesothelioma (MPM); non-small-cell lung cancer (NSCLC), prostate; Microsatellite Instability-High/deficient mismatch repair (MSI-H/dMMR) tumor (Part 1B and Part 2B) and Human Papilloma Virus (HPV)-positive or Epstein-Barr (EBV)-positive tumor (Part 1B and Part 2B). * Disease that has progressed after standard therapy for the specific tumor type, or for which standard therapy has proven to be ineffective, intolerable, or is considered inappropriate, or if no further standard therapy exists; exceptions are in these tumor types in which pembrolizumab single agent may be a standard: NSCLC, head and neck squamous cell cancer (HNSCC), bladder/urothelial cancer, MSI-H/dMMR cancers and melanoma and cervical cancer. In Part 2B pembrolizumab combination expansion cohorts, prior treatment with anti-Programmed cell death protein 1(PD-1)/ Ligand-1 (L1) may not be required. 1) Participants must not have received more than 5 prior lines of therapy for advanced disease including both standards of care and investigational therapies. 2) Participants who received prior PD-1/L1 therapy must fulfill the following requirements (Part 1B \[except PK/PD cohort\]/ Part 2B):a) Have achieved a CR, PR or SD and subsequently had disease progression while still on PD-1/L1 therapy; b) Have received at least 2 doses of an approved PD-1/L1 inhibitor (by any regulatory authority), c) Have demonstrated disease progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 within 18 weeks from the last dose of the PD-1/L1 inhibitor. 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 Progressive Disease (PD) (the confirmatory scan could be the Baseline eligibility scan for this study). 3) In Part 2A 5-fluorouracil (FU)/platinum combination with GSK3359609 and pembrolizumab cohort, participants must not have received prior systemic therapy administered in the recurrent or metastatic setting (with the exception of systemic therapy given as part of multimodal treatment for locally advanced disease). * Archival tumor tissue obtained at any time from the initial diagnosis to study entry; a fresh tumor biopsy using a procedure that is safe for the participant on a lesion not previously irradiated unless lesion progressed will be required if archival tissue is unavailable. * Agree to undergo a pre-treatment and on treatment biopsy and have disease amenable to biopsy required in pharmacokinetic (PK) / pharmacodynamics (PD), dose randomized HNSCC, Melanoma dose expansion and Biomarker cohorts.. * Measurable disease per RECIST version 1.1. Palpable lesions that are not measurable by radiographic or photographic evaluations may not be utilized as the only measurable lesion. Any measurable lesion biopsied at Screening cannot be followed as a target/index lesion unless agreed upon by GlaxoSmithKline (GSK). * Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1. * Life expectancy of at least 12 weeks. * Adequate organ function. * QT interval corrected for heart rate according to Fridericia's formula (QTcF) \<450 milliseconds (msec) or QTcF \<480 msec for participants with bundle branch block. * A female participant is eligible to participate if she is not pregnant (as confirmed by a negative serum beta-human chorionic gonadotrophin \[beta-hCG\] test in females of reproductive potential), and not lactating or reproductive potential agrees to follow one of the options listed in protocol from 30 days prior to the first dose of study medication and until 120 days after the last dose of study treatment. * Male participants with female partners of child bearing potential must agree to use one of the methods of contraception specified in protocol from time of first dose of study treatment until 120 days after the last dose of study treatment. * Documented HPV/ EBV-positive tumor as determined by a local laboratory for Part 1B and Part 2B pembrolizumab combination viral-positive expansion cohorts only. * Documented MSI-H or dMMR-positive tumor as determined by local laboratory for Part 1B and Part 2B pembrolizumab combination MSI-H/dMMR expansion cohorts only. * ICOS expression result using an analytically validated immunohistochemistry (IHC) assay by central laboratory for Part 1B biomarker cohort only. * Gene expression (GEX) result using an analytically validated method by central laboratory (Part 1B Biomarker Cohort only). * PD-L1 combined positive score (CPS) \<1 using the Food and Drug Administration (FDA) approved PD-L1 IHC 22C3 pharmdx assay by central laboratory testing for Part 2B HNSCC PD-L1 CPS \<1 Cohort. Documented test result from FDA approved PD-L1 IHC 22C3 pharmDx assay in local laboratory, if available, may be accepted in lieu of the central laboratory test result. Exclusion Criteria * Prior treatment with the following therapies: Â• Anticancer therapy within 30 days or 5 half-lives of the drug, whichever is shorter. At least 14 days must have elapsed between the last dose of prior anticancer agent and the first dose of study drug is administered. Â• Part 2B (GSK3359609/pembrolizumab combination): prior pembrolizumab washout is not required. Â• Prior radiation therapy: permissible if at least one 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 two weeks before start of study drug for radiation of any intended use to the extremities for bone metastases and 4 weeks for radiation to the chest, brain, or visceral organs is required. Â• Investigational therapy within 30 days or 5 half-lives of the investigational product (whichever is shorter). At least 14 days must have elapsed between the last dose of investigational agent and the first dose of study drug is administered. * Prior allogeneic or autologous bone marrow transplantation or other solid organ transplantation. * Toxicity from previous anticancer treatment * Invasive malignancy or history of invasive malignancy other than disease under study within the last two years except: Any other invasive malignancy for which the participant was definitively treated, has been disease-free for \<=2 years and in the opinion of the principal investigator and GSK Medical Monitor will not affect the evaluation of the effects of the study treatment on the currently targeted malignancy, may be included in this clinical trial; and curatively treated non-melanoma skin cancer. * Central nervous system (CNS) metastases, with the following exception: Â• Participants who have previously-treated CNS metastases, are asymptomatic, and have no requirement for steroids at least 14 days prior to first dose of study drug. Participants with carcinomatous meningitis or leptomeningeal spread are excluded regardless of clinical stability. * 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, recombinant erythropoietin) within 14 days prior to the first dose of GSK3359609. * 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 two years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (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 7 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. * Condition requiring treatment with strong inhibitors/inducers of cytochrome p (CYP) 450 3A4 within 7 days prior to first dose of chemotherapy (requirement applies to participants enrolled to Part 2 chemotherapy combination with docetaxel). * Active infection requiring systemic therapy, known human immunodeficiency virus infection, or positive test for hepatitis B active infection or hepatitis C active infection. * 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). * Recent history (within the past 6 months) of acute diverticulitis, inflammatory bowel disease, intra-abdominal abscess, or gastrointestinal obstruction that required surgery. * Receipt of any live vaccine within 4 weeks prior to first dose of study treatment. * Recent history of allergen desensitization therapy within 4 weeks of starting study treatment. * History of severe hypersensitivity to monoclonal antibodies or to the chemotherapies under investigation including any ingredient used in the formulation. * History or evidence of cardiac abnormalities. * History of (current and past) idiopathic pulmonary fibrosis, pneumonitis (for past pneumonitis exclusion only if steroids were required for treatment), interstitial lung disease, or organizing pneumonia. 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 Medical Monitor. * 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 participant's safety, obtaining informed consent, or compliance to the study procedures.

