Safety and Efficacy of LAG525 Single Agent and in Combination With PDR001 in Patients With Advanced Malignancies.

Phase 1

Completed

Conditions: Advanced Solid Tumors

Interventions: Drug: LAG525
Drug: PDR001

Registration Number: NCT02460224

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: This study was to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and anti-tumor activity of LAG525 as a single agent and in combination with PDR001 to adult patients with solid tumors. The study consists of a dose escalation (phase 1) to determine the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) for LAG525 as a single agent and in combination with PDR001, and a dose expansion (phase 2) which characterized treatment of LAG525 in combination with PDR001 at the MTD or RP2D.

Detailed Description: This was a Phase 1/2, multi-center, open-label study comprising a Phase 1 dose escalation part followed by a Phase 2 dose expansion part.

During the Phase 1 dose escalation part patients with any advanced solid tumor received the study treatment until the MTD was reached or a lower RP2D was established. The study had the following 3 dose escalation parts: 1) Single-agent LAG525; 2) Single-agent LAG525 in Japanese patients; 3) Combination of LAG525 with PDR001.

Once the RP2D or MTD had been determined in the escalation parts, additional patients were to be enrolled in the Phase 2 expansion parts in order to assess the preliminary anti-tumor activity. Phase 2 expansion cohorts testing single-agent LAG525 were not opened for enrollment based on emerging data including but not limited to preliminary anti-tumor activity. Phase 2 expansion cohorts for the combination of LAG525 with PDR001 were opened and 5 tumor types were assessed: 1) Non-small cell lung cancer (NSCLC); 2) Melanoma; 3) Renal cell cancer (RCC); 4) Mesothelioma; 5) Triple negative breast cancer (TNBC). The efficacy and safety of the combination of LAG525 with PDR001 in these tumor types was assessed in both the PD-1/PD-L1 pre-treated and naïve settings.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 490

Inclusion Criteria

Phase I part:

Patients with advanced/metastatic solid tumors, with measurable or non-measurable disease as determined by RECIST version 1.1, who have progressed despite standard therapy or are intolerant of standard therapy, or for whom no standard therapy exists

Phase II part:

Patients with advanced/metastatic solid tumors, with at least one measurable lesion as determined by RECIST version 1.1, who have had disease progression following their last prior therapy and fit into one of the following groups:
Group 1: NSCLC
Group 2: Melanoma
Group 3: Renal cancer
Group 4: Mesothelioma
Group 5: TNBC
Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1
Patient must have a site of disease amenable to biopsy, and be a candidate for tumor biopsy.

