Phase I-Ib/II Study of MBG453 as Single Agent and in Combination With PDR001 in Patients With Advanced Malignancies

Phase I-Ib/II Open-label Multi-center Study of the Safety and Efficacy of MBG453 as Single Agent and in Combination With PDR001 in Adult Patients With Advanced Malignancies

The purpose of this first-in-human study of MBG453 was to characterize the safety, tolerability, pharmacokinetics, pharmacodynamics and anti-tumor activity of MBG453 administered i.v. as a single agent or in combination with PDR001 or decitabine in adult patients with advanced solid tumors

Study Overview

• Status: Terminated
• Conditions: Advanced Malignancies
• Intervention / Treatment: Drug: Decitabine; Drug: MBG453; Drug: PDR001

Detailed Description

This study was a first in human (FIH), open-label, Phase I-Ib/II, multi-center study which consisted of a Phase I dose escalation part of sabatolimab (MBG453) as single agent, and a Phase Ib dose escalation part of sabatolimab in combination with spartalizumab (PDR001) that commenced after two cohorts in the dose escalation with single agent were completed. Once the maximum tolerated dose (MTD)/recommended Phase II dose (RP2D) of sabatolimab as single agent and in combination with spartalizumab was achieved, a dose ranging part and a Phase II part started.

• Phase I dose escalation part (sabatolimab single agent): In the Phase I part of the study, cohorts of subjects were treated with sabatolimab as single agent either every 2 weeks (Q2W) or every 4 weeks (Q4W) until the MTD was reached or a lower RP2D was established.

The sabatolimab single agent dose escalation part in Japan ran separately in order to ensure that the safety and pharmacokinetics (PK) profiles of single-agent sabatolimab are adequately characterized in Japanese patients. If the recommended dose of single agent sabatolimab in Japanese patients was the same as in the rest of the world (ROW) patients, then patients enrolled in Japan were to be recruited into the other parts of the study.

• Phase Ib dose escalation part (sabatolimab in combination with spartalizumab): The combination Phase Ib part of the study was to be commenced after at least two cohorts of sabatolimab as single agent were completed, and safety data suggested acceptable toxicity for subjects to begin treatment in combination. Following identification of the MTD/RP2D for the combination of sabatolimab and spartalizumab with a Q2W dosing schedule, a further dose escalation was planned to identify the MTD/RP2D with a Q4W dosing schedule.

The sabatolimab in combination with decitabine treatment arm (Phase Ib) was not opened for enrollment.

• Dose ranging part: During the dose ranging part various dose levels of single agent sabatolimab were tested to better understand the safety, tolerability and PK.
• Phase II part (sabatolimab in combination with spartalizumab): Once the MTD and/or RP2D were declared for sabatolimab in combination with spartalizumab, additional subjects were enrolled in the Phase II part in the selected indications (melanoma and non-small cell lung carcinoma) in order to assess the preliminary anti-tumor activity.

The Phase II single agent sabatolimab treatment arm was not opened for enrollment.

• Study Type: Interventional
• Enrollment (Actual): 252
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2C1
      • Novartis Investigative Site
• Italy
  • MI
    • Milano, MI, Italy, 20141
      • Novartis Investigative Site
    • Rozzano, MI, Italy, 20089
      • Novartis Investigative Site
• Japan
  • Chiba
    • Kashiwa, Chiba, Japan, 277 8577
      • Novartis Investigative Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Novartis Investigative Site
• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • Novartis Investigative Site
  • Leiden, Netherlands, 2300 RC
    • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 168583
    • Novartis Investigative Site
• Switzerland
  • Geneve 14, Switzerland, CH 1211
    • Novartis Investigative Site
• Taiwan
  • Taipei, Taiwan, 10002
    • Novartis Investigative Site
• United States
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Sidney Kimmel CCC At JH Sidney Kimmel CCC
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute DFCI - Brookline
  • Texas
    • Houston, Texas, United States, 77030
      • UT M.D Anderson Cancer Center
    • San Antonio, Texas, United States, 78229
      • Mays Cancer Ctr Uthsa Mdacc

