Study of NIS793 and Other Novel Investigational Combinations With SOC Anti-cancer Therapy for the 2L Treatment of mCRC (daNIS-3)

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)

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Metastatic Colorectal Cancer
• Intervention / Treatment: Drug: NIS793; Drug: Bevacizumab; Drug: Modified FOLFOX6; Drug: FOLFIRI; Drug: Tislelizumab

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 Type: Interventional
• Enrollment (Actual): 205
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Novartis Pharmaceuticals; Phone Number: 1-888-669-6682; Email: novartis.email@novartis.com
• Study Contact Backup: Name: Novartis Pharmaceuticals; Phone Number: +41613241111

Study Locations

• Australia
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Novartis Investigative Site
  • Victoria
    • Bendigo, Victoria, Australia, 3550
      • Novartis Investigative Site
  • Western Australia
    • Perth, Western Australia, Australia, 6009
      • Novartis Investigative Site
• Belgium
  • Bruxelles, Belgium, 1200
    • Novartis Investigative Site
  • Bruxelles, Belgium, 1000
    • Novartis Investigative Site
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
• Canada
  • Ontario
    • Brampton, Ontario, Canada, L6R 3J7
      • Novartis Investigative Site
    • Cambridge, Ontario, Canada, N1R 3G2
      • Novartis Investigative Site
  • Quebec
    • Montreal, Quebec, Canada, H2W 1T8
      • Novartis Investigative Site
    • Montreal, Quebec, Canada, H3T 1E2
      • Novartis Investigative Site
• Czechia
  • Praha 4, Czechia, 140 59
    • Novartis Investigative Site
  • CZE
    • Hradec Kralove, CZE, Czechia, 500 05
      • Novartis Investigative Site
  • Czech Republic
    • Brno, Czech Republic, Czechia, 656 53
      • Novartis Investigative Site
• France
  • Avignon, France, 84082
    • Novartis Investigative Site
  • Creteil, France, 94010
    • Novartis Investigative Site
  • Nantes Cedex 1, France, 44093
    • Novartis Investigative Site
• Germany
  • Berlin, Germany, 13353
    • Novartis Investigative Site
  • Bochum, Germany, 44791
    • Novartis Investigative Site
  • Dresden, Germany, 01307
    • Novartis Investigative Site
  • Essen, Germany, 45147
    • Novartis Investigative Site
  • Frankfurt, Germany, 60488
    • Novartis Investigative Site
  • Hamburg, Germany, 20249
    • Novartis Investigative Site
  • Ulm, Germany, 89081
    • Novartis Investigative Site
• Hong Kong
  • Pokfulam, Hong Kong
    • Novartis Investigative Site
  • Shatin New Territories, Hong Kong
    • Novartis Investigative Site
• Israel
  • Haifa, Israel, 3109601
    • Novartis Investigative Site
  • Petach Tikva, Israel, 4941492
    • Novartis Investigative Site
• Italy
  • MI
    • Milano, MI, Italy, 20162
      • Novartis Investigative Site
    • Milano, MI, Italy, 20133
      • Novartis Investigative Site
    • Rozzano, MI, Italy, 20089
      • Novartis Investigative Site
• Japan
  • Aichi
    • Nagoya, Aichi, Japan, 464 8681
      • Novartis Investigative Site
  • Chiba
    • Kashiwa, Chiba, Japan, 277 8577
      • Novartis Investigative Site
  • Kanagawa
    • Kawasaki-city, Kanagawa, Japan, 216-8511
      • Novartis Investigative Site
  • Osaka
    • Osaka-city, Osaka, Japan, 541-8567
      • Novartis Investigative Site
  • Toyama
    • Toyama-city, Toyama, Japan, 930-0194
      • Novartis Investigative Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 05505
    • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 119074
    • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28040
    • Novartis Investigative Site
  • Barcelona
    • Sabadell, Barcelona, Spain, 08208
      • Novartis Investigative Site
  • Cantabria
    • Santander, Cantabria, Spain, 39008
      • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
    • Barcelona, Catalunya, Spain, 08036
      • Novartis Investigative Site
• Switzerland
  • St. Gallen, Switzerland, 9007
    • Novartis Investigative Site
• Taiwan
  • Tainan, Taiwan, 70403
    • Novartis Investigative Site
  • Taipei, Taiwan, 10002
    • Novartis Investigative Site
• United Kingdom
  • Cambridge, United Kingdom, 01223 7620
    • Novartis Investigative Site
  • Oxford, United Kingdom, OX3 7LJ
    • Novartis Investigative Site
  • Scotland
    • Aberdeen, Scotland, United Kingdom, AB25 2ZN
      • Novartis Investigative Site
• United States
  • California
    • Los Angeles, California, United States, 90025
      • The Angeles Clinic and Research Institute .
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0331
      • University of Michigan Medical .
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington Uni School of Med .
  • New Jersey
    • East Brunswick, New Jersey, United States, 08816
      • Astera Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute DeptofSarahCannonRes.Inst. (2)
  • Texas
    • Houston, Texas, United States, 77030
      • Uni of TX MD Anderson Cancer Cntr
