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

A Phase I/II, Open Label, Multicenter Study of the Safety and Efficacy of LAG525 Single Agent and in Combination With PDR001 Administered to Patients With Advanced Malignancies

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.

Study Overview

• Status: Completed
• Conditions: Advanced Solid Tumors
• Intervention / Treatment: Drug: LAG525; Drug: PDR001

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.

• Study Type: Interventional
• Enrollment (Actual): 490
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • Novartis Investigative Site
  • Victoria
    • Heidelberg, Victoria, Australia, 3084
      • Novartis Investigative Site
• Belgium
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Novartis Investigative Site
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Novartis Investigative Site
• France
  • Lyon Cedex, France, 69373
    • Novartis Investigative Site
  • Saint-Herblain Cédex, France, 44805
    • Novartis Investigative Site
• Germany
  • Heidelberg, Germany, 69120
    • Novartis Investigative Site
  • Wuerzburg, Germany, 97080
    • Novartis Investigative Site
• Hong Kong
  • Hong Kong, Hong Kong
    • Novartis Investigative Site
• Italy
  • MI
    • Milano, MI, Italy, 20133
      • Novartis Investigative Site
  • MO
    • Modena, MO, Italy, 41124
      • Novartis Investigative Site
• Japan
  • Fukuoka
    • Fukuoka-city, Fukuoka, Japan, 811-1395
      • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 119228
    • Novartis Investigative Site
  • Singapore, Singapore, 169610
    • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28009
    • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
• Taiwan
  • Taipei, Taiwan, 10002
    • Novartis Investigative Site
• United States
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center SC LAG X2101C
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center SC
  • North Carolina
    • Durham, North Carolina, United States, 27704
      • Duke Clinical Research Institute SC
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas MD Anderson Cancer Center
    • San Antonio, Texas, United States, 78229
      • Cancer Therapy and Research Center UT Health Science Center CTRC 2
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute Huntsman Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

