Platform Trial of Novel Regimens Versus Standard of Care (SoC) in Participants With Non-small Cell Lung Cancer (NSCLC) - Sub-study 3

Phase 2

Completed

Conditions: Neoplasms

Interventions: Drug: Dostarlimab
Drug: Belrestotug.
Drug: Nelistotug

Registration Number: NCT06926673

Lead Sponsor: GlaxoSmithKline

Brief Summary: This study is a sub-study of the master protocol 205801 (NCT03739710). This sub study will assess safety and pharmacokinetics and pharmacodynamics (PK/PD) of novel regimens (Dostarlimab plus belrestotug , and Dostarlimab plus belrestotug plus nelistotug) in participants with previously treated NSCLC.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 62

Inclusion Criteria

Participants capable of giving signed informed consent/assent.
Male or female, aged 18 years or older at the time consent is obtained.
Participants with histologically or cytologically confirmed diagnosis of NSCLC (squamous or non-squamous) and
1. Documented disease progression based on radiographic imaging, during or after a maximum of 2 lines of systemic treatment for locally/regionally advanced recurrent, Stage IIIb/Stage IIIc/Stage IV or metastatic disease. Two components of treatment must have been received in the same line or as separate lines of therapy: i) No more than or less than 1 line of platinum-containing chemotherapy regimen, and ii) No more than or less than 1 line of Programmed cell death ligand 1 (PD[L]1) monoclonal antibody (mAb) containing regimen.
2. Participants with known V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF) molecular alterations must have had disease progression after receiving the locally available SoC treatment for the molecular alteration.
3. Participants who received prior anti-PD(L)1 therapy must fulfill the following requirements: i) Have achieved a CR, PR or SD and subsequently had disease progression (per RECIST 1.1 criteria) either on or after completing PD(L)1 therapy ii) Have not progressed or recurred within the first 12 weeks of PD(L)1 therapy, either clinically or per RECIST 1.1 criteria
Measurable disease, presenting with at least 1 measurable lesion per RECIST 1.1.
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 or 1.
A tumor tissue sample obtained at any time from the initial diagnosis of NSCLC to time of study entry is mandatory. Although a fresh tumor tissue sample obtained during screening is preferred, archival tumor specimen is acceptable.
Adequate organ function as defined in the protocol.
A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions apply:

i) Not a woman of childbearing potential (WOCBP) as defined in the protocol or ii) A WOCBP who agrees to follow the protocol defined contraceptive guidance during the treatment period and for at least 120 days after the last dose of study treatment.
Life expectancy of at least 12 weeks.

Exclusion Criteria

Participants who received prior treatment with the following therapies (calculation is based on date of last therapy to date of first dose of study treatment):

Docetaxel at any time.
Any of the investigational agents being tested in the current study.
Systemic approved or investigational 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 administered.
Prior radiation therapy: permissible if at least one non-irradiated measurable lesion is available for assessment per RECIST version 1.1 or if a solitary measurable lesion was irradiated, objective progression is documented. A wash out of at least 2 weeks before start of study drug for radiation of any intended use is required.
- Received greater than (>) 2 prior lines of therapy for NSCLC, including participants with BRAF molecular alternations.
- Invasive malignancy or history of invasive malignancy other than disease under study within the last 2 years.
- Carcinomatous meningitis (regardless of clinical status) and uncontrolled or symptomatic Central nervous system (CNS) metastases.
- Major surgery less than or equal to (<=) 28 days of first dose of study treatment.
- Autoimmune disease (current or history) or syndrome that required systemic treatment within the past 2 years. Replacement therapies which include physiological doses of corticosteroids for treatment of endocrinopathies (for example, adrenal insufficiency) are not considered systemic treatments.
- Receiving systemic steroids (>10 milligrams [mg]) oral prednisone or equivalent) or other immunosuppressive agents within 7 days prior to first dose of study treatment. Steroids as premedication for hypersensitivity reactions (e.g., computed tomography [CT] scan premedication) are permitted.
- Prior allogeneic/autologous bone marrow or solid organ transplantation.
- Receipt of any live vaccine within 30 days prior to first dose of study treatment.
- Toxicity from previous anticancer treatment that includes:
Greater than or equal to (>=) Grade 3 toxicity considered related to prior immunotherapy and that led to treatment discontinuation.
History of myocarditis of any grade during a previous treatment with immunotherapy 3. Toxicity related to prior treatment that has not resolved to <= Grade 1 (except alopecia, hearing loss, endocrinopathy managed with replacement therapy, and peripheral neuropathy which must be <= Grade 2).