Locations (28)

GSK Investigational Site

Duarte, California, United States

GSK Investigational Site

Los Angeles, California, United States

GSK Investigational Site

Sarasota, Florida, United States

GSK Investigational Site

New York, New York, United States

GSK Investigational Site

New York, New York, United States

GSK Investigational Site

Oklahoma City, Oklahoma, United States

GSK Investigational Site

Philadelphia, Pennsylvania, United States

GSK Investigational Site

Nashville, Tennessee, United States

GSK Investigational Site

Nashville, Tennessee, United States

GSK Investigational Site

Heidelberg, Victoria, Australia

...and 18 more locations

Outcomes

Primary Outcomes

Part 1A: Number of Participants With Any Adverse Event(s) (AEs) and Serious Adverse Event(s) (SAEs)

An AE 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. 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, or is a congenital anomaly/birth defect, other situations which involve medical or scientific judgment or is associated with liver injury and impaired liver function. SAEs are subset of AEs. A summary of number of participants with any AEs and SAEs is presented. AEs were coded using the Medical Dictionary for Regulatory Affairs (MedDRA dictionary).

Time frame: Up to approximately 367 weeks

Part 1A: Number of Participants With Dose Limiting Toxicity (DLT)

DLT is an AE that is considered by the investigator to be clinically relevant and attributed to the study therapy during the 28-day DLT period and meets at least one of the DLT criteria: Febrile neutropenia; Grade 4 neutropenia of \>7 days in duration or requiring Granulocyte Colony-stimulating Factor (G-CSF), anemia, thrombocytopenia, non-hematologic toxicity; Grade 3 thrombocytopenia with bleeding, pneumonitis, toxicity that does not resolve to Grade 1 or baseline within 3 days; Grade 2 ocular toxicity; Toxicity that results in permanent discontinuation of feladilimab during the first four weeks of treatment; any other event which in the judgment of the investigator and GSK Medical Monitor is considered to be a DLT.

Time frame: Up to 28 days

Part 1A: Number of Participants With Worst-case Grade Change From Baseline in Clinical Chemistry Parameters

Blood samples were collected for analysis of clinical chemistry parameters. Laboratory parameters were graded according to CTCAE v4.03. Grade (G) 0: None; G1: mild; G2: moderate; G3: severe or medically significant; G4: life-threatening consequences. Higher grade indicates greater severity and increase in grade was defined relative to Baseline grade. Baseline (Day 1) was defined as latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Only grade change data is presented for Baseline (B) and Worst-Case Post-Baseline (WCPB) as G0, G1, G2, G3, G4, and missing (M) here as "Parameter name, B GX, WCPB GX" where X=grade digit.