Exclusion Criteria

History of severe hypersensitivity reactions to study treatment ingredients or other mAbs
Active, known or suspected autoimmune disease
Active infection requiring systemic antibiotic therapy
HIV infection. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
Patients receiving chronic treatment with systemic steroid therapy, other than replacement-dose corticosteroids in the setting of adrenal insufficiency
Patients receiving systemic treatment with any immunosuppressive medication
Use of live vaccines against infectious disease within 4 weeks of initiation of study treatment
Systemic anti-cancer therapy within 2 weeks of the first dose of study treatment.
Presence of symptomatic central nervous system (CNS) metastases or CNS metastases that require local CNS-directed therapy or increasing doses of corticosteroids within the prior 2 weeks
History of drug-induced pneumonitis or current pneumonitis.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Phase 1: LAG525 0.3 mg/kg Q2W + PDR001 1 mg/kg Q2W	PDR001	Combination LAG525 0.3 mg/kg + PDR001 1 mg/kg (Q2W/Q2W)
Phase 1: LAG525 240 mg Q2W + PDR001 240 mg Q2W	PDR001	Combination LAG525 240 mg + PDR001 240 mg (Q2W/Q2W)
Phase 1: LAG525 80 mg Q2W + PDR001 80 mg Q2W	PDR001	Combination LAG525 80 mg + PDR001 80 mg (Q2W/Q2W)
Phase 2: Naive - LAG525 600 mg Q4W + PDR001 400 mg Q4W	PDR001	Combination LAG525 600 mg + PDR001 400 mg (Q4W/Q4W) in patients naïve to anti-PD-1/PD-L1
Phase 1: LAG525 80 mg Q4W + PDR001 240 mg Q4W	PDR001	Combination LAG525 80 mg + PDR001 240 mg (Q4W/Q4W)
Phase 1: LAG525 0.3 mg/kg Q2W + PDR001 1 mg/kg Q2W	LAG525	Combination LAG525 0.3 mg/kg + PDR001 1 mg/kg (Q2W/Q2W)
Phase 1: LAG525 80 mg Q2W + PDR001 80 mg Q2W	LAG525	Combination LAG525 80 mg + PDR001 80 mg (Q2W/Q2W)
Phase 1: LAG525 10 mg/kg Q2W	LAG525	Single-agent LAG525 10 mg/kg Q2W
Phase 1: LAG525 1 mg/kg Q2W	LAG525	Single-agent LAG525 1 mg/kg Q2W
Phase 1: LAG525 1 mg/kg Q2W + PDR001 1 mg/kg Q2W	PDR001	Combination LAG525 1 mg/kg + PDR001 1 mg/kg (Q2W/Q2W)
Phase 1: LAG525 400 mg Q4W + PDR001 400 mg Q4W	LAG525	Combination LAG525 400 mg + PDR001 400 mg (Q4W/Q4W)
Phase 1: LAG525 1000 mg Q4W + PDR001 400 mg Q4W	PDR001	Combination LAG525 1000 mg + PDR001 400 mg (Q4W/Q4W)
Phase 1: LAG525 240 mg Q3W + PDR001 300 mg Q3W	LAG525	Combination LAG525 240 mg + PDR001 300 mg (Q3W/Q3W)
Phase 1: LAG525 3 mg/kg Q2W	LAG525	Single-agent LAG525 3 mg/kg Q2W
Phase 1: LAG525 80 mg Q2W + PDR001 240 mg Q2W	PDR001	Combination LAG525 80 mg + PDR001 240 mg (Q2W/Q2W)
Phase 1: LAG525 5 mg/kg Q2W	LAG525	Single-agent LAG525 5 mg/kg Q2W
Phase 1: LAG525 240 mg Q2W	LAG525	Single-agent LAG525 240 mg Q2W
Phase 1: LAG525 240 mg Q2W + PDR001 400 mg Q4W	PDR001	Combination LAG525 240 mg + PDR001 400 mg (Q2W/Q4W)
Phase 1: LAG525 300 mg Q2W + PDR001 400 mg Q4W	PDR001	Combination LAG525 300 mg + PDR001 400 mg (Q2W/Q4W)