History (current and past) of idiopathic pulmonary fibrosis, pneumonitis (for pastpneumonitis exclusion only if steroids were required for treatment), interstitial lung disease, or organizing pneumonia.
Recent history (within the past 6 months) of uncontrolled symptomatic ascites, pleural or pericardial effusions.
Recent history (within the past 6 months) of gastrointestinal obstruction that required surgery, acute diverticulitis, inflammatory bowel disease, or intra-abdominal abscess.
History or evidence of cardiac abnormalities within the 6 months prior to enrollment which include
1. Serious, uncontrolled cardiac arrhythmia or clinically significant electrocardiogram abnormalities including second degree (Type II) or third degree atrioventricular block.
2. Cardiomyopathy, myocardial infarction, acute coronary syndromes (including unstable angina pectoris), coronary angioplasty, stenting or bypass grafting.
3. Symptomatic pericarditis.
Current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypo-albuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis.
Active infection requiring systemic therapy <=7 days prior to first dose of study treatment.
Participants with known human immunodeficiency virus infection.
Participants with history of severe hypersensitivity to mAbs or hypersensitivity to any of the study treatment(s) or their excipients.
Any serious and/or unstable pre-existing medical (aside from malignancy), psychiatric disorder, or other condition that could interfere with participant's safety, obtaining informed consent, or compliance to the study procedures in the opinion of the investigator.
Pregnant or lactating female participants.
Participant who is currently participating in or has participated in a study of an investigational device within 4 weeks prior to the first dose of study treatment.
Participants with presence of hepatitis B surface antigen (HBsAg) at screening or within 3 months prior to first dose of study intervention.
Participants with positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study intervention.
Participants with positive hepatitis C ribonucleic acid (RNA) test result at screening or within 3 months prior to first dose of study treatment.
Receipt of 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 intervention.
Known hypersensitivity to components or excipients of dostarlimab, belrestotug, and/or nelistotug
Has received prior antibodies or drugs targeting TIGIT, CD96, PVRIG, or other therapies targeting the CD226 axis pathway

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Dostarlimab plus Belrestotug	Dostarlimab	-
Dostarlimab plus Belrestotug	Belrestotug.	-
Dostarlimab plus Belrestotug plus Nelistotug	Dostarlimab	-
Dostarlimab plus Belrestotug plus Nelistotug	Belrestotug.	-
Dostarlimab plus Belrestotug plus Nelistotug	Nelistotug	-