Time frame: Baseline (Day 1) and up to approximately 367 weeks

Part 1A: Number of Participants With Worst Case Chemistry Results Relative to Normal Range Post-Baseline Relative to Baseline

Normal ranges were 0.1 to 0.3 micromoles (umol)/liter (L) (direct bilirubin); 6 to 8.3 grams/L (protein); 100 to 250 international units (IU)/L (Lactate Dehydrogenase(LDH)); 2.3 - 4.1 picomoles/L (Free Triiodothyronine(T3)); 4.6 to 11.2 picomoles/L (Free Thyroxine(T4)); 0 and 0.04 microgram (ug)/L (Troponin I); 0 - 0.01 ug/L (Troponin T); 0.45 to 4.5 milliunits (Mu)/L (Thyrotropin(TSH)); and 6 to 24 millimoles/L (Urea). Participants were counted in worst case category that their value changes to low, normal or no change \[NC\] or high), unless there is NC in their category. Participants whose laboratory value category was unchanged (e.g. High to High) or whose value became normal, were recorded in "To Normal or No Change" category. Participants were counted twice if participant had values that changed To Low and To High, so percentages may not add to 100%.

Time frame: Up to approximately 367 weeks

Part 1A: Number of Participants With Worst-case Grade Change From Baseline in Hematology Parameters

Blood samples were collected for analysis of hematology parameters. Laboratory parameters were graded according to CTCAE v4.03. Grade (G) 0: None; G1: mild; G2: moderate; G3: severe or medically significant; G4: life-threatening consequences. Higher grade indicates greater severity and increase in grade was defined relative to Baseline grade. Baseline (Day 1) was defined as latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Only grade change data is presented for Baseline (B) and Worst-Case Post-Baseline (WCPB) as G0, G1, G2, G3, G4, and missing (M) here as "Parameter name, B GX, WCPB GX" where X=grade digit.

Time frame: Baseline (Day 1) and up to approximately 367 weeks

Part 1A: Number of Participants With Worst Case Hematology Results Relative to Normal Range Post-Baseline Relative to Baseline

Normal ranges were 0.01 to 0.3\*10\^9 cells/L (basophils), 0 to 500 cells /L (eosinophils), 41 to 50 percentage of red blood cells (RBC) in blood (hematocrit), 1,000 - 4,800 lymphocytes per microliter (ÂµL) of blood (lymphocytes), 80-100 femtoliters (fl) (erythrocytes, mean corpuscular volume), 2 to 8 percentage of WBC (monocytes), 40 to 60 cells/mcL (neutrophils) and Women: 4.2 to 5.4 million RBC/ microliter (mcL) of blood and Men: 4.7 to 6.1 million RBC/ mcL (erythrocytes count). Participants were counted in worst case category that their value changes to low, normal or no change \[NC\] or high), unless there is NC in their category. Participants whose laboratory value category was unchanged (e.g. High to High) or whose value became normal, were recorded in "To Normal or No Change" category. Participants were counted twice if participant had values that changed To Low and To High, so percentages may not add to 100%.

Time frame: Up to approximately 367 weeks

Part 1A: Number of Participants With Worst Case Urinalysis Results Post-Baseline Relative to Baseline

Urine samples were collected to assess urine glucose, ketones and occult blood using dipstick method. The dipstick test gave results in a semi-quantitative manner, and results for urinalysis parameters were recorded as negative, trace, 1+, 2+, 3+ indicating proportional concentrations in the urine sample. Baseline (Day 1) was defined as the most recent, non-missing value prior to or on the first study treatment dose date. Result for urinalysis parameters were recorded as no change/decreased and any increase.

Time frame: Up to approximately 367 weeks

Part 1A: Number of Participants With Dose Modifications of Feladilimab

Number of participants with dose modifications (including dose delays, dose escalations and infusion interruptions) were reported for Feladilimab.

Time frame: Up to approximately 367 weeks

Part 2A: Number of Participants With Any Adverse Event(s) (AEs) and Serious Adverse Event(s) (SAEs)

An AE 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. 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 or Is a congenital anomaly/birth defect, Other situations which involve medical or scientific judgment or is associated with liver injury and impaired liver function. SAEs are subset of AEs. A summary of number of participants with any AEs and SAEs is presented. AEs were coded using the MedDRA dictionary.

