An Open-label, Multi-center, ph II Platform Study Evaluating the Efficacy and Safety of NIS793 and Other New Investigational Drug Combinations With SOC Anti-cancer Therapy for the 2L Treatment of Metastatic Colorectal Cancer (mCRC)
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 204
- 试验地点
- 8
- 主要终点
- Safety run-in: 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 is to evaluate the preliminary efficacy and safety of NIS793 and other novel investigational combinations with standard of care (SOC) anti-cancer therapy vs SOC anti-cancer therapy for the second line treatment of mCRC.
This study aims to explore whether different mechanisms of action may reverse resistance and improve responsiveness to the currently considered SOC anti-cancer therapy in the second line metastatic colorectal cancer (mCRC) setting.
详细描述
This is an open-label, multi-center, phase II, 2-part platform study with Safety run-in and Expansion parts.
The platform design of this study is adaptive to allow flexibility in the introduction of additional treatment arms with new investigational drugs in combination with SOC anti-cancer therapy for the second line treatment of mCRC.
The study will include a control arm that will enroll participants treated with SOC anti-cancer therapy (bevacizumab with mFOLFOX6 or FOLFIRI) for the second line treatment of mCRC. The choice of the chemotherapy medications (mFOLFOX6 or FOLFIRI) will be determined by the Investigator based on prior exposure to oxaliplatin or irinotecan.
Each investigational arm will include a combination of an investigational drug and the SOC anti-cancer therapy. The first investigational arm of the study will explore the combination of anti-transforming growth factor β (TGF-β) monoclonal antibody, NIS793 with SOC anti-cancer therapy. The second investigational arm of the study will explore the combination of anti-transforming growth factor β (TGF-β) monoclonal antibody, NIS793 with Tislelizumab, which is an anti-PD1 monoclonal antibody, and SOC anti-cancer therapy. Combination of other investigational drugs with SOC anti-cancer therapy may be added by protocol amendments an additional investigational arms.
In each investigational arm, a Safety run-in part will be conducted before opening the expansion part to confirm the recommended phase 2 dose (RP2D) for a combination of any investigational drug with SOC anti-cancer therapy unless the dose has been confirmed externally to this trial.
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
- •Participants age 18 or older with histologically or cytologically confirmed (by local laboratory and local clinical guidelines) metastatic colorectal adenocarcinoma that is not amenable to potentially curative surgery in the opinion of the investigator and progressed on or within 6 months after the last dose of one prior line of systemic anti-cancer therapy administered for metastatic disease.
- •Presence of at least one measurable lesion assessed by CT and/or MRI according to RECIST 1.
- •Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or
- •Adequate organ function (assessed by central laboratory for eligibility).
排除标准
- •Previously administered TGF-β targeted therapies or anti-cancer immunotherapy.
- •Microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) and/or BRAFV600 mutation positive colorectal cancer.
- •Known complete or partial dipyrimidine dehydrogenase (DPD) enzyme deficiency (testing for DPD enzyme deficiency is not mandatory unless required by local regulations and can be conducted at a local laboratory).
- •For participants treated with irinotecan: Known history or clinical evidence of reduced UGT1A1 activity (testing for UGT1A1 status is not mandatory unless required by local regulations and can be conducted at a local laboratory).
- •Participants who have not recovered from a major surgery performed prior to start of study treatment or have had a major surgery within 4 weeks prior to start of study treatment.
- •Impaired cardiac function or clinically significant cardio-vascular disease.
- •Participants with 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.
- •Stroke or transient ischemic attack, or other ischemic event, or thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 3 months before start of study treatment.
- •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 required.