Primary Outcome Measures

Name	Time	Method
Part 1: Number of Participants With Worst-case Post Baseline Relative to Baseline ECG Findings (Arm 5)	Up to approximately 107 weeks	Number of participants with worst-case post baseline (WCPB) from baseline ECG findings is summarized as clinically significant. Data is summarized as Normal, Abnormal - Not Clinically Significant (NCS) and Abnormal - Clinically Significant (CS). Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Worst Case Post-Baseline includes all scheduled and unscheduled visits post baseline.
Part 1: Number of Participants Requiring Dose Modifications (Arm 4)	Up to approximately 97 weeks	Number of participants with dose modifications (missed doses, dose delays and infusion interruptions) is summarized.
Part 1: Number of Participants With Any Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) (Arm 4)	Up to approximately 97 weeks	An AE 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. SAE is defined as any untoward medical occurrence that, at any dose resulted in death, is life threatening, required hospitalization or prolongation of existing hospitalization, resulted in disability/ incapacity, is a congenital anomaly/ birth defect, other situations and is associated with liver injury or impaired liver function. SAEs are subset of AEs. A TEAE is any event that was not present prior to the initiation of study treatment or any event already present that worsens in either intensity or frequency following exposure to study treatment. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) coding system.
Part 1: Number of Participants With Any TEAEs and SAEs (Arm 5)	Up to approximately 107 weeks	An AE 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. SAE is defined as any untoward medical occurrence that, at any dose resulted in death, is life threatening, required hospitalization or prolongation of existing hospitalization, resulted in disability/ incapacity, is a congenital anomaly/ birth defect, other situations and is associated with liver injury or impaired liver function. SAEs are subset of AEs. A TEAE is any event that was not present prior to the initiation of study treatment or any event already present that worsens in either intensity or frequency following exposure to study treatment. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) coding system.
Part 1: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (Arm 5)	Up to approximately 107 weeks	Performance Status was assessed using the ECOG scale (Grades 0-5), where 0: Fully active, able to carry on all pre-disease performance without restriction. Grade 1: Restricted in physically strenuous activity but ambulatory \& able to carry out work of light or sedentary nature; Grade 2 - Ambulatory \& capable of all self-care but unable to carry out any work activities. Up and about more than (\>) 50% of waking hours; Grade 3 -Capable of only limited self-care, confined to bed or chair \> 50% of waking hours; Grade 4 -Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair; Grade 5 -Dead
Part 1: Number of Participants With Worst-case Post Baseline Relative to Baseline Electrocardiogram (ECG) Findings (Arm 4)	Up to approximately 97 weeks	Number of participants with worst-case post baseline (WCPB) from baseline ECG findings is summarized as clinically significant. Data is summarized as Normal, Abnormal - Not Clinically Significant (NCS) and Abnormal - Clinically Significant (CS). Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Worst Case Post-Baseline includes all scheduled and unscheduled visits post baseline.
Part 1: Number of Participants With Dose Limiting Toxicity (DLT) (Arm 4 and Arm 5)	Up to 21 days	A DLT is an AE meeting criteria such as, hematologic toxicities of Grade (G) 4 neutropenia/anemia/thrombocytopenia (G3 if bleeding). Non-hematological toxicities include persistent G2 eye events, colitis/diarrhea (G2 unresolved to ≤ G1 within 7 days despite immunosuppressive therapy, G3 for ≥ 72 hours, any G4), G3 pneumonitis, rash (unresolved to ≤ G2 within 2 weeks despite treatment), hypersensitivity/IRR, liver events meeting Hy's Law criteria. G3 toxicity unresolved to ≤G1 or baseline within 3 days with supportive care, or any G4 toxicity. Exclusions include G3 events of electrolyte imbalances correctable within 72 hours without effects, nausea/vomiting/fatigue resolving within 7 days, lymphopenia, and enzyme elevations without pancreatitis. Considerations for DLTs include permanent treatment discontinuation, investigator/sponsor judgment-based events including post-observation period toxicities.
Part 1: Number of Participants Requiring Dose Modifications (Arm 5)	Up to approximately 107 weeks	Number of participants with dose modifications (missed doses, dose delays and infusion interruptions) is summarized.
Part 1: Number of Participants With Worst-case Post Baseline Relative to Baseline in Left Ventricular Ejection Fraction (LVEF) (Arm 5)	Up to approximately 107 weeks	Number of participants with worst case post-baseline in LVEF from baseline is summarized as 'any decrease (\>0%-\<10% Decrease, 10%-19% Decrease, \>=20% Decrease)', '\>=10% Decrease and \>= Lower limit of normal (LLN)', '\>=10% Decrease and \< LLN', '\>=20% Decrease and \>= LLN' and '\>=20% Decrease and \< LLN' . An increase is defined as an increase in grade relative to Baseline grade. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Worst Case Post-Baseline includes all scheduled and unscheduled visits post baseline.
