A Randomized, Double-blind, Phase III Study, Comparing NIS793 in Combination With Gemcitabine and Nab-paclitaxel Versus (vs.) Placebo Combined With Gemcitabine and Nab-paclitaxel for First Line Treatment of Metastatic Pancreatic Ductal Adenocarcinoma (mPDAC) - daNIS-2
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 511
- 试验地点
- 113
- 主要终点
- Safety run-in Part: Percentage of Participants With Dose Limiting Toxicities (DLTs) During the First Cycle (4 Weeks) of Treatment.
研究概览
简要总结
The purpose of this study was to evaluate the efficacy and safety of NIS793 in combination with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel and placebo in first-line metastatic pancreatic ductal adenocarcinoma (mPDAC). This study aimed to explore whether blockade of Transforming Growth Factor β (TGFβ) in combination with gemcitabine/nab-paclitaxel could reduce fibrosis in PDAC, restore chemo-sensitivity and ultimately lead to improvements in overall survival (OS) and other clinically relevant outcomes.
详细描述
This was a randomized, double-blind, multicenter, two- group, phase III study that consisted of two parts: a Safety Run-in part and a Randomized part.
The decision to open the randomized part of the study was based on dose confirmation and available safety, relevant PK, and other clinical and laboratory data from the Safety Run-in part.
The open-label Safety Run-in part was conducted to confirm the recommended phase 3 dose (RP3D) of NIS793 in combination with gemcitabine and nab-paclitaxel. The safety run-in part started with one treatment regimen - NIS793 (2100 mg intravenous (i.v.) every 2 weeks (Q2W)) in combination with gemcitabine and nab-paclitaxel during the DLT assessment period. Dose limiting toxicity assessment period is defined as first cycle (i.e. 28 days, or 4 weeks) of dosing of the study treatment.
The Randomized part randomized participants 1:1 to one of the two treatment groups:
- Investigational group (Arm A); combination of NIS793, gemcitabine and nab-paclitaxel
- Control group (Arm B): combination of placebo, gemcitabine and nab-paclitaxel
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Applicable for both Safety run-in and Randomized part
- •Participants aged ≥18 years with histologically or cytologically confirmed (based on local assessment and per local guidelines) mPDAC eligible for treatment in the first line setting and not amenable for potentially curative surgery
- •Presence of at least one measurable lesion assessed by Computerized Tomography (CT) and/or Magnetic Resonance Imaging (MRI) according to RECIST 1.1
- •Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1
- •Adequate organ function (assessed by central laboratory for eligibility)
- •Participants must have recovered from treatment-related toxicities of prior anticancer therapies to grade ≤ 1 (CTCAE v 5.0) at time of screening, except alopecia.
排除标准
- •Applicable for both Safety run-in and Randomized part
- •Previous systemic anti-cancer treatment for metastatic PDAC
- •Pancreatic neuroendocrine (islet) or acinar tumors
- •Participants with known status of microsatellite instability-high (MSI-H) or mismatch repair-deficient pancreatic cancer (if status is not already available, testing is not required at screening).
- •Participant has not recovered from a major surgery performed prior to start of study treatment or has had a major surgery within 4 weeks prior to start of study treatment.
- •Radiation therapy or brain radiotherapy ≤ 4 weeks prior to start of study treatment (palliative radiotherapy to bone lesions allowed > 2 weeks prior to start of study treatment).
- •Impaired cardiac function or clinically significant cardio-vascular disease
- •Use of hematopoietic growth factors or transfusion support ≤ 2 weeks prior to start of study treatment.
- •Participant has conditions that are considered to have a high risk of clinically significant gastrointestinal tract bleeding or any other condition associated with or history of significant bleeding.
- •Serious non-healing wounds.
- •Pregnant or breast-feeding women
- •Women of childbearing potential, unless willing to use highly effective contraception methods during treatment and after stopping study treatments as indicated
- •Pre-existing peripheral neuropathy > grade 1 (CTCAE v5.0)
- •Other Inclusion/Exclusion criteria may apply.