Time frame: Up to approximately 367 weeks

Part 2A: Number of Participants With Dose Limiting Toxicity (DLT)

DLT is an AE that is considered by the investigator to be clinically relevant and attributed to the study therapy during the 28-day DLT period and meets at least one of the DLT criteria: Febrile neutropenia; Grade 4 neutropenia of \>7 days in duration or requiring Granulocyte Colony-stimulating Factor (G-CSF), anemia, thrombocytopenia, non-hematologic toxicity; Grade 3 thrombocytopenia with bleeding, pneumonitis, toxicity that does not resolve to Grade 1 or baseline within 3 days; Grade 2 ocular toxicity; Toxicity that results in permanent discontinuation of feladilimab monotherapy or in combination during the first four weeks of treatment; any other event which in the judgment of the investigator and GSK Medical Monitor is considered to be a DLT.

Time frame: Up to 28 days

Part 2A: Number of Participants With Worst-case Grade Change From Baseline in Clinical Chemistry Parameters

Time frame: Baseline (Day 1) and up to approximately 367 weeks

Part 2A: Number of Participants With Worst Case Chemistry Results Relative to Normal Range Post-Baseline Relative to Baseline

Normal ranges were 6 to 8.3 grams/L (protein); 100 to 250 international units (IU)/L (Lactate Dehydrogenase(LDH)); 2.3 - 4.1 picomoles/L (Free Triiodothyronine(T3)); 4.6 to 11.2 picomoles/L (Free Thyroxine(T4)); 0 and 0.04 microgram (ug)/L (Troponin I); 0 - 0.01 ug/L (Troponin T); 0.45 to 4.5 milliunits (Mu)/L (Thyrotropin(TSH)); and 6 to 24 millimoles/L (Urea). Participants were counted in worst case category that their value changes to low, normal or no change \[NC\] or high), unless there is NC in their category. Participants whose laboratory value category was unchanged (e.g. High to High) or whose value became normal, were recorded in "To Normal or No Change" category. Participants were counted twice if participant had values that changed To Low and To High, so percentages may not add to 100%.

Time frame: Up to approximately 367 weeks

Part 2A: Number of Participants With Worst-case Grade Change From Baseline in Hematology Parameters

Time frame: Baseline (Day 1) and up to approximately 367 weeks

Part 2A: Number of Participants With Worst Case Hematology Results Relative to Normal Range Post-Baseline Relative to Baseline

Normal ranges were 0.01 to 0.3\*10\^9 cells/L (basophils), 0 to 500 cells /L (eosinophils), 41 to 50 percentage of RBC in blood (hematocrit), 2 to 8 percentage of WBC (monocytes), 40 to 60 cells/mcL (neutrophils) and Women: 4.2 to 5.4 million RBC/mcL of blood and Men: 4.7 to 6.1 million RBC/ mcL (erythrocytes count). Participants were counted in worst case category that their value changes to low, normal or no change \[NC\] or high), unless there is NC in their category. Participants whose laboratory value category was unchanged (e.g. High to High) or whose value became normal, were recorded in "To Normal or No Change" category. Participants were counted twice if participant had values that changed To Low and To High, so percentages may not add to 100%.

Time frame: Up to approximately 367 weeks

Part 2A: Number of Participants With Worst Case Urinalysis Results Post-Baseline Relative to Baseline

Time frame: Up to approximately 367 weeks

Part 2A: Number of Participants With Dose Modifications of Feladilimab

Number of participants with dose modifications (including dose delays, dose escalations, and infusion interruptions) were reported for Feladilimab

Time frame: Up to approximately 367 weeks

Secondary Outcomes

Part 1B: Number of Participants With Any Adverse Event(s) (AEs) and Serious Adverse Event(s) (SAEs)

An AE 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. 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 or Is a congenital anomaly/birth defect, Other situations which involve medical or scientific judgment or is associated with liver injury and impaired liver function. SAEs are subset of AEs. A summary of number of participants with any AEs and SAEs is presented. AEs were coded using the MedDRA dictionary.

Time frame: Up to approximately 367 weeks

Part 1B: Number of Participants With Worst-case Grade Change From Baseline in Clinical Chemistry Parameters

Time frame: Baseline (Day 1) and up to approximately 367 weeks

Part 1B: Number of Participants With Worst Case Chemistry Results Relative to Normal Range Post-Baseline Relative to Baseline

Data from ClinicalTrials.gov

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Time frame: Up to approximately 367 weeks

Part 1B: Number of Participants With Worst-case Grade Change From Baseline in Hematology Parameters

Time frame: Baseline (Day 1) and up to approximately 367 weeks

Part 1B: Number of Participants With Worst Case Hematology Results Relative to Normal Range Post-Baseline Relative to Baseline

Normal ranges were 0.01 to 0.3\*10\^9 cells/L (basophils), 0 to 500 cells /L (eosinophils), 41 to 50 percentage of RBC in blood (hematocrit), 2 to 8 percentage of WBC (monocytes), and Women: 4.2 to 5.4 million RBC/ mcL of blood and Men: 4.7 to 6.1 million RBC/ mcL (erythrocyte count). Participants were counted in worst case category that their value changes to low, normal or no change \[NC\] or high), unless there is NC in their category. Participants whose laboratory value category was unchanged (e.g. High to High) or whose value became normal, were recorded in "To Normal or No Change" category. Participants were counted twice if participant had values that changed To Low and To High, so percentages may not add to 100%.