Part 1: Number of Participants With Worst Case Change Post-baseline in Clinical Chemistry Parameters (Arm 4)	Up to approximately 97 weeks	Blood samples were collected for analysis of clinical chemistry. The summaries of worst-case post baseline (WCPB) from baseline (B) with respect to normal range was analyzed. Data is presented as "XXX B YYY, WCPB YYY", where XXX denotes lab parameter and YYY is high/normal/low. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Worst Case Post-Baseline includes all scheduled and unscheduled visits post baseline.
Part 2: Overall Survival (OS)	Up to approximately 107 weeks	OS is defined as the time from date of randomization to the date of death, irrespective of the cause of death.
Part 1: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (Arm 4)	Up to approximately 97 weeks	Performance Status was assessed using the ECOG scale (Grades 0-5), where 0: Fully active, able to carry on all pre-disease performance without restriction. Grade 1: Restricted in physically strenuous activity but ambulatory \& able to carry out work of light or sedentary nature; Grade 2 - Ambulatory \& capable of all self-care but unable to carry out any work activities. Up and about more than (\>) 50% of waking hours; Grade 3 -Capable of only limited self-care, confined to bed or chair \> 50% of waking hours; Grade 4 -Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair; Grade 5 -Dead.
Part 1: Number of Participants With Worst-case Post Baseline Increase From Baseline in Vital Signs (Arm 4)	Up to approximately 97 weeks	Vital signs including systolic blood pressure (SBP), diastolic BP (DBP), pulse rate (PR) and body temperature (BT) were measured for the participants. DBP: Grade 0 (\<80 millimeters of mercury \[mmHg\]), Grade 1 (80-89 mmHg), Grade 2 (90-99 mmHg), Grade 3 (\>=100 mmHg); SBP: Grade 0 (\<120 mmHg), Grade 1 (120-139 mmHg), Grade 2 (140-159 mmHg), Grade 3 (\>=160 mmHg); PR categories include: 'Decrease to \< 60 beats per minutes \[bpm\]', 'Change to Normal' or 'No Change', and 'Increase to \>100 bpm'; BT categories include 'Decrease to \<=35 degrees Celsius °C', 'Change to Normal' or 'No Change', and 'Increase to \>=38 °C'. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Worst Case Post-Baseline includes all scheduled and unscheduled visits post baseline.
Part 1: Number of Participants With Worst-case Post Baseline Increase From Baseline in Vital Signs (Arm 5)	Up to approximately 107 weeks	Vital signs including systolic blood pressure (SBP), diastolic BP (DBP), pulse rate (PR) and body temperature (BT) were measured for the participants. DBP: Grade 0 (\<80 millimeters of mercury \[mmHg\]), Grade 1 (80-89 mmHg), Grade 2 (90-99 mmHg), Grade 3 (\>=100 mmHg); SBP: Grade 0 (\<120 mmHg), Grade 1 (120-139 mmHg), Grade 2 (140-159 mmHg), Grade 3 (\>=160 mmHg); PR categories include: 'Decrease to \< 60 beats per minutes \[bpm\]', 'Change to Normal' or 'No Change', and 'Increase to \>100 bpm'; BT categories include 'Decrease to \<=35 degrees Celsius °C', 'Change to Normal' or 'No Change', and 'Increase to \>=38 °C'. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Worst Case Post-Baseline includes all scheduled and unscheduled visits post baseline.
Part 1: Number of Participants Who Received Concomitant Medications (Arm 5)	Up to approximately 107 weeks	Number of participants who received Concomitant medications is summarized.
Part 1: Number of Participants With Worst-case Post Baseline Relative to Baseline in QTcF Interval (Arm 4)	Up to approximately 97 weeks	The QTcF values based on Fridericia formula were rounded to the integer and the values are categorized into the following ranges, inclusively: Grade 0 (\<450 millisecond (msec)), Grade 1 (≥450-≤480 msec), Grade 2 (≥481-≤500 msec), and Grade 3 (≥501 msec). Missing baseline grades were assumed to be Grade 0. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Worst Case Post-Baseline includes all scheduled and unscheduled visits post baseline.
Part 1: Number of Participants With Worst Case Hematology Results by Maximum Grade Increase Post-Baseline Relative to Baseline (Arm 4)	Up to approximately 97 weeks	Blood samples were collected for the analysis of hematology parameters and are categorized in alignment with Common Terminology Criteria for Adverse Events (CTCAE) version 5 as Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; and Grade 4: life-threatening consequences. Higher grade indicates greater severity. An increase in grade is defined relative to the Baseline grade. Participants with missing baseline values are assumed to have baseline value of grade 0. Any worst-case post baseline increase in grade along with any increase to a maximum grade of 3 and 4 is summarized. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Worst Case Post-Baseline includes all scheduled and unscheduled visits post baseline.