- •Other inclusion/exclusion criteria may apply
研究组 & 干预措施
Safety run-in: NIS793+SOC (Investigational arm 1)
In the safety run-in part for investigational arm 1, participants will be treated with a combination of SOC anti-cancer therapy (bevacizumab with either modified FOLFOX6 or FOLFIRI) and NIS793 to confirm the RP2D of the NIS793
干预措施: NIS793 (Drug)
Safety run-in: NIS793+SOC (Investigational arm 1)
In the safety run-in part for investigational arm 1, participants will be treated with a combination of SOC anti-cancer therapy (bevacizumab with either modified FOLFOX6 or FOLFIRI) and NIS793 to confirm the RP2D of the NIS793
干预措施: Bevacizumab (Drug)
Safety run-in: NIS793+SOC (Investigational arm 1)
In the safety run-in part for investigational arm 1, participants will be treated with a combination of SOC anti-cancer therapy (bevacizumab with either modified FOLFOX6 or FOLFIRI) and NIS793 to confirm the RP2D of the NIS793
干预措施: Modified FOLFOX6 (Drug)
Safety run-in: NIS793+SOC (Investigational arm 1)
In the safety run-in part for investigational arm 1, participants will be treated with a combination of SOC anti-cancer therapy (bevacizumab with either modified FOLFOX6 or FOLFIRI) and NIS793 to confirm the RP2D of the NIS793
干预措施: FOLFIRI (Drug)
Expansion: NIS793+SOC (Investigational arm 1)
In the expansion part, participants in the investigational arm 1 will be treated with a combination of SOC anti-cancer therapy (bevacizumab with either modified FOLFOX6 or FOLFIRI) and NIS793 at the RP2D defined in the safety run-in
干预措施: NIS793 (Drug)
Expansion: NIS793+SOC (Investigational arm 1)
In the expansion part, participants in the investigational arm 1 will be treated with a combination of SOC anti-cancer therapy (bevacizumab with either modified FOLFOX6 or FOLFIRI) and NIS793 at the RP2D defined in the safety run-in
干预措施: Bevacizumab (Drug)
Expansion: NIS793+SOC (Investigational arm 1)
In the expansion part, participants in the investigational arm 1 will be treated with a combination of SOC anti-cancer therapy (bevacizumab with either modified FOLFOX6 or FOLFIRI) and NIS793 at the RP2D defined in the safety run-in
干预措施: Modified FOLFOX6 (Drug)
Expansion: NIS793+SOC (Investigational arm 1)
In the expansion part, participants in the investigational arm 1 will be treated with a combination of SOC anti-cancer therapy (bevacizumab with either modified FOLFOX6 or FOLFIRI) and NIS793 at the RP2D defined in the safety run-in
干预措施: FOLFIRI (Drug)
Expansion: SOC (control arm)
In the expansion part, participants in the control arm will be treated with a combination of SOC anti-cancer therapy (bevacizumab with either modified FOLFOX6 or FOLFIRI)
干预措施: Bevacizumab (Drug)
Expansion: SOC (control arm)
In the expansion part, participants in the control arm will be treated with a combination of SOC anti-cancer therapy (bevacizumab with either modified FOLFOX6 or FOLFIRI)
干预措施: Modified FOLFOX6 (Drug)
Expansion: SOC (control arm)
In the expansion part, participants in the control arm will be treated with a combination of SOC anti-cancer therapy (bevacizumab with either modified FOLFOX6 or FOLFIRI)
干预措施: FOLFIRI (Drug)
Safety run-in: NIS793+Tislelizumab+SOC (Investigational arm 2)
In the safety run-in part for investigational arm 2, participants will be treated with a combination of SOC anti-cancer therapy (bevacizumab with either modified FOLFOX6 or FOLFIRI), NIS793 and tislelizumab to confirm the RP2D of NIS793.
干预措施: NIS793 (Drug)
Safety run-in: NIS793+Tislelizumab+SOC (Investigational arm 2)
In the safety run-in part for investigational arm 2, participants will be treated with a combination of SOC anti-cancer therapy (bevacizumab with either modified FOLFOX6 or FOLFIRI), NIS793 and tislelizumab to confirm the RP2D of NIS793.
干预措施: Bevacizumab (Drug)
Safety run-in: NIS793+Tislelizumab+SOC (Investigational arm 2)
In the safety run-in part for investigational arm 2, participants will be treated with a combination of SOC anti-cancer therapy (bevacizumab with either modified FOLFOX6 or FOLFIRI), NIS793 and tislelizumab to confirm the RP2D of NIS793.
干预措施: Modified FOLFOX6 (Drug)
Safety run-in: NIS793+Tislelizumab+SOC (Investigational arm 2)
In the safety run-in part for investigational arm 2, participants will be treated with a combination of SOC anti-cancer therapy (bevacizumab with either modified FOLFOX6 or FOLFIRI), NIS793 and tislelizumab to confirm the RP2D of NIS793.
干预措施: FOLFIRI (Drug)
Safety run-in: NIS793+Tislelizumab+SOC (Investigational arm 2)
In the safety run-in part for investigational arm 2, participants will be treated with a combination of SOC anti-cancer therapy (bevacizumab with either modified FOLFOX6 or FOLFIRI), NIS793 and tislelizumab to confirm the RP2D of NIS793.