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Histologically documented advanced or metastatic solid tumors.
• Phase I-Ib part (including dose ranging part): Patients with advanced/metastatic solid tumors, with measurable or non-measurable disease as determined by RECIST v1.1, who have progressed despite standard therapy or are intolerant of standard therapy, or for whom no standard therapy exists and who did not receive prior anti-PD-1/PD-L1 treatment.
• Phase II part (MBG453 single agent): Patients with advanced/metastatic solid tumors in the indication in which at least one confirmed PR or CR was seen during the dose escalation phase I part. Patients must have measurable disease as determined by RECIST v1.1, have progressed despite standard therapy or be intolerant to standard therapy.

• Phase II part (MBG453 in combination PDR001): Patients with advanced/metastatic tumors in the below selected indications, with at least one measurable lesion as determined by RECIST v1.1, who have received standard therapy and are intolerant of standard therapy or have progressed following their last prior therapy.:

  • Melanoma (anti-PD-1/PD-L1 therapy naïve or pre-treated)
  • Non small cell lung cancer (anti-PD-1/PD-L1 therapy naïve or pre-treated)
  • Renal Cell Carcinoma (anti-PD-1/PD-L1 therapy naïve or pre-treated)
• Must have a site of disease amenable to biopsy, and be a candidate for tumor biopsy according to the treating institution's guidelines. Patient must be willing to undergo a new tumor biopsy at screening/baseline, and during therapy on the study.
• For MBG453 in combination with decitabine: anti-PD-1/PD-L1 therapy naïve SCLC patients who have failed no more than two lines of standard chemotherapy including topotecan

Exclusion Criteria:

• Presence of symptomatic central nervous system metastases.
• History of severe hypersensitivity reactions to other monoclonal antibodies.
• Human Immunodeficiency Virus, Hepatitis B Virus or Hepatitis C Virus infection.
• Active autoimmune disease or a documented history of autoimmune disease, including ulcerative colitis and Crohn's disease or any condition that requires systemic steroids.
• Systemic steroid therapy or any immunosuppressive therapy (≥10mg/day prednisone or equivalent).
• Use of any vaccines against infectious diseases (e.g. varicella, pneumococcus) within 4 weeks of initiation of study treatment.
• Pre-treatment with anti-CTLA4 antibodies in combination with any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathway.
• Participation in an interventional, investigational non-immunotherapy study within 2 weeks of the first dose of study treatment.
• Prior participation in an interventional, investigational cancer vaccine or immunotherapy study except for an anti-PD-1/PD-L1 study.
• For MBG453 in combination with decitabine: Hypersensitivity to decitabine or to any of the excipients, listed in decitabine country specific label