研究组 & 干预措施
Safety run-in part: NIS793 plus (Gemcitabine and Nab-paclitaxel)
Participants received a combination of NIS793, Gemcitabine and Nab-paclitaxel :
- NIS793 at 2100 mg (Days 1 and 15)
- Gemcitabine at 1000 mg/m² (Days 1, 8 and 15)
- Nab-paclitaxel at 125 mg/m² (Days 1, 8 and 15)
Note: As of 7-Jul-2023, treatment with NIS793/placebo was stopped. Study participants were allowed to continue with standard of care (SoC) chemotherapy (gemcitabine+ nab-paclitaxel) per investigator assessment.
干预措施: NIS793 (Drug)
Randomized part (Arm A): NIS793 plus (Gemcitabine and Nab-paclitaxel)
Participants received a combination of NIS793, gemcitabine and nab-paclitaxel:
- NIS793 at 2100 mg (Days 1 and 15) assuming this was the confirmed RP3D in the safety run-in part or NIS793 at 2100 mg on Day 1 if dose level -1 was the confirmed RP3D in the safety run-in
- Gemcitabine at 1000 mg/m² (Days 1, 8 and 15)
- Nab-paclitaxel at 125 mg/m² (Days 1, 8 and 15)
Note: As of 7-Jul-2023, treatment with NIS793/placebo was stopped. Study participants were allowed to continue with standard of care (SoC) chemotherapy (gemcitabine+ nab-paclitaxel) per investigator assessment.
干预措施: Placebo (Drug)
Randomized part (Arm B): Placebo plus (Gemcitabine and Nab-paclitaxel)
Participants received a combination of placebo, gemcitabine and nab-paclitaxel:
- Placebo for NIS793 (Days 1 and 15)
- Gemcitabine at 1000 mg/m² (Days 1, 8 and 15)
- Nab-paclitaxel at 125 mg/m² (Days 1, 8 and 15)
Note: As of 7-Jul-2023, treatment with NIS793/placebo was stopped. Study participants were allowed to continue with standard of care (SoC) chemotherapy (gemcitabine+ nab-paclitaxel) per investigator assessment.
干预措施: Placebo (Drug)
Randomized part (Arm B): Placebo plus (Gemcitabine and Nab-paclitaxel)
Participants received a combination of placebo, gemcitabine and nab-paclitaxel:
- Placebo for NIS793 (Days 1 and 15)
- Gemcitabine at 1000 mg/m² (Days 1, 8 and 15)
- Nab-paclitaxel at 125 mg/m² (Days 1, 8 and 15)
Note: As of 7-Jul-2023, treatment with NIS793/placebo was stopped. Study participants were allowed to continue with standard of care (SoC) chemotherapy (gemcitabine+ nab-paclitaxel) per investigator assessment.
干预措施: Nab-paclitaxel (Drug)
Randomized part (Arm B): Placebo plus (Gemcitabine and Nab-paclitaxel)
Participants received a combination of placebo, gemcitabine and nab-paclitaxel:
- Placebo for NIS793 (Days 1 and 15)
- Gemcitabine at 1000 mg/m² (Days 1, 8 and 15)
- Nab-paclitaxel at 125 mg/m² (Days 1, 8 and 15)
Note: As of 7-Jul-2023, treatment with NIS793/placebo was stopped. Study participants were allowed to continue with standard of care (SoC) chemotherapy (gemcitabine+ nab-paclitaxel) per investigator assessment.
干预措施: Gemcitabine (Drug)
Safety run-in part: NIS793 plus (Gemcitabine and Nab-paclitaxel)
Participants received a combination of NIS793, Gemcitabine and Nab-paclitaxel :
- NIS793 at 2100 mg (Days 1 and 15)
- Gemcitabine at 1000 mg/m² (Days 1, 8 and 15)
- Nab-paclitaxel at 125 mg/m² (Days 1, 8 and 15)
Note: As of 7-Jul-2023, treatment with NIS793/placebo was stopped. Study participants were allowed to continue with standard of care (SoC) chemotherapy (gemcitabine+ nab-paclitaxel) per investigator assessment.