Phase 2: Naive - LAG525 400 mg Q3W + PDR001 300 mg Q3W	LAG525	Combination LAG525 400 mg + PDR001 300 mg (Q3W/Q3W) in patients naïve to anti-PD-1/PD-L1
Phase 1: LAG525 80 mg Q2W + PDR001 400 mg Q4W	PDR001	Combination LAG525 80 mg + PDR001 400 mg (Q2W/Q4W)
Phase 1: LAG525 240 mg Q3W + PDR001 300 mg Q3W	PDR001	Combination LAG525 240 mg + PDR001 300 mg (Q3W/Q3W)
Phase 1: LAG525 600 mg Q3W + PDR001 300 mg Q3W	LAG525	Combination LAG525 600 mg + PDR001 300 mg (Q3W/Q3W)
Phase 1: LAG525 600 mg Q3W + PDR001 300 mg Q3W	PDR001	Combination LAG525 600 mg + PDR001 300 mg (Q3W/Q3W)
Phase 2: Pre-treated - LAG525 400 mg Q3W + PDR001 300 mg Q3W	PDR001	Combination LAG525 400 mg + PDR001 300 mg (Q3W/Q3W) in patients pre-treated with anti-PD-1/PD-L1
Phase 1: LAG525 400 mg Q3W + PDR001 300 mg Q3W	PDR001	Combination LAG525 400 mg + PDR001 300 mg (Q3W/Q3W)
Phase 1: LAG525 800 mg Q4W + PDR001 400 mg Q4W	PDR001	Combination LAG525 800 mg + PDR001 400 mg (Q4W/Q4W)
Phase 1: LAG525 240 mg Q2W + PDR001 400 mg Q4W	LAG525	Combination LAG525 240 mg + PDR001 400 mg (Q2W/Q4W)
Phase 2: Naive - LAG525 400 mg Q3W + PDR001 300 mg Q3W	PDR001	Combination LAG525 400 mg + PDR001 300 mg (Q3W/Q3W) in patients naïve to anti-PD-1/PD-L1
Phase 1: LAG525 400 mg Q4W + PDR001 400 mg Q4W	PDR001	Combination LAG525 400 mg + PDR001 400 mg (Q4W/Q4W)
Phase 1: LAG525 1000 mg Q4W + PDR001 400 mg Q4W	LAG525	Combination LAG525 1000 mg + PDR001 400 mg (Q4W/Q4W)
Phase 1: LAG525 400 mg Q2W	LAG525	Single-agent LAG525 400 mg Q2W
Phase 1: LAG525 3 mg/kg Q4W	LAG525	Single-agent LAG525 3 mg/kg Q4W
Phase 1: LAG525 10 mg/kg Q4W	LAG525	Single-agent LAG525 10 mg/kg Q4W
Phase 1: LAG525 5 mg/kg Q4W	LAG525	Single-agent LAG525 5 mg/kg Q4W
Phase 1: LAG525 80 mg Q2W + PDR001 240 mg Q2W	LAG525	Combination LAG525 80 mg + PDR001 240 mg (Q2W/Q2W)
Phase 1: LAG525 240 mg Q2W + PDR001 240 mg Q2W	LAG525	Combination LAG525 240 mg + PDR001 240 mg (Q2W/Q2W)
Phase 1: LAG525 15 mg/kg Q2W	LAG525	Single-agent LAG525 15 mg/kg Q2W
Phase 1: LAG525 400 mg Q4W	LAG525	Single-agent LAG525 400 mg Q4W
Phase 1: LAG525 1 mg/kg Q2W + PDR001 1 mg/kg Q2W	LAG525	Combination LAG525 1 mg/kg + PDR001 1 mg/kg (Q2W/Q2W)
Phase 1: LAG525 300 mg Q2W + PDR001 400 mg Q4W	LAG525	Combination LAG525 300 mg + PDR001 400 mg (Q2W/Q4W)
Phase 1: LAG525 400 mg Q3W + PDR001 300 mg Q3W	LAG525	Combination LAG525 400 mg + PDR001 300 mg (Q3W/Q3W)
Phase 1: LAG525 80 mg Q4W + PDR001 240 mg Q4W	LAG525	Combination LAG525 80 mg + PDR001 240 mg (Q4W/Q4W)
Phase 2: Naive - LAG525 600 mg Q4W + PDR001 400 mg Q4W	LAG525	Combination LAG525 600 mg + PDR001 400 mg (Q4W/Q4W) in patients naïve to anti-PD-1/PD-L1
Phase 1: LAG525 800 mg Q4W + PDR001 400 mg Q4W	LAG525	Combination LAG525 800 mg + PDR001 400 mg (Q4W/Q4W)
Phase 1: LAG525 80 mg Q2W + PDR001 400 mg Q4W	LAG525	Combination LAG525 80 mg + PDR001 400 mg (Q2W/Q4W)
Phase 2: Pre-treated - LAG525 400 mg Q3W + PDR001 300 mg Q3W	LAG525	Combination LAG525 400 mg + PDR001 300 mg (Q3W/Q3W) in patients pre-treated with anti-PD-1/PD-L1