Time frame: Up to approximately 367 weeks

Part 1B: Number of Participants With Worst Case Urinalysis Results Post-Baseline Relative to Baseline

Time frame: Up to approximately 367 weeks

Part 1B: Number of Participants With Dose Modifications of Feladilimab

Number of participants with dose modifications (including dose delays, dose escalation and infusion interruptions) were reported for Feladilimab.

Time frame: Up to approximately 367 weeks

Part 2B: Number of Participants With Any Adverse Event(s) (AEs) and Serious Adverse Event(s) (SAEs)

An AE 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. 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 or is a congenital anomaly/birth defect, other situations which involve medical or scientific judgment or is associated with liver injury and impaired liver function. SAEs are subset of AEs. A summary of number of participants with any AEs and SAEs is presented. AEs were coded using the MedDRA dictionary.

Time frame: Up to approximately 367 weeks

Part 2B: Number of Participants With Worst-case Grade Change From Baseline in Clinical Chemistry Parameters

Time frame: Baseline (Day 1) and up to approximately 367 weeks

Part 2B: Number of Participants With Worst Case Chemistry Results Relative to Normal Range Post-Baseline Relative to Baseline

Normal ranges were 0.1 to 0.3 micromoles (umol)/liter (L) (direct bilirubin); 6 to 8.3 grams/L (protein); 100 to 250 international units (IU)/L (Lactate Dehydrogenase(LDH)); 2.3 - 4.1 picomoles/L (Free Triiodothyronine(T3)); 4.6 to 11.2 picomoles/L (Free Thyroxine(T4)); 0 and 0.04 microgram (ug)/L (Troponin I); 0 - 0.01 ug/L (Troponin T); 0.45 to 4.5 milliunits (Mu)/L (Thyrotropin(TSH)); 24-204 ug/L (creatine kinase); and 6 to 24 millimoles/L (Urea). Participants were counted in worst case category that their value changes to low, normal or no change \[NC\] or high), unless there is NC in their category. Participants whose laboratory value category was unchanged (e.g. High to High) or whose value became normal, were recorded in "To Normal or No Change" category. Participants were counted twice if participant had values that changed To Low and To High, so percentages may not add to 100%.

Time frame: Up to approximately 367 weeks

Part 2B: Number of Participants With Worst-case Grade Change From Baseline in Hematology Parameters

Time frame: Baseline (Day 1) and up to approximately 367 weeks

Part 2B: Number of Participants With Worst Case Hematology Results Relative to Normal Range Post-Baseline Relative to Baseline

Normal ranges were 0.01 to 0.3\*10\^9 cells/L (basophils), 0 to 500 cells/L(eosinophils), 41 to 50 percentage of RBC in blood (hematocrit), 1,000 - 4,800 lymphocytes per microliter (ÂµL) of blood (lymphocytes), 80-100 fl (erythrocytes, mean corpuscular volume), 2 to 8 percentage of WBC (monocytes), 40 to 60 cells/mcL (neutrophils) and Women: 4.2 to 5.4 million RBC/ mcL of blood and Men: 4.7 to 6.1 million RBC/ mcL (erythrocytes count). Participants were counted in worst case category that their value changes to low, normal or no change \[NC\] or high), unless there is NC in their category. Participants whose laboratory value category was unchanged (e.g. High to High) or whose value became normal, were recorded in "To Normal or No Change" category. Participants were counted twice if participant had values that changed To Low and To High, so percentages may not add to 100%.

Time frame: Up to approximately 367 weeks

Part 2B: Number of Participants With Worst Case Urinalysis Results Post-Baseline Relative to Baseline

Time frame: Up to approximately 367 weeks

Part 2B: Number of Participants With Dose Modifications of Feladilimab

Number of participants with dose modifications (including dose delays, dose escalations, and infusion interruptions) were reported for Feladilimab.

Time frame: Up to approximately 367 weeks

Part 1A: Overall Response Rate (ORR)

ORR was defined as the percentage of participants with immune-related confirmed complete response (irCR) or ir confirmed partial response (irPR) per Immune-related Response Evaluation Criteria in Solid Tumors Criteria (irRECIST). irCR is defined as disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<)10 millimeters (mm). irPR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters.

