Clinical trial NCT02608268: Phase I-Ib/II Study of MBG453 as Single Agent and in Combination With PDR001 in Patients With Advanced Malignancies
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Advanced Malignancies
Keywords: Solid tumors
Melanoma
Non small cell lung cancer
NSCLC
Renal cell carcinoma
RCC
Phase I-Ib/II
MBG453
PDR001
Checkpoint inhibitor
PD-1
TIM-3
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2015-11-18
Enrollment: 252
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: 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

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.

Eligibility criteria: 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

Primary outcomes:
measure: Phase I-Ib and Dose Ranging Part: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period
timeFrame: 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
measure: Phase I-Ib: Number of Participants With Dose-Limiting Toxicities (DLTs)
timeFrame: 28 days (sabatolimab single agent) and 56 days (sabatolimab+spartalizumab)
measure: Phase I-Ib and Dose Ranging Part: Number of Participants With Dose Reductions and Dose Interruptions of Sabatolimab
timeFrame: 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
measure: Phase Ib: Number of Participants With Dose Reductions and Dose Interruptions of Spartalizumab
timeFrame: From first dose of study medication up to last dose, with a maximum duration of 4.9 years
measure: Phase I-Ib and Dose Ranging Part: Dose Intensity of Sabatolimab
timeFrame: 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
measure: Phase Ib: Dose Intensity of Spartalizumab
timeFrame: From first dose of study medication up to last dose, with a maximum duration of 4.9 years
measure: Phase II: Overall Response Rate (ORR) Per RECIST v1.1
timeFrame: From start of treatment until end of treatment, assessed up to 2.9 years
Secondary outcomes:
measure: Best Overall Response (BOR) Per RECIST v1.1
timeFrame: 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
measure: Progression-Free Survival (PFS) Per RECIST v1.1
timeFrame: 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
measure: Duration of Response (DOR) Per RECIST v1.1
timeFrame: 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
measure: Overall Response Rate (ORR) Per irRC
timeFrame: 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
measure: Progression-Free Survival (PFS) Per irRC
timeFrame: 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
measure: Overall Survival (OS)
timeFrame: 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
measure: Maximum Observed Serum Concentration (Cmax) of Sabatolimab
timeFrame: 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.
measure: Time to Reach Maximum Serum Concentration (Tmax) of Sabatolimab
timeFrame: 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.
measure: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Sabatolimab
timeFrame: 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.
measure: Terminal Elimination Half-life (T1/2) of Sabatolimab
timeFrame: 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.
measure: Maximum Observed Serum Concentration (Cmax) of Spartalizumab
timeFrame: 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.
measure: Time to Reach Maximum Serum Concentration (Tmax) of Spartalizumab
timeFrame: 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.
measure: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Spartalizumab
timeFrame: 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.
measure: Terminal Elimination Half-life (T1/2) of Spartalizumab
timeFrame: 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.
measure: Number of Participants With Anti-sabatolimab Antibodies
timeFrame: 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)
measure: Number of Participants With Anti-spartalizumab Antibodies
timeFrame: Baseline (before first dose) and post-baseline (assessed throughout the treatment up to 4.9 years).
measure: Baseline Expression of PD-L1
timeFrame: Screening
measure: Baseline Expression of CD8+
timeFrame: Screening
measure: Baseline Expression of TIM-3
timeFrame: Screening
measure: Baseline Expression of LAG-3
timeFrame: Screening
measure: Baseline Expression of CD163
timeFrame: Screening
measure: Percentage Change From Baseline of Tumor Infiltrating Lymphocytes (TILs) Count
timeFrame: Baseline (screening) and post-baseline (assessed throughout the treatment up to maximum 193 days)
measure: Phase II: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period
timeFrame: From first dose of study medication up to 30 days after last dose, with a maximum duration of 3 years
measure: Phase II: Number of Participants With Dose Reductions and Dose Interruptions of Sabatolimab
timeFrame: From first dose of study medication up to last dose, with a maximum duration of 2.9 years
measure: Phase II: Number of Participants With Dose Reductions and Dose Interruptions of Spartalizumab
timeFrame: From first dose of study medication up to last dose, with a maximum duration of 2.9 years
measure: Phase II: Dose Intensity of Sabatolimab
timeFrame: From first dose of study medication up to last dose, with a maximum duration of 2.9 years
measure: Phase II: Dose Intensity of Spartalizumab
timeFrame: From first dose of study medication up to last dose, with a maximum duration of 2.9 years
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Sidney Kimmel CCC At JH Sidney Kimmel CCC
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute DFCI - Brookline
state: Massachusetts
city: Houston
country: United States
facility: UT M.D Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: Mays Cancer Ctr Uthsa Mdacc
state: Texas
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Rozzano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Kashiwa
country: Japan
facility: Novartis Investigative Site
state: Chiba
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Leiden
country: Netherlands
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Geneve 14
country: Switzerland
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_CHAIR
References:
citation: 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.