Primary Outcome Measures

Name	Time	Method
Phase 1: Number of Participants With Dose-Limiting Toxicities (DLTs)	15 days for single-agent LAG525 arms and 30 days for the combination LAG525 + PDR001 arms	A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 assessed as having a suspected relationship to study drug, and unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first cycle of treatment with single-agent LAG525 or within the first two cycles of treatment with the combination of LAG525 and PDR001. Other clinically significant toxicities may be considered to be DLTs, even if not CTCAE grade 3 or higher.
Phase 2: Overall Response Rate (ORR) Per RECIST 1.1	From start of treatment until end of treatment, assessed up to 2.6 years	Tumor response was based on local investigator assessment and the assessment criteria was Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). ORR per RECIST 1.1 is defined as the percentage of participants with a best overall response of Complete Response (CR) or Partial Response (PR). For RECIST v1.1, CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR= At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters. ORR is reported by tumor type.

Secondary Outcome Measures

Name	Time	Method
Phase 2: Number of Participants With Dose Reductions and Dose Interruptions of LAG525 and PDR001	From start of treatment until end of treatment, assessed up to 2.6 years.	Number of participants with at least one dose reduction of LAG525, at least one dose interruption of LAG525, at least one dose reduction of PDR001 and at least one dose interruption of PDR001. The number of participants with dose reductions and dose interruptions of both study drugs is reported for each tumor type.
Phase 2: Relative Dose Intensity (RDI) of LAG525 and PDR001	From start of treatment until end of treatment, assessed up to 2.6 years.	Relative dose intensity of each study drug is calculated with the following formula: 100 x actual dose intensity (mg/day)/planned dose intensity (mg/day). The RDI of both study drugs is reported for each tumor type.
Phase 1: Time to Reach Maximum Serum Concentration (Tmax) of LAG525	pre-infusion, 1, 24, 168, 240 and 336 hours post-infusion, and 504 hours (Q3W regimens only) and 672 hours (Q4W regimens only) post infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The duration of one cycle was 14 days (Q2W), 21 days (Q3W) and 28 days (Q4W).	Pharmacokinetic (PK) parameters were calculated based on LAG525 serum concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) serum concentration following a dose. Actual recorded sampling times were considered for the calculations.
Phase 2: Terminal Elimination Half-life (T1/2) of LAG525	pre-infusion, 1, 24, 168, 240 and 336 hours post-infusion, and 504 hours (Q3W regimens only) and 672 hours (Q4W regimens only) post infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The duration of one cycle was 21 days (Q3W) and 28 days (Q4W).	Pharmacokinetic (PK) parameters were calculated based on LAG525 serum concentrations by using non-compartmental methods. Elimination half-life (T1/2) values were calculated as 0.693/terminal elimination rate constant.
Phase 1: Number of Participants With Dose Reductions and Dose Interruptions of LAG525 and PDR001	From start of treatment until end of treatment, assessed up to 4.4 years.	Number of participants with at least one dose reduction of LAG525, at least one dose interruption of LAG525, at least one dose reduction of PDR001 and at least one dose interruption of PDR001. Japanese patients were not treated with PDR001 and therefore the dose reductions and dose interruptions of this study drug are not applicable.
Phase 1: Terminal Elimination Half-life (T1/2) of LAG525	pre-infusion, 1, 24, 168, 240 and 336 hours post-infusion, and 504 hours (Q3W regimens only) and 672 hours (Q4W regimens only) post infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The duration of one cycle was 14 days (Q2W), 21 days (Q3W) and 28 days (Q4W).	Pharmacokinetic (PK) parameters were calculated based on LAG525 serum concentrations by using non-compartmental methods. Elimination half-life (T1/2) values were calculated as 0.693/terminal elimination rate constant.
Phase 1: Time to Reach Maximum Serum Concentration (Tmax) of PDR001	pre-infusion, 1, 24, 168, 240 and 336 hours post-infusion, and 504 hours (Q3W regimens only) and 672 hours (Q4W regimens only) post infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The duration of one cycle was 14 days (Q2W), 21 days (Q3W) and 28 days (Q4W).	Pharmacokinetic (PK) parameters were calculated based on PDR001 serum concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) serum concentration following a dose. Actual recorded sampling times were considered for the calculations. Japanese patients were not treated with PDR001 and therefore the PK parameters of this study drug are not applicable.
