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.

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.

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.