Time frame: Up to approximately 367 weeks

Part 1A: Disease Control Rate (DCR)

DCR was defined as percentage of participants with best overall response of irCR or irPR at any time + ir stable disease (irSD) meeting the minimum time criteria from the start of treatment until ir disease progression (irPD) or death due to any cause or the start of new anticancer therapy/crossover. irCR is defined as disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm. irPR defined as at least 30% decrease in the sum of diameters of target lesions, taking as a reference, the baseline sum of the diameters. irSD defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease. IrPD defined as the date of radiological disease progression based on imaging data per irRECIST. A one-week visit window was considered in the duration of irSD, i.e. a minimum of 8 weeks (irSD\>=9 weeks) and 17 weeks (irSD\>=18 weeks) were considered.

Time frame: Up to approximately 367 weeks

Part 1A: Overall Survival (OS)

OS was defined as the interval between the date of first assigned study therapy/randomization and date of death due to any cause.

Time frame: Up to approximately 367 weeks

Part 1A: Progression-free Survival (PFS)

PFS was defined as the interval between the date of first dose of study treatment (or date of randomization for randomized cohorts) and the date of disease progression according to radiological response from investigator assessment, or death due to any cause, whichever occurs earlier. Disease progression was defined as the date of radiological disease progression based on imaging data per RECIST v1.1

Time frame: Up to approximately 367 weeks

Part 1A: Time to Overall Response (TTR)

TTR was defined as the time from date of first dose of study treatment/randomization to the date of first documented confirmed (=4 weeks) CR or PR. CR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<)10 mm. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters.

Time frame: Up to approximately 367 weeks

Part 1A: Duration of Response (DOR)

DOR was defined as the interval of time in months from the date of the first documented evidence of a response (confirmed CR or PR) to the date of first documented evidence of disease progression according to radiological response from investigator assessment per RECIST v1.1, or date of last adequate assessment of response or the date of death due to any cause (whichever occurs earlier). CR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<)10 mm. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters. Disease progression was defined as the date of radiological disease progression based on imaging data per RECIST v1.1.

Time frame: Up to approximately 367 weeks

Part 2A: Overall Response Rate (ORR)

ORR was defined as the percentage of participants with irCR or irPR per irRECIST. irCR is defined as disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 millimeters (mm). irPR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters.

Time frame: Up to approximately 367 weeks

Part 2A: Disease Control Rate (DCR)

DCR was defined as percentage of participants with best overall response of irCR or irPR at any time + irSD meeting the minimum time criteria from the start of treatment until irPD or death due to any cause or the start of new anticancer therapy/crossover. irCR defined as disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm. irPR defined as at least 30% decrease in the sum of diameters of target lesions, taking as a reference, the baseline sum of the diameters. irSD defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease. IrPD defined as the date of radiological disease progression based on imaging data per irRECIST. A one-week visit window was considered in the duration of irSD, i.e. a minimum of 8 weeks (irSD\>=9 weeks) and 17 weeks (irSD\>=18 weeks) were considered.

Time frame: Up to approximately 367 weeks

Part 2A: Overall Survival (OS)

OS was defined as the interval between the date of first assigned study therapy/randomization and date of death due to any cause.

Time frame: Up to approximately 367 weeks

Part 2A: Progression-free Survival (PFS)

PFS was defined as the interval between the date of first dose of study treatment (or date of randomization for randomized cohorts) and the date of disease progression according to radiological response from investigator assessment, or death due to any cause, whichever occurs earlier. Disease Progression was defined as the date of radiological disease progression based on imaging data per RECIST v1.1.

Time frame: Up to approximately 367 weeks

Part 2A: Time to Overall Response (TTR)

Time frame: Up to approximately 367 weeks

Part 2A: Duration of Response (DOR)

DOR was defined as the interval of time in months from the date of the first documented evidence of a response (confirmed CR or PR) to the date of first documented evidence of disease progression according to radiological response from investigator assessment per RECIST v1.1, or date of last adequate assessment of response or the date of death due to any cause (whichever occurs earlier). CR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<)10 mm. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters. Disease progression is defined as the date of radiological disease progression based on imaging data per RECIST v1.1.

Time frame: Up to approximately 367 weeks

Part 1B: Overall Response Rate (ORR)

ORR was defined as the percentage of participants with a confirmed irCR or confirmed irPR per irRECIST. irCR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. irPR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters.

Time frame: Up to approximately 367 weeks

Part 1B: Disease Control Rate (DCR)

DCR was defined as percentage of participants with best overall response of irCR or irPR at any time + irSD meeting the minimum time criteria from the start of treatment until irPD or death due to any cause or the start of new anticancer therapy/crossover. irCR is defined as disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm. irPR defined as at least 30% decrease in the sum of diameters of target lesions, taking as a reference, the baseline sum of the diameters. irSD defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease. IrPD defined as the date of radiological disease progression based on imaging data per irRECIST. A one-week visit window was considered in the duration of irSD, i.e. a minimum of 8 weeks (irSD\>=9 weeks) and 17 weeks (irSD\>=18 weeks) were considered.

