A Phase II, Open Label, Randomized, Parallel Arm Study of NIS793 (With and Without Spartalizumab) in Combination With SOC Chemotherapy Gemcitabine/Nab-paclitaxel, and Gemcitabine/Nab-paclitaxel Alone in First-line Metastatic Pancreatic Ductal Adenocarcinoma (mPDAC)
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 164
- 试验地点
- 6
- 主要终点
- Safety run-in Part: Number of Participants With Dose-Limiting Toxicities (DLTs)
研究概览
简要总结
The purpose of this Phase II study is to assess the efficacy and safety of NIS793 with and without spartalizumab in combination with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel in previously untreated mPDAC.
详细描述
This is a randomized, parallel arms, open-label, multi-center, Phase II study to evaluate the efficacy and safety of NIS793 with and without spartalizumab in combination with gemcitabine/nab-paclitaxel in participants with first-line metastatic pancreatic ductal adenocarcinoma (mPDAC).
The study started with a Safety Run-in to assess the safety and tolerability of NIS793 in combination with spartalizumab and standard of care (SOC) gemcitabine/nab-paclitaxel. Doses defined for each study treatment, as part of this quadruplet were administered in the Randomized part in the quadruplet/triplet/doublet-based treatment arms.
The Randomized part opened after the Safety Run-in had completed. Participants were randomized in a 1:1:1 ratio to one of the three treatment arms:
- Arm 1: NIS793 with spartalizumab and gemcitabine/nab-paclitaxel
- Arm 2: NIS793 with gemcitabine/nab-paclitaxel
- Arm 3: gemcitabine/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
- None
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
- •Signed informed consent must be obtained prior to participation in the study.
- •Male or female ≥ 18 years of age at the time of informed consent.
- •Participants with histologically or cytologically confirmed treatment-naïve metastatic adenocarcinoma of the pancreas with measurable disease as per RECIST 1.
- •Participants must have a site of disease amenable to biopsy, and be candidate for tumor biopsy according to the treating institution's guidelines. Participants must be willing to undergo a tumor biopsy at screening and during therapy on the study. In the event a new biopsy cannot be safely performed at study entry, an archival sample (collected <6 months prior) may be substituted following documented discussion with Novartis.
- •ECOG performance status ≤ 1.
排除标准
- •Previous radiotherapy, surgery (with exception of placement of biliary stent, which is allowed), chemotherapy or any other investigational therapy for the treatment of metastatic pancreatic cancer. Participants having received previous chemotherapy in the adjuvant setting.
- •Participants amenable to potentially curative resection.
- •Participants with a diagnosis of pancreatic neuroendocrine tumors (NETs), acinar, or islet cell tumors.
- •Having out of range laboratory values as pre-defined in the protocol.
- •Participants with MSI-H pancreatic adenocarcinoma.
- •Presence of symptomatic CNS metastases, or CNS metastases that require local CNS directed therapy (such as radiotherapy or surgery), or increasing doses of corticosteroids 2 weeks prior to study entry.
- •History of severe hypersensitivity reactions to any ingredient of study drug(s) and other mAbs and/or their excipients.
- •The participant exhibits any of the events outlined in the contra-indications or special warnings and precautions sections of gemcitabine and nab-paclitaxel as per locally approved labels.
- •Impaired cardiac function or clinically significant cardiac disease.
- •Known history of testing positive HIV infection.
- •Active HBV or HCV infection. Participants whose disease is controlled under antiviral therapy should not be excluded.
- •History of or current interstitial lung disease or pneumonitis grade ≥ 2
- •High risk of clinically significant gastrointestinal tract bleeding or any other condition associated with or history of significant bleeding.
