Clinical trial NCT02460224: Safety and Efficacy of LAG525 Single Agent and in Combination With PDR001 in Patients With Advanced Malignancies.
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Advanced Solid Tumors
Keywords: Non-small cell lung cancer
Melanoma
Renal cancer
Mesothelioma
Triple Negative Breast
TNBC
Renal
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2015-06-02
Enrollment: 490
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Phase 1: Number of Participants With Dose-Limiting Toxicities (DLTs)
timeFrame: 15 days for single-agent LAG525 arms and 30 days for the combination LAG525 + PDR001 arms
measure: Phase 2: Overall Response Rate (ORR) Per RECIST 1.1
timeFrame: From start of treatment until end of treatment, assessed up to 2.6 years
Secondary outcomes:
measure: Phase 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: From first dose of study treatment until last dose of study treatment plus 30 days post treatment, assessed up to 4.5 years.
measure: Phase 2: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: From first dose of study treatment until last dose of study treatment plus 30 days post treatment, assessed up to 2.7 years.
measure: Phase 1: Number of Participants With Dose Reductions and Dose Interruptions of LAG525 and PDR001
timeFrame: From start of treatment until end of treatment, assessed up to 4.4 years.
measure: Phase 2: Number of Participants With Dose Reductions and Dose Interruptions of LAG525 and PDR001
timeFrame: From start of treatment until end of treatment, assessed up to 2.6 years.
measure: Phase 1: Relative Dose Intensity (RDI) of LAG525 and PDR001
timeFrame: From start of treatment until end of treatment, assessed up to 4.4 years.
measure: Phase 2: Relative Dose Intensity (RDI) of LAG525 and PDR001
timeFrame: From start of treatment until end of treatment, assessed up to 2.6 years.
measure: Phase 1: Maximum Observed Serum Concentration (Cmax) of LAG525
timeFrame: 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).
measure: Phase 2: Maximum Observed Serum Concentration (Cmax) of LAG525
timeFrame: 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).
measure: Phase 1: Time to Reach Maximum Serum Concentration (Tmax) of LAG525
timeFrame: 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).
measure: Phase 2: Time to Reach Maximum Serum Concentration (Tmax) of LAG525
timeFrame: 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).
measure: Phase 1: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of LAG525
timeFrame: 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).
measure: Phase 2: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of LAG525
timeFrame: 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).
measure: Phase 1: Terminal Elimination Half-life (T1/2) of LAG525
timeFrame: 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).
measure: Phase 2: Terminal Elimination Half-life (T1/2) of LAG525
timeFrame: 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).
measure: Phase 1: Maximum Observed Serum Concentration (Cmax) of PDR001
timeFrame: 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).
measure: Phase 2: Maximum Observed Serum Concentration (Cmax) of PDR001
timeFrame: 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).
measure: Phase 1: Time to Reach Maximum Serum Concentration (Tmax) of PDR001
timeFrame: 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).
measure: Phase 2: Time to Reach Maximum Serum Concentration (Tmax) of PDR001
timeFrame: 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).
measure: Phase 1: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of PDR001
timeFrame: 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).
measure: Phase 2: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of PDR001
timeFrame: 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).
measure: Phase 1: Terminal Elimination Half-life (T1/2) of PDR001
timeFrame: 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).
measure: Phase 2: Terminal Elimination Half-life (T1/2) of PDR001
timeFrame: 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).
measure: Phase 1: Number of Participants With Anti-LAG525 Antibodies
timeFrame: Baseline (pre-infusion on Cycle 1 Day 1) and post-baseline (assessed throughout the treatment up to maximum 4.4 years).
measure: Phase 2: Number of Participants With Anti-LAG525 Antibodies
timeFrame: Baseline (pre-infusion on Cycle 1 Day 1) and post-baseline (assessed throughout the treatment up to maximum 2.6 years).