Phase 2: Progression-free Survival (PFS) Per RECIST 1.1	From start of treatment to first documented progression or death due to any cause, assessed up to 2.6 years	PFS is the time from the date of start of treatment to the date of event defined as the first documented progression or death due to any cause. If a patient has not had an event, PFS is censored at the date of last adequate tumor assessment. Tumor response was based on local investigator assessment and the assessment criteria was RECIST 1.1. PFS is reported by tumor type.
Phase 2: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	From first dose of study treatment until last dose of study treatment plus 30 days post treatment, assessed up to 2.7 years.	Number of participants with AEs and SAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs. The number of participants with AEs and SAEs is reported for each tumor type.
Phase 1: Relative Dose Intensity (RDI) of LAG525 and PDR001	From start of treatment until end of treatment, assessed up to 4.4 years.	Relative dose intensity of each study drug is calculated with the following formula: 100 x actual dose intensity (mg/day)/planned dose intensity (mg/day). Japanese patients were not treated with PDR001 and therefore the RDI of this study drug is not applicable.
Phase 2: Maximum Observed Serum Concentration (Cmax) of LAG525	pre-infusion, 1, 24, 168, 240 and 336 hours post-infusion, and 504 hours (Q3W regimens only) and 672 hours (Q4W regimens only) post infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The duration of one cycle was 21 days (Q3W) and 28 days (Q4W).	Pharmacokinetic (PK) parameters were calculated based on LAG525 serum concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed serum concentration following a dose.
Phase 2: Time to Reach Maximum Serum Concentration (Tmax) of LAG525	pre-infusion, 1, 24, 168, 240 and 336 hours post-infusion, and 504 hours (Q3W regimens only) and 672 hours (Q4W regimens only) post infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The duration of one cycle was 21 days (Q3W) and 28 days (Q4W).	Pharmacokinetic (PK) parameters were calculated based on LAG525 serum concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) serum concentration following a dose. Actual recorded sampling times were considered for the calculations.
Phase 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	From first dose of study treatment until last dose of study treatment plus 30 days post treatment, assessed up to 4.5 years.	Number of participants with AEs and SAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs. The number of participants in each category (Rest of the World (ROW) patients, Japanese patients) with AEs and SAEs are reported in this record.
Phase 1: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of LAG525	pre-infusion, 1, 24, 168, 240 and 336 hours post-infusion, and 504 hours (Q3W regimens only) and 672 hours (Q4W regimens only) post infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The duration of one cycle was 14 days (Q2W), 21 days (Q3W) and 28 days (Q4W).	Pharmacokinetic (PK) parameters were calculated based on LAG525 serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC calculation.
Phase 1: Maximum Observed Serum Concentration (Cmax) of LAG525	pre-infusion, 1, 24, 168, 240 and 336 hours post-infusion, and 504 hours (Q3W regimens only) and 672 hours (Q4W regimens only) post infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The duration of one cycle was 14 days (Q2W), 21 days (Q3W) and 28 days (Q4W).	Pharmacokinetic (PK) parameters were calculated based on LAG525 serum concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed serum concentration following a dose.
Phase 1: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of PDR001	pre-infusion, 1, 24, 168, 240 and 336 hours post-infusion, and 504 hours (Q3W regimens only) and 672 hours (Q4W regimens only) post infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The duration of one cycle was 14 days (Q2W), 21 days (Q3W) and 28 days (Q4W).	Pharmacokinetic (PK) parameters were calculated based on PDR001 serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC calculation. Japanese patients were not treated with PDR001 and therefore the PK parameters of this study drug are not applicable.
Phase 2: Terminal Elimination Half-life (T1/2) of PDR001	pre-infusion, 1, 24, 168, 240 and 336 hours post-infusion, and 504 hours (Q3W regimens only) and 672 hours (Q4W regimens only) post infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The duration of one cycle was 21 days (Q3W) and 28 days (Q4W).	Pharmacokinetic (PK) parameters were calculated based on PDR001 serum concentrations by using non-compartmental methods. Elimination half-life (T1/2) values were calculated as 0.693/terminal elimination rate constant.
Phase 2: Number of Participants With Anti-PDR001 Antibodies	Baseline (pre-infusion on Cycle 1 Day 1) and post-baseline (assessed throughout the treatment up to maximum 2.6 years).	Validated immunoassays were used for screening and confirmation of the presence of anti-PDR001 antibodies (ADA, anti-drug antibodies) in serum. Number of participants with ADA in each category is reported in this record.
