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
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 252
- 试验地点
- 5
- 主要终点
- Phase I-Ib and Dose Ranging Part: Number of Participants With Dose Reductions and Dose Interruptions of Sabatolimab
研究概览
简要总结
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
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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
干预措施: MBG453 (Drug)
Phase I Dose escalation: MBG453 Q2W Japan
Sabatolimab Q2W in Phase I Dose Escalation Part in Japanese patients
干预措施: MBG453 (Drug)
Phase I Dose escalation: MBG453 Q4W ROW
Sabatolimab every 4 weeks (Q4W) in Phase I Dose Escalation Part in ROW patients
干预措施: MBG453 (Drug)
Phase I Dose escalation: MBG453 Q4W Japan
Sabatolimab Q4W in Phase I Dose Escalation Part in Japanese patients
干预措施: MBG453 (Drug)
Phase Ib Dose Escalation: MBG453 Q2W + PDR001 Q2W
Sabatolimab Q2W in combination with spartalizumab Q2W in Phase Ib Dose Escalation Part
干预措施: MBG453 (Drug)
Phase Ib Dose Escalation: MBG453 Q2W + PDR001 Q2W
Sabatolimab Q2W in combination with spartalizumab Q2W in Phase Ib Dose Escalation Part
干预措施: PDR001 (Drug)
Phase Ib Dose Escalation: MBG453 Q4W + PDR001 Q4W
Sabatolimab Q4W in combination with spartalizumab Q4W in Phase Ib Dose Escalation Part
干预措施: MBG453 (Drug)
Phase Ib Dose Escalation: MBG453 Q4W + PDR001 Q4W
Sabatolimab Q4W in combination with spartalizumab Q4W in Phase Ib Dose Escalation Part
干预措施: PDR001 (Drug)
Phase Ib Dose Escalation: MBG453 + Decitabine
Sabatolimab in combination with decitabine in Phase Ib Dose Escalation Part. This arm was not opened for enrollment.
干预措施: MBG453 (Drug)
Phase Ib Dose Escalation: MBG453 + Decitabine
Sabatolimab in combination with decitabine in Phase Ib Dose Escalation Part. This arm was not opened for enrollment.
干预措施: Decitabine (Drug)
Dose Ranging Part: MBG453 Q4W
Sabatolimab Q4W in Dose Ranging Part
干预措施: MBG453 (Drug)
Phase II: MBG453 + PDR001
Sabatolimab Q4W in combination with spartalizumab Q4W in non-small cell lung carcinoma (NSCLC) and melanoma
干预措施: MBG453 (Drug)
Phase II: MBG453 + PDR001
Sabatolimab Q4W in combination with spartalizumab Q4W in non-small cell lung carcinoma (NSCLC) and melanoma
干预措施: PDR001 (Drug)
Phase II: MBG453
Sabatolimab alone in Phase II. This arm was not opened for enrollment.
干预措施: MBG453 (Drug)
结局指标
主要结局
Phase I-Ib and Dose Ranging Part: Number of Participants With Dose Reductions and Dose Interruptions of Sabatolimab
时间窗: 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
Number of participants with at least one dose reduction of sabatolimab and number of participants with at least one dose interruption of sabatolimab.
Phase Ib: Number of Participants With Dose Reductions and Dose Interruptions of Spartalizumab
时间窗: From first dose of study medication up to last dose, with a maximum duration of 4.9 years
Number of participants with at least one dose reduction of spartalizumab and number of participants with at least one dose interruption of spartalizumab.
Phase II: Overall Response Rate (ORR) Per RECIST v1.1
时间窗: From start of treatment until end of treatment, assessed up to 2.9 years
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.
Phase I-Ib: Number of Participants With Dose-Limiting Toxicities (DLTs)
时间窗: 28 days (sabatolimab single agent) and 56 days (sabatolimab+spartalizumab)
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.
Phase I-Ib and Dose Ranging Part: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period
时间窗: 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
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.
Phase I-Ib and Dose Ranging Part: Dose Intensity of Sabatolimab
时间窗: 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
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.
Phase Ib: Dose Intensity of Spartalizumab
时间窗: From first dose of study medication up to last dose, with a maximum duration of 4.9 years
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.
次要结局
- Overall Response Rate (ORR) Per irRC(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(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)
- Time to Reach Maximum Serum Concentration (Tmax) of Sabatolimab(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.)
- Maximum Observed Serum Concentration (Cmax) of Spartalizumab(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(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.)
- Baseline Expression of PD-L1(Screening)
- Baseline Expression of CD8+(Screening)
- Phase II: Number of Participants With Dose Reductions and Dose Interruptions of Spartalizumab(From first dose of study medication up to last dose, with a maximum duration of 2.9 years)
- Number of Participants With Anti-sabatolimab Antibodies(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))
- Phase II: Number of Participants With Dose Reductions and Dose Interruptions of Sabatolimab(From first dose of study medication up to last dose, with a maximum duration of 2.9 years)
- Phase II: Dose Intensity of Sabatolimab(From first dose of study medication up to last dose, with a maximum duration of 2.9 years)
- Best Overall Response (BOR) Per RECIST v1.1(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)
- Duration of Response (DOR) Per RECIST v1.1(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)
- Progression-Free Survival (PFS) Per irRC(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)(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(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(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.)
- Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Sabatolimab(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 Spartalizumab(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(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-spartalizumab Antibodies(Baseline (before first dose) and post-baseline (assessed throughout the treatment up to 4.9 years).)
- Baseline Expression of CD163(Screening)
- Baseline Expression of TIM-3(Screening)
- Baseline Expression of LAG-3(Screening)
- Percentage Change From Baseline of Tumor Infiltrating Lymphocytes (TILs) Count(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(From first dose of study medication up to 30 days after last dose, with a maximum duration of 3 years)
- Phase II: Dose Intensity of Spartalizumab(From first dose of study medication up to last dose, with a maximum duration of 2.9 years)