A Phase Ib/II, Open-label, Multi-center Study of INC280 in Combination With PDR001 or PDR001 Single Agent in Advanced Hepatocellular Carcinoma.
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 89
- 试验地点
- 1
- 主要终点
- Phase Ib: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib and Spartalizumab
研究概览
简要总结
The purpose of this study of capmatinib (INC280) and spartalizumab (PDR001) was to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of spartalizumab administered intravenously (i.v.) as a single agent or in combination with capmatinib administered orally in adult patients with advanced hepatocellular carcinoma (HCC).
详细描述
This was a Phase Ib/II, open label, multicenter study starting with a Phase Ib dose escalation part followed by a randomized Phase II part in patients with advanced hepatocellular carcinoma. Capmatinib was administered orally twice daily (BID) and spartalizumab was administered i.v. every 3 weeks (Q3W) until the occurrence of unacceptable toxicity, progressive disease as per irRC and/or treatment was discontinued at the discretion of the Investigator or the participant. A complete cycle of treatment was defined as 21 days.
During the Phase Ib dose escalation part of the study, participants were treated with capmatinib in combination with a fixed dose of spartalizumab until the maximum tolerated dose (MTD) was reached or the recommended phase 2 dose (RP2D) was established. The capmatinib dose was increased and the spartalizumab dose remained constant.
Once the MTD and/or RP2D were declared for capmatinib in combination with spartalizumab, additional participants were enrolled in the Phase II part in order to assess the anti-tumor activity of capmatinib in combination with spartalizumab and spartalizumab single agent. Participants were randomly assigned, in a 1:1 ratio, to treatment with either capmatinib in combination with spartalizumab or spartalizumab single agent.
研究设计
- 研究类型
- Interventional
- 分配方式
- 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 or cytologically documented locally advanced recurrent or metastatic HCC or for patients with cirrhosis according to the American Association for the Study of Liver Diseases (AASLD) and Asian Pacific Association for the study of the liver (APASL) criteria. Current cirrhotic status of Child Pugh Class A (5-6 points), with no encephalopathy and/or clinically significant ascites (defined as requiring the use of diuretics or paracentesis treatment).
- •Patients must have received prior systemic sorafenib treatment for HCC with documented progression during or after discontinuation of sorafenib treatment (for France only: patients must have received at least 8 weeks of prior sorafenib treatment), or are intolerant to sorafenib (defined as documented Grade 3 or 4 adverse events that led to sorafenib discontinuation),.
- •ECOG Performance Status ≤
- •Willing and able to swallow and retain oral medication.
排除标准
- •Use of any live vaccines within 4 weeks of initiation of study treatment.
- •History of severe hypersensitivity reactions to other monoclonal antibodies (mAbs).
- •Clinically significant pleural effusion that either required pleurocentesis or is associated with shortness of breath.
- •Active autoimmune disease or a documented history of autoimmune disease.
- •Clinically significant, uncontrolled heart diseases.
- •Patient having out of range laboratory values defined as:
- •Total bilirubin > 2 mg/dL, except for patients with Gilbert's syndrome who are excluded if total bilirubin > 3.0 x ULN or direct bilirubin > 1.5 x ULN
- •Alanine aminotransferase (ALT) > 5 x ULN
- •Aspartate aminotransferase (AST) > 5 x ULN
- •Coagulation: Prothrombin Time (PT) > 4 seconds more than the ULN or International Normalized Ratio (INR) > 1.7
- •Absolute neutrophil count (ANC) < 1.5 x 109/L
- •Platelet count < 75 x 109/L
- •Hemoglobin < 9 g/dL
- •Creatinine clearance (calculated using Cockcroft-Gault formula, or measured) < 45 mL/min
- •Asymptomatic serum amylase grade > 2 (1.5-2.0 x ULN). Patients with grade 1 or grade 2 serum amylase at the beginning of the study must be confirmed to have no signs or symptoms suggesting pancreatitis or pancreatic injury (e.g., elevated P-amylase, abnormal imaging findings of pancreas, etc.)
- •Serum lipase > ULN
- •Potassium, Magnesium, Phosphorus, total Calcium (corrected for serum albumin) outside of normal limits (patients may be enrolled if corrected to within normal limits with supplements during screening)
研究组 & 干预措施
Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W
Capmatinib 200 mg administered orally on a continuous twice daily (BID) dosing schedule in combination with spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase Ib
干预措施: Spartalizumab (Drug)
Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W
Capmatinib 200 mg administered orally on a continuous twice daily (BID) dosing schedule in combination with spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase Ib
干预措施: Capmatinib (Drug)
Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W
Capmatinib 300 mg administered orally on a continuous twice daily (BID) dosing schedule in combination with spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase Ib
干预措施: Spartalizumab (Drug)
Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W
Capmatinib 300 mg administered orally on a continuous twice daily (BID) dosing schedule in combination with spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase Ib
干预措施: Capmatinib (Drug)
Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W
Capmatinib 400 mg administered orally on a continuous twice daily (BID) dosing schedule in combination with spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase Ib
干预措施: Spartalizumab (Drug)
Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W
Capmatinib 400 mg administered orally on a continuous twice daily (BID) dosing schedule in combination with spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase Ib
干预措施: Capmatinib (Drug)
Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W
Capmatinib 400 mg administered orally on a continuous twice daily (BID) dosing schedule in combination with spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase II
干预措施: Spartalizumab (Drug)
Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W
Capmatinib 400 mg administered orally on a continuous twice daily (BID) dosing schedule in combination with spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase II
干预措施: Capmatinib (Drug)
Phase II: Spartalizumab 300 mg Q3W
Spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase II
干预措施: Spartalizumab (Drug)
结局指标
主要结局
Phase Ib: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib and Spartalizumab
时间窗: From first dose of study medication up to last dose, with a maximum duration of 3.2 years
Number of participants with at least one dose reduction of capmatinib and spartalizumab and number of participants with at least one dose interruption of capmatinib and spartalizumab. No dose modifications (i.e. dose reduction) were allowed for spartalizumab.