Phase 1: Overall Response Rate (ORR) Per RECIST 1.1	From start of treatment until end of treatment, assessed up to 4.4 years	Tumor response was based on local investigator assessment and the assessment criteria was Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). ORR per RECIST 1.1 is defined as the percentage of participants with a best overall response of Complete Response (CR) or Partial Response (PR). For RECIST v1.1, CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR= At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters. ORR is reported for ROW and Japanese patients.
Phase 1: Duration of Response (DOR) Per irRC	From first documented response (irCR or irPR) to first documented progression or death due to study indication, assessed up to 4.4 years	DOR only applies to subjects for whom best overall response is immune related complete response (irCR) or immune related partial response (irPR). DOR is defined as the time from the date of first documented response (irCR or irPR) to the date of first documented progression or death due to study indication. If a patient not had an event, duration was censored at the date of last adequate tumor assessment. Tumor response was based on local investigator assessment and the assessment criteria was irRC.
Phase 2: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of LAG525	pre-infusion, 1, 24, 168, 240 and 336 hours post-infusion, and 504 hours (Q3W regimens only) and 672 hours (Q4W regimens only) post infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The duration of one cycle was 21 days (Q3W) and 28 days (Q4W).	Pharmacokinetic (PK) parameters were calculated based on LAG525 serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC calculation.
Phase 1: Maximum Observed Serum Concentration (Cmax) of PDR001	pre-infusion, 1, 24, 168, 240 and 336 hours post-infusion, and 504 hours (Q3W regimens only) and 672 hours (Q4W regimens only) post infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The duration of one cycle was 14 days (Q2W), 21 days (Q3W) and 28 days (Q4W).	Pharmacokinetic (PK) parameters were calculated based on PDR001 serum concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed serum concentration following a dose. Japanese patients were not treated with PDR001 and therefore the PK parameters of this study drug are not applicable.
Phase 2: Maximum Observed Serum Concentration (Cmax) of PDR001	pre-infusion, 1, 24, 168, 240 and 336 hours post-infusion, and 504 hours (Q3W regimens only) and 672 hours (Q4W regimens only) post infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The duration of one cycle was 21 days (Q3W) and 28 days (Q4W).	Pharmacokinetic (PK) parameters were calculated based on PDR001 serum concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed serum concentration following a dose.
Phase 1: Disease Control Rate (DCR) Per irRC	From start of treatment until end of treatment, assessed up to 4.4 years	Tumor response was based on local investigator assessment and the assessment criteria was immune-related Response Criteria (irRC). DCR per irRC is defined as the percentage of participants with a best overall response of immune related Complete Response (irCR), immune related Partial Response (irPR) or immune related Stable Disease (irSD). For irRC, irCR=Disappearance of all non-nodal target lesions and non-target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; irPR= At least a 30% decrease in the sum of diameters of all target lesions including new target lesions, taking as reference the baseline sum of diameters; SD= Neither sufficient shrinkage to qualify for irPR or irCR nor an increase in lesions which would qualify for progression. DCR is reported for ROW and Japanese patients.
Phase 2: Duration of Response (DOR) Per irRC	From first documented response (irCR or irPR) to first documented progression or death due to study indication, assessed up to 2.6 years	DOR only applies to subjects for whom best overall response is immune related complete response (irCR) or immune related partial response (irPR). DOR is defined as the time from the date of first documented response (irCR or irPR) to the date of first documented progression or death due to study indication. If a patient not had an event, duration was censored at the date of last adequate tumor assessment. Tumor response was based on local investigator assessment and the assessment criteria was irRC. DOR is reported by tumor type.
Phase 1: Progression-free Survival (PFS) Per RECIST 1.1	From start of treatment to first documented progression or death due to any cause, assessed up to 4.4 years	PFS is the time from the date of start of treatment to the date of event defined as the first documented progression or death due to any cause. If a patient has not had an event, PFS is censored at the date of last adequate tumor assessment. Tumor response was based on local investigator assessment and the assessment criteria was RECIST 1.1. PFS is reported for ROW and Japanese patients.