Time frame: Up to approximately 367 weeks

Part 1B: Overall Survival (OS)

OS was defined as the interval between the date of first assigned study therapy/randomization and date of death due to any cause.

Time frame: Up to approximately 367 weeks

Part 1B: Progression-free Survival (PFS)

Time frame: Up to approximately 367 weeks

Part 1B: Time to Overall Response (TTR)

Time frame: Up to approximately 367 weeks

Part 1B: Duration of Response (DOR)

DOR was defined as the interval of time in months from the date of the first documented evidence of a response (confirmed CR or PR) to the date of first documented evidence of disease progression according to radiological response from investigator assessment per RECIST v1.1, or date of last adequate assessment of response or the date of death due to any cause (whichever occurs earlier). CR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<)10 mm. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters. Disease progression is defined as the date of radiological disease progression based on imaging data per RECIST v1.1.

Time frame: Up to approximately 367 weeks

Part 2B: Overall Response Rate (ORR)

Time frame: Up to approximately 367 weeks

Part 2B: Disease Control Rate (DCR)

DCR was defined as the percentage of participants with a best overall response of irCR or irPR at any time plus irSD meeting the minimum time criteria from the start of treatment until irPD or death due to any cause or the start of new anticancer therapy/crossover. irCR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. irPR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters. irSD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease. irPD is defined as the date of radiological disease progression based on imaging data per irRECIST. A one-week visit window was considered in the duration of irSD, i.e. a minimum of 8 weeks (irSD\>=9 weeks) and 17 weeks (irSD\>=18 weeks) were considered.

Time frame: Up to approximately 367 weeks

Part 2B: Overall Survival (OS)

OS was defined as the interval between the date of first assigned study therapy/randomization and date of death due to any cause.

Time frame: Up to approximately 367 weeks

Part 2B: Progression-free Survival (PFS)

Time frame: Up to approximately 367 weeks

Part 2B: Time to Overall Response (TTR)

Time frame: Up to approximately 367 weeks

Part 2B: Duration of Response (DOR)

DOR was defined as the interval of time in months from the date of the first documented evidence of a response (confirmed CR or PR) to the date of first documented evidence of disease progression according to radiological response from investigator assessment per RECIST v1.1, or date of last adequate assessment of response or the date of death due to any cause (whichever occurs earlier). CR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters. Disease progression is defined as the date of radiological disease progression based on imaging data per RECIST v1.1

Time frame: Up to approximately 367 weeks

Part 1A: Maximum Observed Plasma Concentration (Cmax) and Minimum Observed Plasma Concentration (Ctau) of Feladilimab

Blood samples were collected for Pharmacokinetic (PK) analysis. PK analysis was calculated based on standard non-compartmental method.

Time frame: Pre-dose; end of infusion (EOI); 0.5, 1, 2, 4, 6, 8, 24, 48-72, 96-120 hours POST EOI; week 1; week 2; Pre-dose and 0.5 hours POST EOI in week 3; week 4; week 5; Pre-dose and 0.5 hours POST EOI in week 6, 9, 12 15; Pre-dose in week 21 and 33

Part 1A: Area Under the Concentration-time Curve From Time 0 to 504 Hours After Dosing [AUC (0-504h)] of Feladilimab

Blood samples were collected for PK analysis. PK analysis was calculated based on standard non-compartmental method.

Time frame: Pre-dose; end of infusion (EOI); 0.5, 1, 2, 4, 6, 8, 24, 48-72, 96-120 hours post-EOI; week 1; week 2; Pre-dose and 0.5 hours post-EOI in week 3; week 4; week 5; Pre-dose and 0.5 hours post-EOI in week 6, 9, 12 15; Pre-dose in week 21 and 33

Part 2A: Ctau of Pembrolizumab

Blood samples were collected for PK analysis. PK analysis was calculated based on standard non-compartmental method.

Time frame: Pre-dose and 24 hours post-EOI on day 1; week 1; week 2; Pre-dose in week 3; week 4; week 5; Pre-dose in week 9, 15, 18, 21, 33, 45, 57, 69, 81 and 93

Part 2A: AUC (0-504h) of Pembrolizumab

Blood samples were collected for PK analysis. PK analysis was calculated based on standard non-compartmental method.

Time frame: Pre-dose and 24 hours post-EOI on day 1; week 1; week 2; Pre-dose in week 3; week 4; week 5; Pre-dose in week 9, 15, 18, 21, 33, 45, 57, 69, 81 and 93

Part 2A: Cmax and Ctau of GSK3174998

Blood samples were collected for PK analysis. PK analysis was calculated based on standard non-compartmental method.