Part 1: Number of Participants With Worst-Case Urinalysis Results Post-Baseline Relative to Baseline (Arm 4)	Up to approximately 97 weeks	Urinalysis was performed. Participants with missing value at baseline are assumed to be negative at baseline. All increases are from baseline. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits.
Part 1: Number of Participants With Worst-Case Urinalysis Results Post-Baseline Relative to Baseline (Arm 5)	Up to approximately 107 weeks	Urinalysis was performed. Participants with missing value at baseline are assumed to be negative at baseline. All increases are from baseline. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits.
Part 1: Number of Participants Who Received Concomitant Medications (Arm 4)	Up to approximately 97 weeks	Number of participants who received Concomitant medications is summarized.
Part 1: Number of Participants With Worst Case Change Post-baseline in Clinical Chemistry Parameters (Arm 5)	Up to approximately 107 weeks	Blood samples were collected for analysis of clinical chemistry. The summaries of worst-case post baseline (WCPB) from baseline (B) with respect to normal range was analyzed. Data is presented as "XXX B YYY, WCPB YYY", where XXX denotes lab parameter and YYY is high/normal/low. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Worst Case Post-Baseline includes all scheduled and unscheduled visits post baseline.
Part 1: Number of Participants With Worst-case Post Baseline Relative to Baseline in QTcF Interval (Arm 5)	Up to approximately 107 weeks	The QTcF values based on Fridericia formula were rounded to the integer and the values are categorized into the following ranges, inclusively: Grade 0 (\<450 millisecond (msec)), Grade 1 (≥450-≤480 msec), Grade 2 (≥481-≤500 msec), and Grade 3 (≥501 msec). Missing baseline grades were assumed to be Grade 0. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Worst Case Post-Baseline includes all scheduled and unscheduled visits post baseline.
Part 1: Number of Participants With Worst Case Clinical Chemistry Results by Maximum Grade Increase Post-Baseline Relative to Baseline (Arm 4)	Up to approximately 97 weeks	Blood samples were collected for the analysis of clinical chemistry parameters and are categorized in alignment with Common Terminology Criteria for Adverse Events (CTCAE) version 5 as Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; and Grade 4: life-threatening consequences. Higher grade indicates greater severity. An increase in grade is defined relative to the Baseline grade. Participants with missing baseline values are assumed to have baseline value of grade 0. Any worst-case post baseline increase in grade along with any increase to a maximum grade of 3 and 4 is summarized. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Worst Case Post-Baseline includes all scheduled and unscheduled visits post baseline.
Part 1: Number of Participants With Worst Case Clinical Chemistry Results by Maximum Grade Increase Post-Baseline Relative to Baseline (Arm 5)	Up to approximately 107 weeks	Blood samples were collected for the analysis of clinical chemistry parameters and are categorized in alignment with Common Terminology Criteria for Adverse Events (CTCAE) version 5 as Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; and Grade 4: life-threatening consequences. Higher grade indicates greater severity. An increase in grade is defined relative to the Baseline grade. Participants with missing baseline values are assumed to have baseline value of grade 0. Any worst-case post baseline increase in grade along with any increase to a maximum grade of 3 and 4 is summarized. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Worst Case Post-Baseline includes all scheduled and unscheduled visits post baseline.
Part 1: Number of Participants With Worst-case Post Baseline Relative to Baseline in Left Ventricular Ejection Fraction (LVEF) (Arm 4)	Up to approximately 97 weeks	Number of participants with worst case post-baseline in LVEF from baseline is summarized as 'any decrease (\>0%-\<10% Decrease, 10%-19% Decrease, \>=20% Decrease)', '\>=10% Decrease and \>= Lower limit of normal (LLN)', '\>=10% Decrease and \< LLN', '\>=20% Decrease and \>= LLN' and '\>=20% Decrease and \< LLN' . An increase is defined as an increase in grade relative to Baseline grade. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Worst Case Post-Baseline includes all scheduled and unscheduled visits post baseline.
Part 1: Number of Participants With Worst Case Hematology Results by Maximum Grade Increase Post-Baseline Relative to Baseline (Arm 5)	Up to approximately 107 weeks	Blood samples were collected for the analysis of hematology parameters and are categorized in alignment with Common Terminology Criteria for Adverse Events (CTCAE) version 5 as Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; and Grade 4: life-threatening consequences. Higher grade indicates greater severity. An increase in grade is defined relative to the Baseline grade. Participants with missing baseline values are assumed to have baseline value of grade 0. Any worst-case post baseline increase in grade along with any increase to a maximum grade of 3 and 4 is summarized. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Worst Case Post-Baseline includes all scheduled and unscheduled visits post baseline.