Phase 2: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of PDR001	pre-infusion, 1, 24, 168, 240 and 336 hours post-infusion, and 504 hours (Q3W regimens only) and 672 hours (Q4W regimens only) post infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The duration of one cycle was 21 days (Q3W) and 28 days (Q4W).	Pharmacokinetic (PK) parameters were calculated based on PDR001 serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC calculation.
Phase 1: Overall Response Rate (ORR) Per irRC	From start of treatment until end of treatment, assessed up to 4.4 years	TTumor response was based on local investigator assessment and the assessment criteria was immune-related Response Criteria (irRC). ORR per irRC is defined as the percentage of participants with a best overall response of immune related Complete Response (irCR) or immune related Partial Response (irPR). For irRC, irCR=Disappearance of all non-nodal target lesions and non-target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; irPR= At least a 30% decrease in the sum of diameters of all target lesions including new target lesions, taking as reference the baseline sum of diameters. ORR is reported for ROW and Japanese patients.
Phase 2: Overall Response Rate (ORR) Per irRC	From start of treatment until end of treatment, assessed up to 2.6 years	Tumor response was based on local investigator assessment and the assessment criteria was immune-related Response Criteria (irRC). ORR per irRC is defined as the percentage of participants with a best overall response of immune related Complete Response (irCR) or immune related Partial Response (irPR). For irRC, irCR=Disappearance of all non-nodal target lesions and non-target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; irPR= At least a 30% decrease in the sum of diameters of all target lesions including new target lesions, taking as reference the baseline sum of diameters. ORR is reported by tumor type.
Phase 2: Disease Control Rate (DCR) Per RECIST 1.1	From start of treatment until end of treatment, assessed up to 2.6 years	Tumor response was based on local investigator assessment and the assessment criteria was Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). DCR per RECIST 1.1 is defined as the percentage of participants with a best overall response of Complete Response (CR), Partial Response (PR) or Stable Disease (SD). For RECIST v1.1, CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR= At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters; SD= Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progression. DCR is reported by tumor type.
Phase 2: Disease Control Rate (DCR) Per irRC	From start of treatment until end of treatment, assessed up to 2.6 years	Tumor response was based on local investigator assessment and the assessment criteria was immune-related Response Criteria (irRC). DCR per irRC is defined as the percentage of participants with a best overall response of immune related Complete Response (irCR), immune related Partial Response (irPR) or immune related Stable Disease (irSD). For irRC, irCR=Disappearance of all non-nodal target lesions and non-target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; irPR= At least a 30% decrease in the sum of diameters of all target lesions including new target lesions, taking as reference the baseline sum of diameters; SD= Neither sufficient shrinkage to qualify for irPR or irCR nor an increase in lesions which would qualify for progression. DCR is reported by tumor type.
Phase 2: Time to Reach Maximum Serum Concentration (Tmax) of PDR001	pre-infusion, 1, 24, 168, 240 and 336 hours post-infusion, and 504 hours (Q3W regimens only) and 672 hours (Q4W regimens only) post infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The duration of one cycle was 21 days (Q3W) and 28 days (Q4W).	Pharmacokinetic (PK) parameters were calculated based on PDR001 serum concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) serum concentration following a dose. Actual recorded sampling times were considered for the calculations.
Phase 1: Terminal Elimination Half-life (T1/2) of PDR001	pre-infusion, 1, 24, 168, 240 and 336 hours post-infusion, and 504 hours (Q3W regimens only) and 672 hours (Q4W regimens only) post infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The duration of one cycle was 14 days (Q2W), 21 days (Q3W) and 28 days (Q4W).	Pharmacokinetic (PK) parameters were calculated based on PDR001 serum concentrations by using non-compartmental methods. Elimination half-life (T1/2) values were calculated as 0.693/terminal elimination rate constant. Japanese patients were not treated with PDR001 and therefore the PK parameters of this study drug are not applicable.
Phase 1: Number of Participants With Anti-LAG525 Antibodies	Baseline (pre-infusion on Cycle 1 Day 1) and post-baseline (assessed throughout the treatment up to maximum 4.4 years).	Validated immunoassays were used for screening and confirmation of the presence of anti-LAG525 antibodies (ADA, anti-drug antibodies) in serum. Number of participants with ADA in each category is reported in this record.