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

10

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase I Dose escalation: MBG453 Q2W ROW; Sabatolimab every 2 weeks (Q2W) in Phase I Dose Escalation Part in rest of the world (ROW) patients	Drug: MBG453; Anti human TIM-3 monoclonal antibody. MBG453 administered via intravenous (i.v.) infusion either every 2 weeks (Q2W) or every 4 weeks (Q4W).; Other Names: sabatolimab
Experimental: Phase I Dose escalation: MBG453 Q2W Japan; Sabatolimab Q2W in Phase I Dose Escalation Part in Japanese patients	Drug: MBG453; Anti human TIM-3 monoclonal antibody. MBG453 administered via intravenous (i.v.) infusion either every 2 weeks (Q2W) or every 4 weeks (Q4W).; Other Names: sabatolimab
Experimental: Phase I Dose escalation: MBG453 Q4W ROW; Sabatolimab every 4 weeks (Q4W) in Phase I Dose Escalation Part in ROW patients	Drug: MBG453; Anti human TIM-3 monoclonal antibody. MBG453 administered via intravenous (i.v.) infusion either every 2 weeks (Q2W) or every 4 weeks (Q4W).; Other Names: sabatolimab
Experimental: Phase I Dose escalation: MBG453 Q4W Japan; Sabatolimab Q4W in Phase I Dose Escalation Part in Japanese patients	Drug: MBG453; Anti human TIM-3 monoclonal antibody. MBG453 administered via intravenous (i.v.) infusion either every 2 weeks (Q2W) or every 4 weeks (Q4W).; Other Names: sabatolimab
Experimental: Phase Ib Dose Escalation: MBG453 Q2W + PDR001 Q2W; Sabatolimab Q2W in combination with spartalizumab Q2W in Phase Ib Dose Escalation Part	Drug: MBG453; Anti human TIM-3 monoclonal antibody. MBG453 administered via intravenous (i.v.) infusion either every 2 weeks (Q2W) or every 4 weeks (Q4W).; Other Names: sabatolimab; Drug: PDR001; Anti-human PD-1 monoclonal antibody. PDR001 administered via intravenous (i.v.) infusion either every 2 weeks (Q2W) or every 4 weeks (Q4W).; Other Names: spartalizumab
Experimental: Phase Ib Dose Escalation: MBG453 Q4W + PDR001 Q4W; Sabatolimab Q4W in combination with spartalizumab Q4W in Phase Ib Dose Escalation Part	Drug: MBG453; Anti human TIM-3 monoclonal antibody. MBG453 administered via intravenous (i.v.) infusion either every 2 weeks (Q2W) or every 4 weeks (Q4W).; Other Names: sabatolimab; Drug: PDR001; Anti-human PD-1 monoclonal antibody. PDR001 administered via intravenous (i.v.) infusion either every 2 weeks (Q2W) or every 4 weeks (Q4W).; Other Names: spartalizumab
Experimental: Phase Ib Dose Escalation: MBG453 + Decitabine; Sabatolimab in combination with decitabine in Phase Ib Dose Escalation Part. This arm was not opened for enrollment.	Drug: Decitabine; commercially available chemotherapy; Drug: MBG453; Anti human TIM-3 monoclonal antibody. MBG453 administered via intravenous (i.v.) infusion either every 2 weeks (Q2W) or every 4 weeks (Q4W).; Other Names: sabatolimab
Experimental: Dose Ranging Part: MBG453 Q4W; Sabatolimab Q4W in Dose Ranging Part	Drug: MBG453; Anti human TIM-3 monoclonal antibody. MBG453 administered via intravenous (i.v.) infusion either every 2 weeks (Q2W) or every 4 weeks (Q4W).; Other Names: sabatolimab
Experimental: Phase II: MBG453 + PDR001; Sabatolimab Q4W in combination with spartalizumab Q4W in non-small cell lung carcinoma (NSCLC) and melanoma	Drug: MBG453; Anti human TIM-3 monoclonal antibody. MBG453 administered via intravenous (i.v.) infusion either every 2 weeks (Q2W) or every 4 weeks (Q4W).; Other Names: sabatolimab; Drug: PDR001; Anti-human PD-1 monoclonal antibody. PDR001 administered via intravenous (i.v.) infusion either every 2 weeks (Q2W) or every 4 weeks (Q4W).; Other Names: spartalizumab
Experimental: Phase II: MBG453; Sabatolimab alone in Phase II. This arm was not opened for enrollment.	Drug: MBG453; Anti human TIM-3 monoclonal antibody. MBG453 administered via intravenous (i.v.) infusion either every 2 weeks (Q2W) or every 4 weeks (Q4W).; Other Names: sabatolimab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase I-Ib and Dose Ranging Part: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period	Number of participants with AEs (any AE regardless of seriousness) and SAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs. AE grades to characterize the severity of the AEs were based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. For CTCAE v4.03, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE. The on-treatment period is defined from the day of first administration of study treatment up to 30 days after the date of its last administration.	From first dose of study medication up to 30 days after last dose, with a maximum duration of 2 years for sabatolimab and 5 years for sabatolimab in combination with spartalizumab
Phase I-Ib: 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 unrelated to disease, disease progression, inter-current illness or concomitant medications, which occurs within the first cycle of treatment with sabatolimab as single agent or in the first two cycles of treatment when sabatolimab is given in combination with spartalizumab during the dose escalation part of the study. Other clinically significant toxicities may be considered to be DLTs, even if not CTCAE grade 3 or higher. The duration of one treatment cycle is 28 days.	28 days (sabatolimab single agent) and 56 days (sabatolimab+spartalizumab)