Time frame: Pre-dose and 24 hours post-EOI on day 1; week 1; week 2; Pre-dose in week 3; week 4; week 5; Pre-dose in week 9, 15, 18, 21, 33, 45, 57, 69, 81 and 93

Part 2A: AUC (0-504 h) of GSK3174998

Blood samples were collected for PK analysis. PK analysis was calculated based on standard non-compartmental method.

Time frame: Pre-dose and 24 hours post-EOI on day 1; week 1; week 2; Pre-dose in week 3; week 4; week 5; Pre-dose in week 9, 15, 18, 21, 33, 45, 57, 69, 81 and 93

Part 1B: Cmax and Ctau of Feladilimab

Blood samples were collected for PK analysis. PK analysis was calculated based on standard non-compartmental method.

Part 1B: AUC (0-504 h) of Feladilimab

Blood samples were collected for PK analysis. PK analysis was calculated based on standard non-compartmental method.

Part 2B: Cmax and Ctau of Feladilimab

Blood samples were collected for PK analysis. PK analysis was calculated based on standard non-compartmental method.

Time frame: Pre-dose; EOI; 0.5, 1, 2, 4, 6, 8, 24, 48-72, 96-120 hours post-EOI; week 1; week 2; Pre-dose and 0.5 hours post-EOI in week 3; week 4; week 5; Pre-dose and 0.5, 4 hours post-EOI in week 6, 9, 12 and15; Pre-dose in week 18, 21, 33, 45, 57, 69, 81 and 93

Part 2B: AUC (0-504 h) of Feladilimab

Blood samples were collected for PK analysis. PK analysis was calculated based on standard non-compartmental method.

Part 2B: AUC (0-1008 h) of Feladilimab

Blood samples were collected for PK analysis. PK analysis was calculated based on standard non-compartmental method.

Part 2B: Cmax and Ctau of Pembrolizumab

Blood samples were collected for PK analysis. PK analysis was calculated based on standard non-compartmental method.

Part 2B: AUC (0-504h) of Pembrolizumab

Blood samples were collected for PK analysis. PK analysis was calculated based on standard non-compartmental method.

Part 1A: Number of Participants With Positive Results in Anti-drug Antibody (ADA) Test by Feladilimab Dose Level

Serum samples collected and tested for the presence of ADA with a screening assay.

Time frame: Up to approximately 367 weeks

Part 2A: Number of Participants With Positive Results in ADA Test by Feladilimab in Combination With GSK3174998 Dose Level

Serum samples collected and tested for the presence of ADA with a screening assay.

Time frame: Up to approximately 367 weeks

Part 2A: Number of Participants With Positive Results in ADA Test by Feladilimab Dose Level in Combination With Pembrolizumab

Serum samples collected and tested for the presence of ADA with a screening assay.

Time frame: Up to approximately 367 weeks

Part 2A: Number of Participants With Positive Results in ADA in Pembrolizumab

Serum samples collected and tested for the presence of ADA with a screening assay.

Time frame: Up to approximately 367 weeks

Part 2A: Number of Participants With Positive Results in ADA in GSK3174998

Serum samples collected and tested for the presence of ADA with a screening assay.

Time frame: Up to approximately 367 weeks

Part 2A: Number of Participants With Positive Results in ADA Test by Feladilimab Combination With Chemotherapies Dose Level

Serum samples collected and tested for the presence of ADA with a screening assay.

Time frame: Up to approximately 367 weeks

Part 1B: Number of Participants With Positive Results in ADA Test by Feladilimab Dose Level

Serum samples collected and tested for the presence of ADA with a screening assay.

Time frame: Up to approximately 367 weeks

Part 2B: Number of Participants With Positive Results in ADA Test by Feladilimab Dose Level

Serum samples collected and tested for the presence of ADA with a screening assay.

Time frame: Up to approximately 367 weeks

Part 2B: Number of Participants With Positive Results in ADA in Pembrolizumab

Serum samples collected and tested for the presence of ADA with a screening assay.

Time frame: Up to approximately 367 weeks

Part 1A: Receptor Occupancy of Feladilimab

Blood samples were collected to assess the cluster of differentiation 4 (CD4+) and cluster of differentiation 8 (CD8+) receptor occupancy by Feladilimab as a pharmacodynamic analysis. It was assessed using validated flow cytometry assay.

Time frame: Up to approximately 367 weeks

Part 2A: Receptor Occupancy of Feladilimab

Time frame: Up to approximately 367 weeks

Part 1B: Receptor Occupancy of Feladilimab

Time frame: Up to approximately 367 weeks

Part 2B: Receptor Occupancy of Feladilimab

Time frame: Up to approximately 367 weeks