Study of NIS793 and Other Novel Investigational Combinations With SOC Anti-cancer Therapy for the 2L Treatment of mCRC

Phase 2

Terminated

• Conditions: Metastatic Colorectal Cancer
• Interventions: Drug: NIS793; Drug: Bevacizumab; Drug: Modified FOLFOX6; Drug: FOLFIRI; Drug: Tislelizumab

• Registration Number: NCT04952753
• Lead Sponsor: Novartis Pharmaceuticals

Brief Summary

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.

Detailed Description

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.

The decision to open the Expansion part of the study will be based on dose confirmation of investigational drug with available safety, relevant PK and other relevant data from Safety run-in part. Participants in the expansion part will be randomized in 1:2 ratio to the control arm or investigational arm.

Study Timeline

• Study First Submitted: 2021-06-28
• Study First Submitted QC: 2021-06-28
• Study First Posted: 2021-07-07
• Study Start: 2021-11-15
• Primary Completion: 2025-01-20
• Study Completion: 2025-01-20
• Status Verified: 2025-03
• Last Update Submitted: 2025-03-24
• Last Update Posted: 2025-03-26

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 204

Inclusion Criteria

• 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 1.1.
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1.
• Adequate organ function (assessed by central laboratory for eligibility).

Key

Exclusion Criteria

• 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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Safety run-in: NIS793+SOC (Investigational arm 1)	NIS793	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
Safety run-in: NIS793+SOC (Investigational arm 1)	Bevacizumab	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
Safety run-in: NIS793+SOC (Investigational arm 1)	Modified FOLFOX6	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
Safety run-in: NIS793+SOC (Investigational arm 1)	FOLFIRI	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
Expansion: NIS793+SOC (Investigational arm 1)	Bevacizumab	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
Expansion: NIS793+SOC (Investigational arm 1)	Modified FOLFOX6	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
Expansion: NIS793+SOC (Investigational arm 1)	FOLFIRI	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
Expansion: SOC (control arm)	Bevacizumab	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)
Expansion: SOC (control arm)	Modified FOLFOX6	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)
Expansion: SOC (control arm)	FOLFIRI	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)
Safety run-in: NIS793+Tislelizumab+SOC (Investigational arm 2)	Bevacizumab	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.
Safety run-in: NIS793+Tislelizumab+SOC (Investigational arm 2)	Modified FOLFOX6	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.
Safety run-in: NIS793+Tislelizumab+SOC (Investigational arm 2)	FOLFIRI	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.
Safety run-in: NIS793+Tislelizumab+SOC (Investigational arm 2)	Tislelizumab	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.
Expansion: NIS793+Tislelizumab+SOC (Investigational arm 2)	NIS793	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
Expansion: NIS793+Tislelizumab+SOC (Investigational arm 2)	Bevacizumab	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
Expansion: NIS793+Tislelizumab+SOC (Investigational arm 2)	Modified FOLFOX6	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
Expansion: NIS793+Tislelizumab+SOC (Investigational arm 2)	FOLFIRI	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
Expansion: NIS793+Tislelizumab+SOC (Investigational arm 2)	Tislelizumab	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
Expansion: NIS793+SOC (Investigational arm 1)	NIS793	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
Safety run-in: NIS793+Tislelizumab+SOC (Investigational arm 2)	NIS793	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.

Primary Outcome Measures

Name	Time	Method
Safety run-in: Percentage of participants with dose limiting toxicities (DLTs) during the first cycle (4 weeks) of treatment.	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	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.