Phase I-Ib and Dose Ranging Part: Number of Participants With Dose Reductions and Dose Interruptions of Sabatolimab	Number of participants with at least one dose reduction of sabatolimab and number of participants with at least one dose interruption of sabatolimab.	From first dose of study medication up to last dose, with a maximum duration of 1.9 years for sabatolimab and 4.9 years for sabatolimab in combination with spartalizumab
Phase Ib: Number of Participants With Dose Reductions and Dose Interruptions of Spartalizumab	Number of participants with at least one dose reduction of spartalizumab and number of participants with at least one dose interruption of spartalizumab.	From first dose of study medication up to last dose, with a maximum duration of 4.9 years
Phase I-Ib and Dose Ranging Part: Dose Intensity of Sabatolimab	Dose intensity of sabatolimab Q2W was calculated as cumulative actual dose in milligrams divided by duration of exposure in days and then multiplied by 14 days. Dose intensity of sabatolimab Q4W was calculated as cumulative actual dose in milligrams divided by duration of exposure in days and then multiplied by 28 days.	From first dose of study medication up to last dose, with a maximum duration of 1.9 years for sabatolimab and 4.9 years for sabatolimab in combination with spartalizumab
Phase Ib: Dose Intensity of Spartalizumab	Dose intensity of spartalizumab Q2W was calculated as cumulative actual dose in milligrams divided by duration of exposure in days and then multiplied by 14 days. Dose intensity of spartalizumab Q4W was calculated as cumulative actual dose in milligrams divided by duration of exposure in days and then multiplied by 28 days.	From first dose of study medication up to last dose, with a maximum duration of 4.9 years
Phase II: Overall Response Rate (ORR) Per RECIST v1.1	Tumor response was based on local investigator assessment as per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. ORR per RECIST v1.1 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 diameter of all target lesions, taking as reference the baseline sum of diameters.	From start of treatment until end of treatment, assessed up to 2.9 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best Overall Response (BOR) Per RECIST v1.1	BOR is defined as the best response recorded from the start of the study treatment until disease progression/recurrence, based on local investigator assessment per RECIST v1.1. 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; PD= At least a 20% increase in the sum of diameters of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition, the sum must also demonstrate an absolute increase of at least 5 mm; SD= Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progression; NCRNPD: Persistence of one or more non-target lesions. Number of participants in each category is reported in the table.	From start of treatment until end of treatment, assessed up to 1.9 years for sabatolimab and 4.9 years for sabatolimab in combination with spartalizumab
Progression-Free Survival (PFS) Per RECIST v1.1	PFS is defined as the time from the date of start of treatment to the date of the first documented progression or death due to any cause. If a patient did not have an event, PFS was censored at the date of the last adequate tumor assessment. Tumor response was based on local investigator assessment per RECIST v1.1. PFS was analyzed using Kaplan-Meier estimates.	From start of treatment until first documented progression or death due to any cause, assessed up to 1.9 years for sabatolimab and 4.9 years for sabatolimab in combination with spartalizumab
Duration of Response (DOR) Per RECIST v1.1	DOR only applies to patients for whom best overall response is complete response (CR) or partial response (PR) based on local investigator assessment according to RECIST v1.1. DOR is defined as the time from the date of first documented response to the date of first documented progression or death due to underlying cancer. If a patient did not have an event, duration was censored at the date of last adequate tumor assessment. According to the statistical analysis plan (SAP), summary estimates of DOR using the Kaplan-Meier method were planned to be reported if there were at least 10 patients achieving a confirmed CR or PR in each treatment group/arm.	From first documented response to first documented disease progression or death due to underlying cancer, assessed up to 1.9 years for sabatolimab and 4.9 years for sabatolimab in combination with spartalizumab
Overall Response Rate (ORR) Per irRC	Tumor response was based on local investigator assessment as per 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 measurable lesions, taking as reference the baseline sum of diameters.	From start of treatment until end of treatment, assessed up to 1.9 years for sabatolimab and 4.9 years for sabatolimab in combination with spartalizumab