Phase Ib: 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 3.3 years
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.
Phase Ib: Number of Participants With Dose-Limiting Toxicities (DLTs) During the First 2 Cycles of Treatment
时间窗: 42 days
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 that occurs within the first 2 cycles of treatment with capmatinib 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 21 days.
Phase II: Overall Response Rate (ORR) Per RECIST v1.1
时间窗: From start of treatment until end of treatment, assessed up to 2.2 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 Ib: Dose Intensity of Capmatinib
时间窗: From first dose of study medication up to last dose, with a maximum duration of 3.2 years
Dose intensity of capmatinib was calculated as actual cumulative dose in milligrams divided by duration of exposure in 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 3.2 years
Dose intensity of spartalizumab was calculated as actual cumulative dose in milligrams divided by duration of exposure in weeks and then multiplied by 3 weeks (3W).
次要结局
- Phase Ib and Phase II: Time to Response (TTR) Per irRC(From start of treatment until first documented response, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II)
- Phase Ib and Phase II: Overall Survival (OS)(From start of treatment until death due to any cause, assessed up to 3.6 years in Phase Ib and up to 2.9 years in Phase II)
- 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 2.3 years)
- Phase Ib and Phase II: Best Overall Response (BOR) Per irRC(From start of treatment until end of treatment, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II)
- Phase Ib: Overall Response Rate (ORR) Per RECIST v1.1(From start of treatment until end of treatment, assessed up to 3.2 years)
- Phase II: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib and Spartalizumab(From first dose of study medication up to last dose, with a maximum duration of 2.2 years)
- Phase Ib and Phase II: Best Overall Response (BOR) Per RECIST v1.1(From start of treatment until end of treatment, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II)
- Phase Ib and Phase II: Overall Response Rate (ORR) Per irRC(From start of treatment until end of treatment, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II)
- Phase Ib and Phase II: Duration of Response (DOR) Per RECIST v1.1(From first documented response to first documented disease progression or death due to any cause, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II)
- Phase Ib and Phase II: Time to Response (TTR) Per RECIST v1.1(From start of treatment until first documented response, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II)
- Phase Ib and Phase II: Time to Progression (TTP) Per RECIST v1.1(From start of treatment until first documented progression or death due to underlying cancer, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II)
- Phase Ib and Phase II: Duration of Response (DOR) Per irRC(From first documented response to first documented disease progression or death due to any cause, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II)
- Phase Ib and Phase II: 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 3.2 years in Phase Ib and up to 2.2 years in Phase II)
- Phase Ib and Phase II: Progression-Free Survival (PFS) Per irRC(From start of treatment until first documented progression or death due to any cause, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II)
- Phase Ib and Phase II: Time to Progression (TTP) Per irRC(From start of treatment until first documented progression or death due to underlying cancer, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II)
- Phase II: Dose Intensity of Capmatinib(From first dose of study medication up to last dose, with a maximum duration of 2.2 years)
- Phase II: Dose Intensity of Spartalizumab(From first dose of study medication up to last dose, with a maximum duration of 2.2 years)
- Phase Ib: Maximum Observed Plasma Concentration (Cmax) of Capmatinib(pre-dose, 0.5, 1, 2, 4 and 8 hours post capmatinib dose on Cycle 2 Day 1 (C2D1). The duration of one cycle was 21 days.)
- Phase Ib: Time to Reach Maximum Plasma Concentration (Tmax) of Capmatinib(pre-dose, 0.5, 1, 2, 4 and 8 hours post capmatinib dose on Cycle 2 Day 1 (C2D1). The duration of one cycle was 21 days.)
- Phase Ib: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Capmatinib(pre-dose, 0.5, 1, 2, 4 and 8 hours post capmatinib dose on Cycle 2 Day 1 (C2D1). The duration of one cycle was 21 days.)
- Phase II: Pre-dose Plasma Concentration of Capmatinib(Pre-dose of capmatinib on Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1 and Cycle 6 Day 1. The duration of one cycle was 21 days.)
- Phase Ib and Phase II: Maximum Observed Serum Concentration (Cmax) of Spartalizumab(pre-dose, 1, 24, 48, 72, 168, 240, 336 and 504 hours after completion of spartalizumab infusion on Cycle 1 and Cycle 3. The duration of one cycle was 21 days.)
- Phase Ib and Phase II: Time to Reach Maximum Serum Concentration (Tmax) of Spartalizumab(pre-dose, 1, 24, 48, 72, 168, 240, 336 and 504 hours after completion of spartalizumab infusion on Cycle 1 and Cycle 3. The duration of one cycle was 21 days.)
- Phase Ib and Phase II: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Spartalizumab(pre-dose, 1, 24, 48, 72, 168, 240, 336 and 504 hours after completion of spartalizumab infusion on Cycle 1 and Cycle 3. The duration of one cycle was 21 days.)
- Phase Ib and Phase II: Percent Marker Area for CD8 Expression in Tumor Samples(Baseline (screening) and post-baseline (assessed throughout the treatment up to maximum 115 days).)
- Phase Ib and Phase II: PD-L1 Percent Positive Tumor(Baseline (screening) and post-baseline (assessed throughout the treatment up to maximum 115 days).)