29

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1: LAG525 1 mg/kg Q2W; Single-agent LAG525 1 mg/kg Q2W	Drug: LAG525; LAG525 was administered via intravenous (i.v.) infusion
Experimental: Phase 1: LAG525 3 mg/kg Q2W; Single-agent LAG525 3 mg/kg Q2W	Drug: LAG525; LAG525 was administered via intravenous (i.v.) infusion
Experimental: Phase 1: LAG525 5 mg/kg Q2W; Single-agent LAG525 5 mg/kg Q2W	Drug: LAG525; LAG525 was administered via intravenous (i.v.) infusion
Experimental: Phase 1: LAG525 10 mg/kg Q2W; Single-agent LAG525 10 mg/kg Q2W	Drug: LAG525; LAG525 was administered via intravenous (i.v.) infusion
Experimental: Phase 1: LAG525 15 mg/kg Q2W; Single-agent LAG525 15 mg/kg Q2W	Drug: LAG525; LAG525 was administered via intravenous (i.v.) infusion
Experimental: Phase 1: LAG525 240 mg Q2W; Single-agent LAG525 240 mg Q2W	Drug: LAG525; LAG525 was administered via intravenous (i.v.) infusion
Experimental: Phase 1: LAG525 400 mg Q2W; Single-agent LAG525 400 mg Q2W	Drug: LAG525; LAG525 was administered via intravenous (i.v.) infusion
Experimental: Phase 1: LAG525 3 mg/kg Q4W; Single-agent LAG525 3 mg/kg Q4W	Drug: LAG525; LAG525 was administered via intravenous (i.v.) infusion
Experimental: Phase 1: LAG525 5 mg/kg Q4W; Single-agent LAG525 5 mg/kg Q4W	Drug: LAG525; LAG525 was administered via intravenous (i.v.) infusion
Experimental: Phase 1: LAG525 10 mg/kg Q4W; Single-agent LAG525 10 mg/kg Q4W	Drug: LAG525; LAG525 was administered via intravenous (i.v.) infusion
Experimental: Phase 1: LAG525 400 mg Q4W; Single-agent LAG525 400 mg Q4W	Drug: LAG525; LAG525 was administered via intravenous (i.v.) infusion
Experimental: Phase 1: LAG525 0.3 mg/kg Q2W + PDR001 1 mg/kg Q2W; Combination LAG525 0.3 mg/kg + PDR001 1 mg/kg (Q2W/Q2W)	Drug: LAG525; LAG525 was administered via intravenous (i.v.) infusion; Drug: PDR001; PDR001 was administered via i.v. infusion
Experimental: Phase 1: LAG525 1 mg/kg Q2W + PDR001 1 mg/kg Q2W; Combination LAG525 1 mg/kg + PDR001 1 mg/kg (Q2W/Q2W)	Drug: LAG525; LAG525 was administered via intravenous (i.v.) infusion; Drug: PDR001; PDR001 was administered via i.v. infusion
Experimental: Phase 1: LAG525 80 mg Q2W + PDR001 80 mg Q2W; Combination LAG525 80 mg + PDR001 80 mg (Q2W/Q2W)	Drug: LAG525; LAG525 was administered via intravenous (i.v.) infusion; Drug: PDR001; PDR001 was administered via i.v. infusion
Experimental: Phase 1: LAG525 80 mg Q2W + PDR001 240 mg Q2W; Combination LAG525 80 mg + PDR001 240 mg (Q2W/Q2W)	Drug: LAG525; LAG525 was administered via intravenous (i.v.) infusion; Drug: PDR001; PDR001 was administered via i.v. infusion
Experimental: Phase 1: LAG525 240 mg Q2W + PDR001 240 mg Q2W; Combination LAG525 240 mg + PDR001 240 mg (Q2W/Q2W)	Drug: LAG525; LAG525 was administered via intravenous (i.v.) infusion; Drug: PDR001; PDR001 was administered via i.v. infusion
Experimental: Phase 1: LAG525 240 mg Q3W + PDR001 300 mg Q3W; Combination LAG525 240 mg + PDR001 300 mg (Q3W/Q3W)	Drug: LAG525; LAG525 was administered via intravenous (i.v.) infusion; Drug: PDR001; PDR001 was administered via i.v. infusion
Experimental: Phase 1: LAG525 400 mg Q3W + PDR001 300 mg Q3W; Combination LAG525 400 mg + PDR001 300 mg (Q3W/Q3W)	Drug: LAG525; LAG525 was administered via intravenous (i.v.) infusion; Drug: PDR001; PDR001 was administered via i.v. infusion
Experimental: Phase 1: LAG525 600 mg Q3W + PDR001 300 mg Q3W; Combination LAG525 600 mg + PDR001 300 mg (Q3W/Q3W)	Drug: LAG525; LAG525 was administered via intravenous (i.v.) infusion; Drug: PDR001; PDR001 was administered via i.v. infusion
Experimental: Phase 1: LAG525 80 mg Q4W + PDR001 240 mg Q4W; Combination LAG525 80 mg + PDR001 240 mg (Q4W/Q4W)	Drug: LAG525; LAG525 was administered via intravenous (i.v.) infusion; Drug: PDR001; PDR001 was administered via i.v. infusion
Experimental: Phase 1: LAG525 400 mg Q4W + PDR001 400 mg Q4W; Combination LAG525 400 mg + PDR001 400 mg (Q4W/Q4W)	Drug: LAG525; LAG525 was administered via intravenous (i.v.) infusion; Drug: PDR001; PDR001 was administered via i.v. infusion
Experimental: Phase 1: LAG525 800 mg Q4W + PDR001 400 mg Q4W; Combination LAG525 800 mg + PDR001 400 mg (Q4W/Q4W)	Drug: LAG525; LAG525 was administered via intravenous (i.v.) infusion; Drug: PDR001; PDR001 was administered via i.v. infusion
Experimental: Phase 1: LAG525 1000 mg Q4W + PDR001 400 mg Q4W; Combination LAG525 1000 mg + PDR001 400 mg (Q4W/Q4W)	Drug: LAG525; LAG525 was administered via intravenous (i.v.) infusion; Drug: PDR001; PDR001 was administered via i.v. infusion
Experimental: Phase 1: LAG525 80 mg Q2W + PDR001 400 mg Q4W; Combination LAG525 80 mg + PDR001 400 mg (Q2W/Q4W)	Drug: LAG525; LAG525 was administered via intravenous (i.v.) infusion; Drug: PDR001; PDR001 was administered via i.v. infusion
Experimental: Phase 1: LAG525 240 mg Q2W + PDR001 400 mg Q4W; Combination LAG525 240 mg + PDR001 400 mg (Q2W/Q4W)	Drug: LAG525; LAG525 was administered via intravenous (i.v.) infusion; Drug: PDR001; PDR001 was administered via i.v. infusion
Experimental: Phase 1: LAG525 300 mg Q2W + PDR001 400 mg Q4W; Combination LAG525 300 mg + PDR001 400 mg (Q2W/Q4W)	Drug: LAG525; LAG525 was administered via intravenous (i.v.) infusion; Drug: PDR001; PDR001 was administered via i.v. infusion
Experimental: Phase 2: Naive - LAG525 400 mg Q3W + PDR001 300 mg Q3W; Combination LAG525 400 mg + PDR001 300 mg (Q3W/Q3W) in patients naïve to anti-PD-1/PD-L1	Drug: LAG525; LAG525 was administered via intravenous (i.v.) infusion; Drug: PDR001; PDR001 was administered via i.v. infusion
Experimental: Phase 2: Naive - LAG525 600 mg Q4W + PDR001 400 mg Q4W; Combination LAG525 600 mg + PDR001 400 mg (Q4W/Q4W) in patients naïve to anti-PD-1/PD-L1	Drug: LAG525; LAG525 was administered via intravenous (i.v.) infusion; Drug: PDR001; PDR001 was administered via i.v. infusion
Experimental: Phase 2: Pre-treated - LAG525 400 mg Q3W + PDR001 300 mg Q3W; Combination LAG525 400 mg + PDR001 300 mg (Q3W/Q3W) in patients pre-treated with anti-PD-1/PD-L1	Drug: LAG525; LAG525 was administered via intravenous (i.v.) infusion; Drug: PDR001; PDR001 was administered via i.v. infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1: Number of Participants With Dose-Limiting Toxicities (DLTs)	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.	15 days for single-agent LAG525 arms and 30 days for the combination LAG525 + PDR001 arms
Phase 2: Overall Response Rate (ORR) Per RECIST 1.1	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.	From start of treatment until end of treatment, assessed up to 2.6 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	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.	From first dose of study treatment until last dose of study treatment plus 30 days post treatment, assessed up to 4.5 years.
Phase 2: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	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.	From first dose of study treatment until last dose of study treatment plus 30 days post treatment, assessed up to 2.7 years.
Phase 1: Number of Participants With Dose Reductions and Dose Interruptions of LAG525 and PDR001	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.	From start of treatment until end of treatment, assessed up to 4.4 years.
Phase 2: Number of Participants With Dose Reductions and Dose Interruptions of LAG525 and PDR001	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.	From start of treatment until end of treatment, assessed up to 2.6 years.