Secondary Outcome Measures

Name	Time	Method
Part 1: Maximum Observed Concentration (Cmax) and Minimum Observed Concentration (Cmin) of Belrestotug (Arm 5)	Up to 21 days (Cycle 1)	Blood samples were collected for pharmacokinetic analysis of Belrestotug.
Part 1: Cmax and Cmin of Dostarlimab (Arm 4)	Up to 21 days (Cycle 1)	Blood samples were collected for pharmacokinetic analysis of Dostarlimab.
Part 1: Cmax and Cmin of Dostarlimab (Arm 5)	Up to 21 days (Cycle 1)	Blood samples were collected for pharmacokinetic analysis of Dostarlimab.
Part 1: Objective Response Rate (ORR) (Arm 5)	Up to approximately 107 weeks	ORR is defined as the percentage of participants with a best overall confirmed CR or PR at any time as per disease-specific criteria per RECIST version 1.1. CR is defined as disappearance of all target and non-target lesions and any pathological lymph nodes must be \<10 millimeter (mm) in the short axis. 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 (e.g. percent change from baseline).
Part 1: Disease Control Rate (DCR) (Arm 4)	Up to approximately 97 weeks	DCR is defined as the percentage of participants with a confirmed CR + PR at any time, plus SD =\>12 weeks as per RECIST v1.1. Complete Response (CR) is defined as disappearance of all target and non-target lesions and any pathological lymph nodes must be \<10 millimeter (mm) in the short axis. Partial Response (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 (e.g. percent change from baseline). Stable Disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease.
Part 2: Survival Rate at 12 and 18 Months	At 12 and 18 months	Survival rate was planned to be anaysed at 12 and 18 months
Part 2: Duration of Response (DOR)	Up to approximately 107 weeks	DOR is defined as the time for first documented evidence of CR or PR until disease progression or death, per RECIST 1.1 criteria. Complete Response (CR) is defined as disappearance of all target and non target lesions and any pathological lymph nodes must be \<10 millimeter (mm) in the short axis. Partial Response (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.
Part 1: Objective Response Rate (ORR) (Arm 4)	Up to approximately 97 weeks	ORR is defined as the percentage of participants with a best overall confirmed Complete response (CR) or Partial response (PR) at any time as per disease-specific criteria per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Complete Response (CR) is defined as disappearance of all target and non-target lesions and any pathological lymph nodes must be \<10 millimeter (mm) in the short axis. Partial Response (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 (e.g. percent change from baseline).
Part 2: Number of Participants With Complete Response (CR), Partial Response (PR), Stable Disease (SD) and Progressive Disease (PD)	Up to approximately 107 weeks	CR, PR, SD and PD was planned to be evaluated as per RECIST version 1.1 criteria. Complete Response (CR) is defined as disappearance of all target and non-target lesions and any pathological lymph nodes must be \<10 millimeter (mm) in the short axis. Partial Response (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 (e.g. percent change from baseline). Stable Disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease. Progressive Disease is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g. percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5mm.
Part 2: Progression-free Survival (PFS)	Up to approximately 107 weeks	PFS is defined as time from the date of randomization to the date of disease progression as per RECIST v1.1. or death whichever occurs earlier. Progressive Disease is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g. percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5mm.
Part 1: Disease Control Rate (DCR) (Arm 5)	Up to approximately 107 weeks	DCR is defined as the percentage of participants with a confirmed CR + PR at any time, plus SD =\>12 weeks as per RECIST v1.1. Complete Response (CR) is defined as disappearance of all target and non-target lesions and any pathological lymph nodes must be \<10 millimeter (mm) in the short axis. Partial Response (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 (e.g. percent change from baseline). Stable Disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease.
Part 1: Maximum Observed Concentration (Cmax) and Minimum Observed Concentration (Cmin) of Belrestotug (Arm 4)	Up to 21 days (Cycle 1)	Blood samples were collected for pharmacokinetic analysis of Belrestotug.
Part 1: Cmax and Cmin of Nelistotug (Arm 5)	Up to 21 days (Cycle 1)	Blood samples were collected for pharmacokinetic analysis of Nelistotug.