Secondary Outcome Measures

Name	Time	Method
Safety run-in: Percentage of participants with dose interruptions and dose reductions of investigational drug	Upto approximately 12 months	Tolerability measured by the percentage of subjects who have dose adjustments (interruptions or reductions) of investigational drug (e.g. NIS793, NIS793+tislelizumab)
Expansion: Overall response rate (ORR) by investigator assessment per RECIST 1.1	Up to approximately 12 months	ORR is defined as the proportion of participants with best overall response (BOR) of complete response (CR) or partial response (PR), as per investigator assessment and according to RECIST 1.1
Expansion: Disease control rate (DCR) by investigator assessment per RECIST 1.1	Up to approximately 12 months	DCR is the proportion of participants with BOR of CR or PR or stable disease (SD) as per investigator assessment and according to RECIST 1.1
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	DOR is defined as the duration of time between the date of the first documented response (CR or PR) and the date of first documented progression or death due to any cause
Safety run-in: Percentage of participants with Adverse Events (AEs)	Up to approximately 12 months	Percentage of participants with AEs and SAEs including changes in laboratory parameters, vital signs, body weight and cardiac assessments
Safety run-in: Dose intensity of investigational drug	Up to approximately 12 months	Tolerability measured by the dose intensity of investigational drug (e.g. NIS793, NIS793+tislelizumab). Dose intensity will be computed as the ratio of actual cumulative dose received and actual duration of exposure
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	PFS defined as the time from the date of enrollment to the date of the first documented progression based on investigator assessment and according to RECIST 1.1 or death due to any cause.
Safety run-in part: Overall Survival (OS)	From enrollment up to death, assessed up to approximately 12 months	OS is defined as the time from the date of enrollment to date of death due to any cause.
Safety run-in: Overall response rate (ORR) by investigator assessment per RECIST 1.1	Up to approximately 12 months	ORR is defined as the proportion of participants with best overall response (BOR) of complete response (CR) or partial response (PR), as per investigator assessment and according to RECIST 1.1
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	DOR is defined as the duration of time between the date of the first documented response (CR or PR) and the date of first documented progression or death due to any cause
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	TTR is defined as the duration of time between the date of enrollment and the date of first documented response of either CR or PR.
Expansion: Percentage of participants with Adverse Events (AEs)	Up to approximately 12 months	Percentage of participants with AEs and SAEs including changes in laboratory parameters, vital signs, body weight and cardiac assessments
Safety run-in: Disease control rate (DCR) by investigator assessment per RECIST 1.1	Up to approximately 12 months	DCR is the proportion of participants with BOR of CR or PR or stable disease (SD) as per investigator assessment and according to RECIST 1.1
Expansion part: Overall Survival (OS)	From randomization up to death, assessed up to approximately 12 months	OS is defined as the time from the date of enrollment to date of death due to any cause.
Expansion part: Percentage of participants with dose interruptions and dose reductions of investigational drug	Up to approximately 12 months	Tolerability measured by the percentage of subjects who have dose adjustments (interruptions) of investigational drug (e.g. NIS793, NIS793+tislelizumab)
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	TTR is defined as the duration of time between the date of enrollment and the date of first documented response of either CR or PR.
Expansion: Dose intensity of investigational drug	Up to approximately 12 months	Tolerability measured by the dose intensity of investigational drug (e.g. NIS793, NIS793+Tislelizumab). Dose intensity will be computed as the ratio of actual cumulative dose received and actual duration of exposure
Maximum concentration (Cmax) of NIS793	From the date of first study drug intake up to approximately 12 months	Blood samples will be collected at indicated time-points for analysis of Cmax of NIS793
Maximum concentration (Cmax) of tislelizumab	From the date of first study drug intake up to approximately 12 months	Blood samples will be collected at indicated time-points for analysis of Cmax of tislelizumab
Trough Concentration (Ctrough) of NIS793	From the date of first study drug intake up to approximately 12 months	Blood samples will be collected at indicated time-points for analysis of Ctrough of NIS793
Trough Concentration (Ctrough) tislelizumab	From the date of first study drug intake up to approximately 12 months	Blood samples will be collected at indicated time-points for analysis of Ctrough of tislelizumab
Antidrug antibodies (ADA) at baseline	Baseline	Prevalence of ADA (anti-NIS793, anti-tislelizumab) at baseline is defined as the proportion of participants who have an ADA positive result at baseline
ADA incidence on treatment	From the date of first study drug intake up to approximately 12 months	Incidence of ADA (anti-NIS793, anti-tislelizumab) on treatment is defined as the proportion of participants who are treatment-induced ADA positive (post-baseline ADA positive with ADA-negative sample at baseline) and treatment-boosted ADA positive (post-baseline ADA positive with titer that is at least the fold titer change greater than the ADA-positive baseline titer)

Trial Locations

Locations (8)

The Angeles Clinic and Research Institute; 🇺🇸 Los Angeles, California, United States

University of Michigan Medical; 🇺🇸 Ann Arbor, Michigan, United States

WA Uni School Of Med; 🇺🇸 Saint Louis, Missouri, United States

Astera Cancer Center; 🇺🇸 East Brunswick, New Jersey, United States

Sarah Cannon Research Institute; 🇺🇸 Nashville, Tennessee, United States

Uni Of TX MD Anderson Cancer Cntr; 🇺🇸 Houston, Texas, United States

Mays Cancer Center; 🇺🇸 San Antonio, Texas, United States

Novartis Investigative Site; 🇬🇧 Oxford, United Kingdom