Progression-Free Survival (PFS) Per irRC	PFS is defined as the time from the date of start of treatment to the date of the first documented and confirmed progression or death due to any cause. If a patient did not have an event, PFS was censored at the date of the last adequate tumor evaluation. Tumor response was based on local investigator assessment per irRC. PFS was analyzed using Kaplan-Meier estimates.	From start of treatment until first documented and confirmed progression or death due to any cause, assessed up to 1.9 years for sabatolimab and 4.9 years for sabatolimab in combination with spartalizumab
Overall Survival (OS)	OS is defined as the time from date of start of treatment to date of death due to any cause. If a patient was not known to have died, survival was censored at the date of last known date patient alive. OS was estimated using Kaplan-Meier estimates.	From start of treatment until death due to any cause, assessed up to 2 years for sabatolimab and 5.3 years for sabatolimab in combination with spartalizumab
Maximum Observed Serum Concentration (Cmax) of Sabatolimab	Pharmacokinetic (PK) parameters were calculated based on sabatolimab serum concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed serum concentration following a dose.	pre-infusion and 1, 24, 168, 240 and 336 hours after completion of the sabatolimab infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The duration of the infusion was 30 minutes. The duration of one cycle was 28 days.
Time to Reach Maximum Serum Concentration (Tmax) of Sabatolimab	PK parameters were calculated based on sabatolimab 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 and 1, 24, 168, 240 and 336 hours after completion of the sabatolimab infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The duration of the infusion was 30 minutes. The duration of one cycle was 28 days.
Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Sabatolimab	PK parameters were calculated based on sabatolimab serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation.	pre-infusion and 1, 24, 168, 240 and 336 hours after completion of the sabatolimab infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The duration of the infusion was 30 minutes. The duration of one cycle was 28 days.
Terminal Elimination Half-life (T1/2) of Sabatolimab	PK parameters were calculated based on sabatolimab serum concentrations by using non-compartmental methods. T1/2 was calculated by regression analysis of the terminal elimination phase. T1/2 was computed as 0.693/terminal elimination rate constant.	pre-infusion and 1, 24, 168, 240 and 336 hours after completion of the sabatolimab infusion on Cycle 3 Day 1. The duration of the infusion was 30 minutes. The duration of one cycle was 28 days.
Maximum Observed Serum Concentration (Cmax) of Spartalizumab	PK parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed serum concentration following a dose.	pre-infusion and 1, 24, 168, 240 and 336 hours after completion of the spartalizumab infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The duration of the infusion was 30 minutes. The duration of one cycle was 28 days.
Time to Reach Maximum Serum Concentration (Tmax) of Spartalizumab	PK parameters were calculated based on spartalizumab 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 and 1, 24, 168, 240 and 336 hours after completion of the spartalizumab infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The duration of the infusion was 30 minutes. The duration of one cycle was 28 days.
Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Spartalizumab	PK parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation.	pre-infusion and 1, 24, 168, 240 and 336 hours after completion of the spartalizumab infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The duration of the infusion was 30 minutes. The duration of one cycle was 28 days.
Terminal Elimination Half-life (T1/2) of Spartalizumab	PK parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. T1/2 was calculated by regression analysis of the terminal elimination phase. T1/2 was computed as 0.693/terminal elimination rate constant.	pre-infusion and 1, 24, 168, 240 and 336 hours after completion of the spartalizumab infusion on Cycle 3 Day 1. The duration of the infusion was 30 minutes. The duration of one cycle was 28 days.
Number of Participants With Anti-sabatolimab Antibodies	Immunogenicity was evaluated in serum in a validated three-tiered assay approach. Samples were screened for potential anti-sabatolimab antibodies and positive screen results were confirmed using a confirmatory assay. For confirmed anti-drug antibodies (ADA) positive samples, titers were determined. Patient ADA status was defined as follows: ADA-negative at baseline: ADA-negative sample at baseline; ADA-positive at baseline: ADA-positive sample at baseline; ADA-negative post-baseline: patient with ADA-negative sample at baseline and at least 1 post baseline determinant sample, all of which are ADA-negative samples; ADA-inconclusive post-baseline = patient who does not qualify as ADA-positive or ADA-negative; Treatment-induced ADA-positive = ADA-negative sample at baseline and at least 1 treatment-induced ADA-positive sample; Treatment-boosted ADA-positive = ADA-positive sample at baseline and at least 1 treatment-boosted ADA-positive sample	Baseline (before first dose) and post-baseline (assessed throughout the treatment up to 1.9 years for sabatolimab and 4.9 years for sabatolimab in combination with spartalizumab)