研究组 & 干预措施
Safety Run-in
Combination of NIS793 + spartalizumab + gemcitabine + nab-paclitaxel
干预措施: NIS793 (Biological)
Safety Run-in
Combination of NIS793 + spartalizumab + gemcitabine + nab-paclitaxel
干预措施: Spartalizumab (Biological)
Safety Run-in
Combination of NIS793 + spartalizumab + gemcitabine + nab-paclitaxel
干预措施: gemcitabine (Drug)
Safety Run-in
Combination of NIS793 + spartalizumab + gemcitabine + nab-paclitaxel
干预措施: nab-paclitaxel (Drug)
Randomized Arm 1
Combination of NIS793 + spartalizumab + gemcitabine + nab-paclitaxel
干预措施: NIS793 (Biological)
Randomized Arm 1
Combination of NIS793 + spartalizumab + gemcitabine + nab-paclitaxel
干预措施: Spartalizumab (Biological)
Randomized Arm 1
Combination of NIS793 + spartalizumab + gemcitabine + nab-paclitaxel
干预措施: gemcitabine (Drug)
Randomized Arm 1
Combination of NIS793 + spartalizumab + gemcitabine + nab-paclitaxel
干预措施: nab-paclitaxel (Drug)
Randomized Arm 2
Combination of NIS793 + gemcitabine + nab-paclitaxel
干预措施: NIS793 (Biological)
Randomized Arm 2
Combination of NIS793 + gemcitabine + nab-paclitaxel
干预措施: gemcitabine (Drug)
Randomized Arm 2
Combination of NIS793 + gemcitabine + nab-paclitaxel
干预措施: nab-paclitaxel (Drug)
Randomized Arm 3
gemcitabine + nab-paclitaxel
干预措施: gemcitabine (Drug)
Randomized Arm 3
gemcitabine + nab-paclitaxel
干预措施: nab-paclitaxel (Drug)
结局指标
主要结局
Safety run-in Part: Number of Participants With Dose-Limiting Toxicities (DLTs)
时间窗: First cycle of treatment (28 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 where the relationship to study treatment cannot be ruled out and is not clearly related solely to disease, disease progression, inter-current illness or concomitant medications, which occurs within the DLT evaluation period. The DLT evaluation period is the first 28 days of treatment with NIS793 with spartalizumab in combination with gemcitabine/nab-paclitaxel. Other clinically significant toxicities may be considered to be DLTs, even if not CTCAE grade 3 or higher.
Safety run-in Part: Number of Participants With AEs and SAEs During the On-treatment Period
时间窗: Up to approximately 0.8 years
Number of participants with AEs (any adverse events regardless of seriousness) and serious adverse events (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 5.0. For CTCAE v5.0, 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 any study treatment up to 30 days after the date of the last actual administration of any study drug.
Safety run-in Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel
时间窗: Up to approximately 0.7 years
Number of participants with at least one dose reduction and at least one dose interruption of study drugs. Dose adjustments were permitted for patients who did not tolerate the protocol-specified dosing schedule. No dose reductions were allowed for NIS793 and spartalizumab beyond the first 28 days period of Safety run-in part.
Safety run-in Part: Dose Intensity of NIS793 and Spartalizumab
时间窗: Cycle 1 and Cycle 3. The duration of each cycle was 28 days.
Dose intensity of NIS973 and spartalizumab was calculated as cumulative actual dose in milligrams divided by duration of exposure in days and multiplied by 28 days. Dose adjustments were permitted for patients who did not tolerate the protocol-specified dosing schedule.
Safety run-in Part: Dose Intensity of Gemcitabine and Nab-paclitaxel
时间窗: Cycle 1 and Cycle 3. The duration of each cycle was 28 days.
Dose intensity of gemcitabine and nab-paclitaxel was calculated as cumulative actual dose in milligrams/m\^2 divided by duration of exposure in days and multiplied by 28 days.
Randomized Part: Progression-Free Survival (PFS) Per RECIST v1.1 - Bayesian Model
时间窗: Up to approximately 2 years. Risk changing timepoint=approximately 0.3 years.
PFS was based on local review of tumor assessments, using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria. PFS is defined as the time from the date of randomization to the date of the first documented progression or death due to any cause. If a subject had not had an event, PFS was censored at the date of last adequate tumor assessment. PFS was estimated using a Bayesian model. For each comparison (arm 1 versus arm 3 and arm 2 versus arm 3), PFS was modeled using a two-piece hazard model, with specifying hazard rates before and after the possible delayed effect for arms 1 and 2 and constant hazard rate for arm 3. Results in the table as expressed as estimated posterior median hazard rate and one-sided 90% credible interval.
Randomized Part: Progression-Free Survival (PFS) Per RECIST v1.1 - Kaplan-Meier Curves and Cox Model
时间窗: Up to approximately 2 years
PFS was based on local review of tumor assessments, using RECIST 1.1 criteria. PFS is defined as the time from the date of randomization to the date of the first documented progression or death due to any cause. If a subject had not had an event, PFS was censored at the date of last adequate tumor assessment. PFS was analyzed based on the Kaplan-Meier curves and the Cox model.