Part 2: Objective Response Rate (ORR)	Up to approximately 107 weeks	ORR is defined as the percentage of participants with a best overall confirmed Complete response (CR) or Partial response (PR) at any time as per disease-specific criteria per RECIST version 1.1. Complete Response (CR) is defined as disappearance of all target and non target lesions and any pathological lymph nodes must be \<10 millimeter (mm) in the short axis. Partial Response (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 (e.g. percent change from baseline).
Part 2: Progression-free Survival (iPFS)	Up to approximately 107 weeks	iPFS is defined as time from the date of randomization to the date of disease progression or death, whichever occurs earlier, per iRECIST criteria. Progressive Disease is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g. percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5mm.
Part 2: Duration of Response (iDOR)	Up to approximately 107 weeks	iDOR is defined as the time from first documented evidence of CR or PR until disease progression or death, per iRECIST criteria. iCR is defined as disappearance of all target and non target lesions and any pathological lymph nodes must be \<10 millimeter (mm) in the short axis. iPR 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.
Part 2: Disease Control Rate (DCR)	Up to approximately 107 weeks	DCR is defined as the percentage of participants with a confirmed CR + PR at any time, plus SD =\>12 weeks as per RECIST v1.1. Complete Response (CR) is defined as disappearance of all target and non target lesions and any pathological lymph nodes must be \<10 millimeter (mm) in the short axis. Partial Response (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 (e.g. percent change from baseline). Stable Disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease.
Part 2: Number of Participants With Immune-based (i) Complete Response (iCR), Partial Response (iPR), Unconfirmed Progressive Disease (iUPD), Confirmed Progressive Disease (iCPD), and Stable Disease (iSD)	Up to approximately 107 weeks	Modified RECIST 1.1 for immune-based therapeutics (iRECIST) is based on RECIST v 1.1 but adapted to account for the unique tumor response seen with immunotherapeutic drugs. iRECIST is used to assess tumor response and progression and make treatment decisions. iCR: disappearance of all target lesions; iPR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters (e.g. percent change from baseline). iCPD: either 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; iSD: stable disease in the absence of CR or PD and iUPD: unconfirmed progressive disease when PD is unconfirmed and NE: not evaluable.
Part 2: Number of Participants With Clinically Significant Changes in Vital Signs and Laboratory Parameters	Up to approximately 107 weeks	Clinically significant changes in vital signs were planned to be assessed. Blood samples were planned to be collected for the analysis of laboratory parameters.
Part 2: Objective Response Rate (iORR)	Up to approximately 107 weeks	iORR is defined as the percentage of participants with a confirmed iCR or iPR at any time per iRECIST criteria. iCR is defined as disappearance of all target and non target lesions and any pathological lymph nodes must be \<10 millimeter (mm) in the short axis. iPR 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.
Part 2: Number of Participants With Positive Anti-drug Antibodies (ADA)	Up to approximately 107 weeks	Serum samples were planned to be collected for the analysis of the presence of ADAs using validated immunoassays.
Part 2: Number of Participants With AEs, SAEs, Adverse Events of Special Interest (AESI), AE/SAEs Leading to Dose Modifications/Delays/Withdrawals	Up to approximately 107 weeks	An AE is defined as any untoward medical occurrence in a clinical study participant, 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 in-patient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect, any other situation such as important medical events according to medical or scientific judgement. AESI are considered to be Infusion Related Reactions (IRRs) and those of potential immunologic etiology. AEs were planned to be coded using the MedDRA coding system.
Part 2: Cmax and Cmin for Dostarlimab	Up to approximately 107 weeks	Blood samples were planned to be collected to assess the pharmacokinetics of Dostarlimab.
Part 2: Cmax and Cmin for Belrestotug	Up to approximately 107 weeks	Blood samples were planned to be collected to assess the pharmacokinetics of Belrestotug.

Trial Locations

Locations (2): GSK Investigational SIte
🇺🇸
Nashville, Tennessee, United States
GSK Investigational Site
🇪🇸
Malaga, Spain
GSK Investigational SIte
🇺🇸Nashville, Tennessee, United States