Number of Participants With Anti-spartalizumab Antibodies	Immunogenicity was evaluated in serum in a validated three-tiered assay approach. Samples were screened for potential anti-spartalizumab antibodies and positive screen results were confirmed using a confirmatory assay. For confirmed anti-drug antibodies (ADA) positive samples, titers were determined. Patient ADA status was defined as follows: ADA-negative at baseline: ADA-negative sample at baseline; ADA-positive at baseline: ADA-positive sample at baseline; ADA-negative post-baseline: patient with ADA-negative sample at baseline and at least 1 post baseline determinant sample, all of which are ADA-negative samples; ADA-inconclusive post-baseline = patient who does not qualify as ADA-positive or ADA-negative; Treatment-induced ADA-positive = ADA-negative sample at baseline and at least 1 treatment-induced ADA-positive sample; Treatment-boosted ADA-positive = ADA-positive sample at baseline and at least 1 treatment-boosted ADA-positive sample	Baseline (before first dose) and post-baseline (assessed throughout the treatment up to 4.9 years).
Baseline Expression of PD-L1	The tumor expression of programmed cell death-ligand 1 (PD-L1) was measured by immunohistochemical methods. This record summarizes the baseline expression of PD-1 and the clinical benefit of study treatment. Clinical benefit (BOR: CR, PR, SD or NCRNPD) and No clinical benefit (BOR: PD) was based on local investigator assessment per RECIST v1.1.	Screening
Baseline Expression of CD8+	The tumor expression of CD8+ was measured by immunohistochemical methods. This record summarizes the baseline expression of CD8+ and the clinical benefit of study treatment. Clinical benefit (BOR: CR, PR, SD or NCRNPD) and No clinical benefit (BOR: PD) was based on local investigator assessment per RECIST v1.1.	Screening
Baseline Expression of TIM-3	The tumor expression of T-cell Immunoglobulin domain and Mucin domain-3 (TIM-3) was measured by immunohistochemical methods. This record summarizes the baseline expression of TIM-3 and the clinical benefit of study treatment. Clinical benefit (BOR: CR, PR, SD or NCRNPD) and No clinical benefit (BOR: PD) was based on local investigator assessment per RECIST v1.1.	Screening
Baseline Expression of LAG-3	The tumor expression of lymphocyte-activation gene-3 (LAG-3) was measured by immunohistochemical methods. This record summarizes the baseline expression of LAG-3 and the clinical benefit of study treatment. Clinical benefit (BOR: CR, PR, SD or NCRNPD) and No clinical benefit (BOR: PD) was based on local investigator assessment per RECIST v1.1.	Screening
Baseline Expression of CD163	The tumor expression of CD163 was measured by immunohistochemical methods. This record summarizes the baseline expression of CD163 and the clinical benefit of study treatment. Clinical benefit (BOR: CR, PR, SD or NCRNPD) and No clinical benefit (BOR: PD) was based on local investigator assessment per RECIST v1.1.	Screening
Percentage Change From Baseline of Tumor Infiltrating Lymphocytes (TILs) Count	The count of TILs was performed by hematoxylin and eosin stain.	Baseline (screening) and post-baseline (assessed throughout the treatment up to maximum 193 days)
Phase II: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period	Number of participants with AEs and SAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs. AE grades to characterize the severity of the AEs were based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. For CTCAE v4.03, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE. The on-treatment period is defined from the day of first administration of study treatment up to 30 days after the date of its last administration.	From first dose of study medication up to 30 days after last dose, with a maximum duration of 3 years
Phase II: Number of Participants With Dose Reductions and Dose Interruptions of Sabatolimab	Number of participants with at least one dose reduction of sabatolimab and number of participants with at least one dose interruption of sabatolimab.	From first dose of study medication up to last dose, with a maximum duration of 2.9 years
Phase II: Number of Participants With Dose Reductions and Dose Interruptions of Spartalizumab	Number of participants with at least one dose reduction of spartalizumab and number of participants with at least one dose interruption of spartalizumab.	From first dose of study medication up to last dose, with a maximum duration of 2.9 years
Phase II: Dose Intensity of Sabatolimab	Dose intensity of sabatolimab was calculated as cumulative actual dose in milligrams divided by duration of exposure in days and then multiplied by 28 days.	From first dose of study medication up to last dose, with a maximum duration of 2.9 years
Phase II: Dose Intensity of Spartalizumab	Dose intensity of spartalizumab was calculated as cumulative actual dose in milligrams divided by duration of exposure in days and then multiplied by 28 days.	From first dose of study medication up to last dose, with a maximum duration of 2.9 years