Phase 1: Relative Dose Intensity (RDI) of LAG525 and PDR001	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.	From start of treatment until end of treatment, assessed up to 4.4 years.
Phase 2: Relative Dose Intensity (RDI) of LAG525 and PDR001	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.	From start of treatment until end of treatment, assessed up to 2.6 years.
Phase 1: Maximum Observed Serum Concentration (Cmax) of LAG525	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.	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).
Phase 2: Maximum Observed Serum Concentration (Cmax) of LAG525	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.	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).
Phase 1: Time to Reach Maximum Serum Concentration (Tmax) of LAG525	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.	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).
Phase 2: Time to Reach Maximum Serum Concentration (Tmax) of LAG525	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.	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).
Phase 1: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of LAG525	Pharmacokinetic (PK) parameters were calculated based on LAG525 serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC calculation.	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).
Phase 2: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of LAG525	Pharmacokinetic (PK) parameters were calculated based on LAG525 serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC calculation.	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).
Phase 1: Terminal Elimination Half-life (T1/2) of LAG525	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.	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).
Phase 2: Terminal Elimination Half-life (T1/2) of LAG525	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.	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).
Phase 1: Maximum Observed Serum Concentration (Cmax) of PDR001	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.	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).
Phase 2: Maximum Observed Serum Concentration (Cmax) of PDR001	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.	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).
Phase 1: Time to Reach Maximum Serum Concentration (Tmax) of PDR001	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.	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).
Phase 2: Time to Reach Maximum Serum Concentration (Tmax) of PDR001	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.	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).
Phase 1: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of PDR001	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.	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).
Phase 2: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of PDR001	Pharmacokinetic (PK) parameters were calculated based on PDR001 serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC calculation.	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).
Phase 1: Terminal Elimination Half-life (T1/2) of PDR001	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.	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).
Phase 2: Terminal Elimination Half-life (T1/2) of PDR001	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.	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).
Phase 1: Number of Participants With Anti-LAG525 Antibodies	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.	Baseline (pre-infusion on Cycle 1 Day 1) and post-baseline (assessed throughout the treatment up to maximum 4.4 years).
Phase 2: Number of Participants With Anti-LAG525 Antibodies	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.	Baseline (pre-infusion on Cycle 1 Day 1) and post-baseline (assessed throughout the treatment up to maximum 2.6 years).
Phase 1: Number of Participants With Anti-PDR001 Antibodies	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.	Baseline (pre-infusion on Cycle 1 Day 1) and post-baseline (assessed throughout the treatment up to maximum 4.4 years).
Phase 2: Number of Participants With Anti-PDR001 Antibodies	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.	Baseline (pre-infusion on Cycle 1 Day 1) and post-baseline (assessed throughout the treatment up to maximum 2.6 years).
Phase 1: Overall Response Rate (ORR) Per RECIST 1.1	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.	From start of treatment until end of treatment, assessed up to 4.4 years
Phase 1: Overall Response Rate (ORR) Per irRC	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.	From start of treatment until end of treatment, assessed up to 4.4 years
Phase 2: Overall Response Rate (ORR) Per irRC	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.	From start of treatment until end of treatment, assessed up to 2.6 years
Phase 1: Disease Control Rate (DCR) Per RECIST 1.1	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.	From start of treatment until end of treatment, assessed up to 4.4 years
Phase 1: Disease Control Rate (DCR) Per irRC	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.	From start of treatment until end of treatment, assessed up to 4.4 years
Phase 2: Disease Control Rate (DCR) Per RECIST 1.1	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.	From start of treatment until end of treatment, assessed up to 2.6 years
Phase 2: Disease Control Rate (DCR) Per irRC	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.	From start of treatment until end of treatment, assessed up to 2.6 years
Phase 1: Duration of Response (DOR) Per RECIST 1.1	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.	From first documented response (CR or PR) to first documented progression or death due to study indication, assessed up to 4.4 years
Phase 1: Duration of Response (DOR) Per irRC	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.	From first documented response (irCR or irPR) to first documented progression or death due to study indication, assessed up to 4.4 years
Phase 2: Duration of Response (DOR) Per RECIST 1.1	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.	From first documented response (CR or PR) to first documented progression or death due to study indication, assessed up to 2.6 years
Phase 2: Duration of Response (DOR) Per irRC	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.	From first documented response (irCR or irPR) to first documented progression or death due to study indication, assessed up to 2.6 years
Phase 1: Progression-free Survival (PFS) Per RECIST 1.1	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.	From start of treatment to first documented progression or death due to any cause, assessed up to 4.4 years
Phase 1: Progression-free Survival (PFS) Per irRC	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.	From start of treatment to first documented progression or death due to any cause, assessed up to 4.4 years
Phase 2: Progression-free Survival (PFS) Per RECIST 1.1	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.	From start of treatment to first documented progression or death due to any cause, assessed up to 2.6 years
Phase 2: Progression-free Survival (PFS) Per irRC	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.	From start of treatment to first documented progression or death due to any cause, assessed up to 2.6 years