Phase 2: Number of Participants With Anti-LAG525 Antibodies	Baseline (pre-infusion on Cycle 1 Day 1) and post-baseline (assessed throughout the treatment up to maximum 2.6 years).	Validated immunoassays were used for screening and confirmation of the presence of anti-LAG525 antibodies (ADA, anti-drug antibodies) in serum. Number of participants with ADA in each category is reported in this record.
Phase 1: Number of Participants With Anti-PDR001 Antibodies	Baseline (pre-infusion on Cycle 1 Day 1) and post-baseline (assessed throughout the treatment up to maximum 4.4 years).	Validated immunoassays were used for screening and confirmation of the presence of anti-PDR001 antibodies (ADA, anti-drug antibodies) in serum. Number of participants with ADA in each category is reported in this record.
Phase 1: Disease Control Rate (DCR) Per RECIST 1.1	From start of treatment until end of treatment, assessed up to 4.4 years	Tumor response was based on local investigator assessment and the assessment criteria was Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). DCR per RECIST 1.1 is defined as the percentage of participants with a best overall response of Complete Response (CR), Partial Response (PR) or Stable Disease (SD). For RECIST v1.1, CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR= At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters; SD= Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progression. DCR is reported for ROW and Japanese patients.
Phase 1: Duration of Response (DOR) Per RECIST 1.1	From first documented response (CR or PR) to first documented progression or death due to study indication, assessed up to 4.4 years	DOR only applies to subjects for whom best overall response is complete response (CR) or partial response (PR). DOR is defined as the time from the date of first documented response (CR or PR) to the date of first documented progression or death due to study indication. If a patient not had an event, duration was censored at the date of last adequate tumor assessment. Tumor response was based on local investigator assessment and the assessment criteria was RECIST 1.1.
Phase 2: Duration of Response (DOR) Per RECIST 1.1	From first documented response (CR or PR) to first documented progression or death due to study indication, assessed up to 2.6 years	DOR only applies to subjects for whom best overall response is complete response (CR) or partial response (PR). DOR is defined as the time from the date of first documented response (CR or PR) to the date of first documented progression or death due to study indication. If a patient not had an event, duration was censored at the date of last adequate tumor assessment. Tumor response was based on local investigator assessment and the assessment criteria was RECIST 1.1. DOR is reported by tumor type.
Phase 1: Progression-free Survival (PFS) Per irRC	From start of treatment to first documented progression or death due to any cause, assessed up to 4.4 years	PFS is the time from the date of start of treatment to the date of event defined as the first documented progression or death due to any cause. If a patient has not had an event, PFS is censored at the date of last adequate tumor assessment. Tumor response was based on local investigator assessment and the assessment criteria was irRC. PFS is reported for ROW and Japanese patients.
Phase 2: Progression-free Survival (PFS) Per irRC	From start of treatment to first documented progression or death due to any cause, assessed up to 2.6 years	PFS is the time from the date of start of treatment to the date of event defined as the first documented progression or death due to any cause. If a patient has not had an event, PFS is censored at the date of last adequate tumor assessment. Tumor response was based on local investigator assessment and the assessment criteria was irRC. PFS is reported by tumor type.

Trial Locations

Locations (7): Duke Clinical Research Institute SC
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Durham, North Carolina, United States
University of Texas MD Anderson Cancer Center
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Houston, Texas, United States
Memorial Sloan Kettering Cancer Center SC
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New York, New York, United States
Columbia University Medical Center SC LAG X2101C
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New York, New York, United States
Cancer Therapy and Research Center UT Health Science Center CTRC 2
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San Antonio, Texas, United States
Huntsman Cancer Institute Huntsman Cancer Institute
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Salt Lake City, Utah, United States
Novartis Investigative Site
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Taipei, Taiwan