次要结局
- Randomized Part: Number of Participants With AEs and SAEs During the On-treatment Period(Up to approximately 1.8 years)
- Randomized Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel(Up to approximately 1.7 years)
- Randomized Part: Dose Intensity of NIS973 and Spartalizumab(Cycle 1 and Cycle 3. The duration of each cycle was 28 days)
- Randomized Part: Dose Intensity of Gemcitabine and Nab-paclitaxel(Cycle 1 and Cycle 3. The duration of each cycle was 28 days)
- Randomized Part: Overall Response Rate (ORR) Per RECIST v1.1(Up to approximately 1.7 years)
- Randomized Part: Duration of Response (DOR) Per RECIST v1.1(Up to approximately 1.7 years)
- Randomized Part: Time to Progression (TTP) Per RECIST v1.1(Up to approximately 1.7 years)
- Randomized Part: Overall Survival (OS)(Up to approximately 2 years)
- Randomized Part: Change From Baseline in PD-L1 Expression(Baseline (Screening), on-treatment (anytime between Cycle 3 Day 2 and Day 4). The duration of each cycle was 28 days.)
- Randomized Part: Change From Baseline in CD8 Expression(Baseline (Screening), on-treatment (anytime between Cycle 3 Day 2 and Day 4). The duration of each cycle was 28 days.)
- Randomized Part: Number of Participants With Anti-NIS793 Antibodies(Baseline (before first dose) and post-baseline (assessed throughout the treatment up to approximately 1.7 years))
- Randomized Part: Number of Participants With Anti-spartalizumab Antibodies(Cycle 1 and Cycle 3. The duration of each cycle was 28 days)
- Randomized Part: Maximum Observed Serum Concentration (Cmax) of NIS793(Cycle 1 and Cycle 3: pre-dose, 1, 24, 168 and 336 hours after the end of the infusion on Day 1. The duration of the infusion was 30 minutes. One cycle=28 days)
- Randomized Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of NIS793(Cycle 1 and Cycle 3: pre-dose, 1, 24, 168 and 336 hours after the end of the infusion on Day 1. The duration of the infusion was 30 minutes. One cycle=28 days)
- Randomized Part: Trough Serum Concentration (Ctrough) of NIS793(Cycle 1: pre-dose on Day 1. Cycle 3: pre-dose on Day 1 and Day 15 (combined). One cycle=28 days)
- Randomized Part: Maximum Observed Serum Concentration (Cmax) of Spartalizumab(Cycle 1 and Cycle 3: pre-dose, 1, 24, 168 and 648 hours after the end of the infusion on Day 1. The duration of the infusion was 30 minutes. One cycle=28 days)
- Randomized Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Spartalizumab(Cycle 1 and Cycle 3: pre-dose, 1, 24, 168 and 648 hours after the end of the infusion on Day 1. The duration of the infusion was 30 minutes. One cycle=28 days)
- Randomized Part: Trough Serum Concentration (Ctrough) of Spartalizumab(Cycle 2, 3 and 4: pre-dose on Day 1. One cycle=28 days)
- Randomized Part: Maximum Observed Plasma Concentration (Cmax) of Gemcitabine(Cycle 1 and Cycle 4: pre-dose, end of infusion, and 2, 3, 5 and 24 hours after the start of infusion on Day 1. The duration of the infusion was according to the product labelling and local guidance. One cycle=28 days)
- Randomized Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Gemcitabine(Cycle 1 and Cycle 4: pre-dose, end of infusion, and 2, 3, 5 and 24 hours after the start of infusion on Day 1. The duration of the infusion was according to the product labelling and local guidance. One cycle=28 days)
- Randomized Part: Trough Serum Concentration (Ctrough) of Gemcitabine(Cycle 4: pre-dose on Day 1. One cycle=28 days)
- Randomized Part: Maximum Observed Plasma Concentration (Cmax) of Nab-paclitaxel(Cycle 1 and Cycle 4: pre-dose, end of infusion, and 2, 3, 5 and 24 hours after the start of infusion on Day 1. The duration of the infusion was according to the product labelling and local guidance. One cycle=28 days)
- Randomized Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Nab-paclitaxel(Cycle 1 and Cycle 4: pre-dose, end of infusion, and 2, 3, 5 and 24 hours after the start of infusion on Day 1. The duration of the infusion was according to the product labelling and local guidance. One cycle=28 days)
- Randomized Part: Trough Serum Concentration (Ctrough) of Nab-paclitaxel(Cycle 4: pre-dose on Day 1. One cycle=28 days)