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Schoffski P, Tan DSW, Martin M, Ochoa-de-Olza M, Sarantopoulos J, Carvajal RD, Kyi C, Esaki T, Prawira A, Akerley W, De Braud F, Hui R, Zhang T, Soo RA, Maur M, Weickhardt A, Krauss J, Deschler-Baier B, Lau A, Samant TS, Longmire T, Chowdhury NR, Sabatos-Peyton CA, Patel N, Ramesh R, Hu T, Carion A, Gusenleitner D, Yerramilli-Rao P, Askoxylakis V, Kwak EL, Hong DS. Phase I/II study of the LAG-3 inhibitor ieramilimab (LAG525) +/- anti-PD-1 spartalizumab (PDR001) in patients with advanced malignancies. J Immunother Cancer. 2022 Feb;10(2):e003776. doi: 10.1136/jitc-2021-003776.

Study record dates

Study Major Dates

• Study Start (Actual): June 17, 2015
• Primary Completion (Actual): December 31, 2020
• Study Completion (Actual): December 31, 2020

Study Registration Dates

• First Submitted: May 9, 2015
• First Submitted That Met QC Criteria: May 29, 2015
• First Posted (Estimate): June 2, 2015

Study Record Updates

• Last Update Posted (Actual): February 10, 2022
• Last Update Submitted That Met QC Criteria: January 17, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: Non-small cell lung cancer; Melanoma; Renal cancer; TNBC; Mesothelioma; Renal; Triple Negative Breast
• Additional Relevant MeSH Terms: Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immune Checkpoint Inhibitors; Spartalizumab
• Other Study ID Numbers: CLAG525X2101C; 2015-000449-21 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No