干预措施: Nab-paclitaxel (Drug)
Randomized part (Arm A): NIS793 plus (Gemcitabine and Nab-paclitaxel)
Participants received a combination of NIS793, gemcitabine and nab-paclitaxel:
- NIS793 at 2100 mg (Days 1 and 15) assuming this was the confirmed RP3D in the safety run-in part or NIS793 at 2100 mg on Day 1 if dose level -1 was the confirmed RP3D in the safety run-in
- Gemcitabine at 1000 mg/m² (Days 1, 8 and 15)
- Nab-paclitaxel at 125 mg/m² (Days 1, 8 and 15)
Note: As of 7-Jul-2023, treatment with NIS793/placebo was stopped. Study participants were allowed to continue with standard of care (SoC) chemotherapy (gemcitabine+ nab-paclitaxel) per investigator assessment.
干预措施: Nab-paclitaxel (Drug)
Safety run-in part: NIS793 plus (Gemcitabine and Nab-paclitaxel)
Participants received a combination of NIS793, Gemcitabine and Nab-paclitaxel :
- NIS793 at 2100 mg (Days 1 and 15)
- Gemcitabine at 1000 mg/m² (Days 1, 8 and 15)
- Nab-paclitaxel at 125 mg/m² (Days 1, 8 and 15)
Note: As of 7-Jul-2023, treatment with NIS793/placebo was stopped. Study participants were allowed to continue with standard of care (SoC) chemotherapy (gemcitabine+ nab-paclitaxel) per investigator assessment.
干预措施: Gemcitabine (Drug)
Randomized part (Arm A): NIS793 plus (Gemcitabine and Nab-paclitaxel)
Participants received a combination of NIS793, gemcitabine and nab-paclitaxel:
- NIS793 at 2100 mg (Days 1 and 15) assuming this was the confirmed RP3D in the safety run-in part or NIS793 at 2100 mg on Day 1 if dose level -1 was the confirmed RP3D in the safety run-in
- Gemcitabine at 1000 mg/m² (Days 1, 8 and 15)
- Nab-paclitaxel at 125 mg/m² (Days 1, 8 and 15)
Note: As of 7-Jul-2023, treatment with NIS793/placebo was stopped. Study participants were allowed to continue with standard of care (SoC) chemotherapy (gemcitabine+ nab-paclitaxel) per investigator assessment.
干预措施: NIS793 (Drug)
Randomized part (Arm A): NIS793 plus (Gemcitabine and Nab-paclitaxel)
Participants received a combination of NIS793, gemcitabine and nab-paclitaxel:
- NIS793 at 2100 mg (Days 1 and 15) assuming this was the confirmed RP3D in the safety run-in part or NIS793 at 2100 mg on Day 1 if dose level -1 was the confirmed RP3D in the safety run-in
- Gemcitabine at 1000 mg/m² (Days 1, 8 and 15)
- Nab-paclitaxel at 125 mg/m² (Days 1, 8 and 15)
Note: As of 7-Jul-2023, treatment with NIS793/placebo was stopped. Study participants were allowed to continue with standard of care (SoC) chemotherapy (gemcitabine+ nab-paclitaxel) per investigator assessment.
干预措施: Gemcitabine (Drug)
结局指标
主要结局
Safety run-in Part: Percentage of Participants With Dose Limiting Toxicities (DLTs) During the First Cycle (4 Weeks) of Treatment.
时间窗: Up to 4 weeks
A dose-limiting toxicity (DLT) was defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurred within the first cycle (i.e., 28 days or 4 weeks) of the treatment with NIS793 in combination with gemcitabine/nab-paclitaxel. The National Cancer Institute Common Terminology Criteria for Adverse events (NCI CTCAE) version 5 was used for all grading.
Randomized Part: Overall Survival (OS)
时间窗: From randomization up to death, assessed up to approximately 34 months
Overall Survival (OS) was defined as the time from date of randomization/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.