measure: Phase 1: Number of Participants With Anti-PDR001 Antibodies
timeFrame: Baseline (pre-infusion on Cycle 1 Day 1) and post-baseline (assessed throughout the treatment up to maximum 4.4 years).
measure: Phase 2: Number of Participants With Anti-PDR001 Antibodies
timeFrame: Baseline (pre-infusion on Cycle 1 Day 1) and post-baseline (assessed throughout the treatment up to maximum 2.6 years).
measure: Phase 1: Overall Response Rate (ORR) Per RECIST 1.1
timeFrame: From start of treatment until end of treatment, assessed up to 4.4 years
measure: Phase 1: Overall Response Rate (ORR) Per irRC
timeFrame: From start of treatment until end of treatment, assessed up to 4.4 years
measure: Phase 2: Overall Response Rate (ORR) Per irRC
timeFrame: From start of treatment until end of treatment, assessed up to 2.6 years
measure: Phase 1: Disease Control Rate (DCR) Per RECIST 1.1
timeFrame: From start of treatment until end of treatment, assessed up to 4.4 years
measure: Phase 1: Disease Control Rate (DCR) Per irRC
timeFrame: From start of treatment until end of treatment, assessed up to 4.4 years
measure: Phase 2: Disease Control Rate (DCR) Per RECIST 1.1
timeFrame: From start of treatment until end of treatment, assessed up to 2.6 years
measure: Phase 2: Disease Control Rate (DCR) Per irRC
timeFrame: From start of treatment until end of treatment, assessed up to 2.6 years
measure: Phase 1: Duration of Response (DOR) Per RECIST 1.1
timeFrame: From first documented response (CR or PR) to first documented progression or death due to study indication, assessed up to 4.4 years
measure: Phase 1: Duration of Response (DOR) Per irRC
timeFrame: From first documented response (irCR or irPR) to first documented progression or death due to study indication, assessed up to 4.4 years
measure: Phase 2: Duration of Response (DOR) Per RECIST 1.1
timeFrame: From first documented response (CR or PR) to first documented progression or death due to study indication, assessed up to 2.6 years
measure: Phase 2: Duration of Response (DOR) Per irRC
timeFrame: From first documented response (irCR or irPR) to first documented progression or death due to study indication, assessed up to 2.6 years
measure: Phase 1: Progression-free Survival (PFS) Per RECIST 1.1
timeFrame: From start of treatment to first documented progression or death due to any cause, assessed up to 4.4 years
measure: Phase 1: Progression-free Survival (PFS) Per irRC
timeFrame: From start of treatment to first documented progression or death due to any cause, assessed up to 4.4 years
measure: Phase 2: Progression-free Survival (PFS) Per RECIST 1.1
timeFrame: From start of treatment to first documented progression or death due to any cause, assessed up to 2.6 years
measure: Phase 2: Progression-free Survival (PFS) Per irRC
timeFrame: From start of treatment to first documented progression or death due to any cause, assessed up to 2.6 years
Other outcomes:
Locations:
city: New York
country: United States
facility: Columbia University Medical Center SC LAG X2101C
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center SC
state: New York
city: Durham
country: United States
facility: Duke Clinical Research Institute SC
state: North Carolina
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: Cancer Therapy and Research Center UT Health Science Center CTRC 2
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute Huntsman Cancer Institute
state: Utah
city: Westmead
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Heidelberg
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Edmonton
country: Canada
facility: Novartis Investigative Site
state: Alberta
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Lyon Cedex
country: France
facility: Novartis Investigative Site
city: Saint-Herblain Cédex
country: France
facility: Novartis Investigative Site
city: Heidelberg
country: Germany
facility: Novartis Investigative Site
city: Wuerzburg
country: Germany
facility: Novartis Investigative Site
city: Hong Kong
country: Hong Kong
facility: Novartis Investigative Site
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Modena
country: Italy
facility: Novartis Investigative Site
state: MO
city: Fukuoka-city
country: Japan
facility: Novartis Investigative Site
state: Fukuoka
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: 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.