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Chair: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Curigliano G, Gelderblom H, Mach N, Doi T, Tai D, Forde PM, Sarantopoulos J, Bedard PL, Lin CC, Hodi FS, Wilgenhof S, Santoro A, Sabatos-Peyton CA, Longmire TA, Xyrafas A, Sun H, Gutzwiller S, Manenti L, Naing A. Phase I/Ib Clinical Trial of Sabatolimab, an Anti-TIM-3 Antibody, Alone and in Combination with Spartalizumab, an Anti-PD-1 Antibody, in Advanced Solid Tumors. Clin Cancer Res. 2021 Jul 1;27(13):3620-3629. doi: 10.1158/1078-0432.CCR-20-4746. Epub 2021 Apr 21.

Study record dates

Study Major Dates

• Study Start (Actual): November 23, 2015
• Primary Completion (Actual): August 30, 2022
• Study Completion (Actual): August 30, 2022

Study Registration Dates

• First Submitted: October 15, 2015
• First Submitted That Met QC Criteria: November 17, 2015
• First Posted (Estimated): November 18, 2015

Study Record Updates

• Last Update Posted (Actual): December 6, 2023
• Last Update Submitted That Met QC Criteria: December 5, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: NSCLC; Checkpoint inhibitor; Solid tumors; Melanoma; PD-1; TIM-3; MBG453; PDR001; Renal cell carcinoma; Non small cell lung cancer; RCC; Phase I-Ib/II
• Additional Relevant MeSH Terms: Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Decitabine; Spartalizumab
• Other Study ID Numbers: CMBG453X2101; 2015-002354-12 (EudraCT Number)

Plan for Individual participant data (IPD)

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

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