次要结局
- Percentage of Participants With Adverse Events (AEs)(Up to approximately 32 months)
- Percentage of Participants With Dose Interruptions and Dose Reductions of NIS793 in Combination With Gemcitabine and Nab-paclitaxel(Up to approximately 32 months)
- Dose Intensity of NIS793 in Combination With Gemcitabine and Nab-paclitaxel(Up to approximately 32 months)
- Progression-Free Survival (PFS)(From enrollment (run-in part) or randomization (randomized part) up to disease progression or death, assessed up to approximately 34 months)
- Overall Response Rate (ORR)(Up to approximately 34 months)
- Disease Control Rate (DCR)(Up to approximately 34 months)
- Duration of Response (DOR)(Up to approximately 34 months)
- Time to Response (TTR)(From enrollment (run-in part) or randomization (randomized part) up to first documented response, assessed up to approximately 34 months)
- Safety run-in Part: Trough Concentration (Ctrough) of NIS793 in Combination With Gemcitabine and Nab-paclitaxel(Cycles 1 and 3 Day 15 (0 hour (pre-dose)), Cycles 2, 4, 6 and 12 Day 1 (0 hour (pre-dose)). 1 cycle = 28 days.)
- Safety run-in Part: Maximum Concentration (Cmax) of NIS793 in Combination With Gemcitabine and Nab-paclitaxel(Cycles 1 and 3 Day 1: 0 hour (pre-dose) and 1 hour. 1 cycle = 28 days.)
- Safety run-in Part: Time to Reach Maximum Concentration (Tmax) of NIS793 in Combination With Gemcitabine and Nab-paclitaxel(Cycles 1 and 3 Day 1: 0 hour (pre-dose) and 1 hour. 1 cycle = 28 days.)
- Randomized Part (Chinese Participants With Intensive PK Sampling): Trough Concentration (Ctrough) of NIS793 in Combination With Gemcitabine and Nab-paclitaxel(Cycle 1 Day 15, Cycle 3 Day 1, Cycle 3 Day 15, Cycle 4 Day 1 and Cycle 6 Day 1: 0 hour (pre-dose). 1 cycle = 28 days.)
- Randomized Part (Chinese Participants With Intensive PK Sampling): Maximum Concentration (Cmax) of NIS793 in Combination With Gemcitabine and Nab-paclitaxel(Cycles 1 and 3 Day 1: 0 hour (pre-dose) and 1 hour. 1 cycle = 28 days.)
- Randomized Part (Chinese Participants With Intensive PK Sampling): Time to Reach Maximum Concentration (Tmax) of NIS793 in Combination With Gemcitabine and Nab-paclitaxel(Cycles 1 and 3 Day 1: 0 hour (pre-dose) and 1 hour. 1 cycle = 28 days.)
- Randomized Part (Chinese Participants With Intensive PK Sampling): Area Under the Curve From Time Zero to the Last Measurable Concentration Sampling Time (AUClast) of NIS793 in Combination With Gemcitabine and Nab-paclitaxel(Cycles 1 Day 1: 0 hour (pre-dose) and 1 hour. 1 cycle = 28 days.)
- Randomized Part (Chinese Participants With Intensive PK Sampling): Area Under the Curve Calculated to the End of a Dosing Interval (Tau) at Steady-state (AUCtau) of NIS793 in Combination With Gemcitabine and Nab-paclitaxel(Cycles 3 Day 1: 0 hour (pre-dose) and 1 hour. 1 cycle = 28 days.)
- Randomized Part (Participants Without Intensive PK Sampling): Trough Concentration (Ctrough) of NIS793 in Combination With Gemcitabine and Nab-paclitaxel(Cycles 2, 3, 4, 6 and 12 Day 1 (0 hour (pre-dose)). 1 cycle = 28 days.)
- Randomized Part (Participants Without Intensive PK Sampling): Maximum Concentration (Cmax) of NIS793 in Combination With Gemcitabine and Nab-paclitaxel(Cycles 1 and 3: Day 1 (0 hour (pre-dose)). 1 cycle = 28 days.)
- Randomized Part (Participants Without Intensive PK Sampling): Time to Reach Maximum Concentration (Tmax) of NIS793 in Combination With Gemcitabine and Nab-paclitaxel(Cycles 1 and 3: Day 1 (0 hour (pre-dose)). 1 cycle = 28 days.)
- Randomized Part: Anti-drug Antibodies (ADA) Against NIS793 Prevalence at Baseline(Baseline)
- Randomized Part: Anti-drug Antibodies (ADA) Against NIS793 Incidence on Treatment(From date of first study drug intake up to approximately 34 months)