干预措施: Tislelizumab (Drug)
Expansion: NIS793+Tislelizumab+SOC (Investigational arm 2)
In the expansion part, participants in the investigational arm 2 will be treated with a combination of SOC anti-cancer therapy (bevacizumab with either modified FLOFOX6 or FOLFIRI) with NIS793 and tislelizumab at the RP2D for NIS793 defined in the safety run-in
干预措施: NIS793 (Drug)
Expansion: NIS793+Tislelizumab+SOC (Investigational arm 2)
In the expansion part, participants in the investigational arm 2 will be treated with a combination of SOC anti-cancer therapy (bevacizumab with either modified FLOFOX6 or FOLFIRI) with NIS793 and tislelizumab at the RP2D for NIS793 defined in the safety run-in
干预措施: Bevacizumab (Drug)
Expansion: NIS793+Tislelizumab+SOC (Investigational arm 2)
In the expansion part, participants in the investigational arm 2 will be treated with a combination of SOC anti-cancer therapy (bevacizumab with either modified FLOFOX6 or FOLFIRI) with NIS793 and tislelizumab at the RP2D for NIS793 defined in the safety run-in
干预措施: Modified FOLFOX6 (Drug)
Expansion: NIS793+Tislelizumab+SOC (Investigational arm 2)
In the expansion part, participants in the investigational arm 2 will be treated with a combination of SOC anti-cancer therapy (bevacizumab with either modified FLOFOX6 or FOLFIRI) with NIS793 and tislelizumab at the RP2D for NIS793 defined in the safety run-in
干预措施: FOLFIRI (Drug)
Expansion: NIS793+Tislelizumab+SOC (Investigational arm 2)
In the expansion part, participants in the investigational arm 2 will be treated with a combination of SOC anti-cancer therapy (bevacizumab with either modified FLOFOX6 or FOLFIRI) with NIS793 and tislelizumab at the RP2D for NIS793 defined in the safety run-in
干预措施: Tislelizumab (Drug)
结局指标
主要结局
Safety run-in: Percentage of participants with dose limiting toxicities (DLTs) during the first cycle (4 weeks) of treatment.
时间窗: Up to 4 weeks
Percentage of participants with DLTs during the first cycle of treatment. A DLT is defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness or concomitant medication that occurs within the first cycle of treatment with NIS793 with or without tislelizumab in combination with Bevacizumab and modified FOLFOX6/ FOLFIRI and meets protocol defined DLT criteria.
Expansion: Progression-free survival (PFS) by investigator assessment per RECIST 1.1
时间窗: From randomization up to disease progression or death, assessed up to approximately 12 months
PFS defined as the time from the date of enrollment (run-in part) or randomization (randomized part) to the date of the first documented progression based on investigator assessment and according to RECIST 1.1 or death due to any cause.
次要结局
- Safety run-in: Percentage of participants with dose interruptions and dose reductions of investigational drug(Upto approximately 12 months)
- Expansion: Overall response rate (ORR) by investigator assessment per RECIST 1.1(Up to approximately 12 months)
- Expansion: Disease control rate (DCR) by investigator assessment per RECIST 1.1(Up to approximately 12 months)
- Expansion: Duration of response (DOR) by investigator assessment per RECIST 1.1(From first documented response up to disease progression or death, assessed up to approximately 12 months)
- Safety run-in: Percentage of participants with Adverse Events (AEs)(Up to approximately 12 months)
- Safety run-in: Dose intensity of investigational drug(Up to approximately 12 months)
- Safety run-in: PFS by investigator assessment per RECIST 1.1(From enrollment up to disease progression or death, assessed up to approximately 12 months)
- Safety run-in part: Overall Survival (OS)(From enrollment up to death, assessed up to approximately 12 months)
- Safety run-in: Overall response rate (ORR) by investigator assessment per RECIST 1.1(Up to approximately 12 months)
- Safety run-in: Duration of response (DOR) by investigator assessment per RECIST 1.1(From first documented response up to disease progression or death, assessed up to approximately 12 months)
- Safety run-in: Time to response (TTR) by investigator assessment per RECIST 1.1(From enrollment up to first documented response, assessed up to approximately 12 months)
- Expansion: Percentage of participants with Adverse Events (AEs)(Up to approximately 12 months)
- Safety run-in: Disease control rate (DCR) by investigator assessment per RECIST 1.1(Up to approximately 12 months)
- Expansion part: Percentage of participants with dose interruptions and dose reductions of investigational drug(Up to approximately 12 months)
- Expansion: Time to response (TTR) by investigator assessment per RECIST 1.1(From enrollment up to first documented response, assessed up to approximately 12 months)
- Expansion: Dose intensity of investigational drug(Up to approximately 12 months)
- Expansion part: Overall Survival (OS)(From randomization up to death, assessed up to approximately 12 months)
- Maximum concentration (Cmax) of NIS793(From the date of first study drug intake up to approximately 12 months)
- Maximum concentration (Cmax) of tislelizumab(From the date of first study drug intake up to approximately 12 months)
- Trough Concentration (Ctrough) of NIS793(From the date of first study drug intake up to approximately 12 months)
- Trough Concentration (Ctrough) tislelizumab(From the date of first study drug intake up to approximately 12 months)
- Antidrug antibodies (ADA) at baseline(Baseline)
- ADA incidence on treatment(From the date of first study drug intake up to approximately 12 months)