    • San Antonio, Texas, United States, 78229
      • Mays Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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	Drug: NIS793; Investigational drug NIS793 will be administered intravenously (IV) at the dose and schedule determined in the safety run-in part.; Drug: Bevacizumab; Bevacizumab will be administered IV; Drug: Modified FOLFOX6; 5-fluorouracil [continuous infusion], leucovorin [administered IV] (or levoleucovorin [administered IV]), and oxaliplatin [administered IV]; Other Names: 5FU+Leucovorin+Oxaliplatin; Drug: FOLFIRI; 5-fluorouracil [continuous infusion], leucovorin [administered IV] (or levoleucovorin [administered IV]), and irinotecan [administered IV]; Other Names: 5FU+Leucovorin+Irinotecan
Experimental: 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	Drug: NIS793; Investigational drug NIS793 will be administered intravenously (IV) at the dose and schedule determined in the safety run-in part.; Drug: Bevacizumab; Bevacizumab will be administered IV; Drug: Modified FOLFOX6; 5-fluorouracil [continuous infusion], leucovorin [administered IV] (or levoleucovorin [administered IV]), and oxaliplatin [administered IV]; Other Names: 5FU+Leucovorin+Oxaliplatin; Drug: FOLFIRI; 5-fluorouracil [continuous infusion], leucovorin [administered IV] (or levoleucovorin [administered IV]), and irinotecan [administered IV]; Other Names: 5FU+Leucovorin+Irinotecan
Active Comparator: 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)	Drug: Bevacizumab; Bevacizumab will be administered IV; Drug: Modified FOLFOX6; 5-fluorouracil [continuous infusion], leucovorin [administered IV] (or levoleucovorin [administered IV]), and oxaliplatin [administered IV]; Other Names: 5FU+Leucovorin+Oxaliplatin; Drug: FOLFIRI; 5-fluorouracil [continuous infusion], leucovorin [administered IV] (or levoleucovorin [administered IV]), and irinotecan [administered IV]; Other Names: 5FU+Leucovorin+Irinotecan
Experimental: 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.	Drug: NIS793; Investigational drug NIS793 will be administered intravenously (IV) at the dose and schedule determined in the safety run-in part.; Drug: Bevacizumab; Bevacizumab will be administered IV; Drug: Modified FOLFOX6; 5-fluorouracil [continuous infusion], leucovorin [administered IV] (or levoleucovorin [administered IV]), and oxaliplatin [administered IV]; Other Names: 5FU+Leucovorin+Oxaliplatin; Drug: FOLFIRI; 5-fluorouracil [continuous infusion], leucovorin [administered IV] (or levoleucovorin [administered IV]), and irinotecan [administered IV]; Other Names: 5FU+Leucovorin+Irinotecan; Drug: Tislelizumab; Investigational drug tislelizumab will be administered intravenously (IV).; Other Names: VDT482
Experimental: 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	Drug: NIS793; Investigational drug NIS793 will be administered intravenously (IV) at the dose and schedule determined in the safety run-in part.; Drug: Bevacizumab; Bevacizumab will be administered IV; Drug: Modified FOLFOX6; 5-fluorouracil [continuous infusion], leucovorin [administered IV] (or levoleucovorin [administered IV]), and oxaliplatin [administered IV]; Other Names: 5FU+Leucovorin+Oxaliplatin; Drug: FOLFIRI; 5-fluorouracil [continuous infusion], leucovorin [administered IV] (or levoleucovorin [administered IV]), and irinotecan [administered IV]; Other Names: 5FU+Leucovorin+Irinotecan; Drug: Tislelizumab; Investigational drug tislelizumab will be administered intravenously (IV).; Other Names: VDT482

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety run-in: Percentage of participants with dose limiting toxicities (DLTs) during the first cycle (4 weeks) of treatment.	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.	Up to 4 weeks
Expansion: Progression-free survival (PFS) by investigator assessment per RECIST 1.1	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.	From randomization up to disease progression or death, assessed up to approximately 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety run-in: Percentage of participants with Adverse Events (AEs)	Percentage of participants with AEs and SAEs including changes in laboratory parameters, vital signs, body weight and cardiac assessments	Up to approximately 12 months
Safety run-in: Percentage of participants with dose interruptions and dose reductions of investigational drug	Tolerability measured by the percentage of subjects who have dose adjustments (interruptions or reductions) of investigational drug (e.g. NIS793, NIS793+tislelizumab)	Upto approximately 12 months
Safety run-in: Dose intensity of investigational drug	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	Up to approximately 12 months
Safety run-in: PFS by investigator assessment per RECIST 1.1	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.	From enrollment up to disease progression or death, assessed up to approximately 12 months
Safety run-in: Overall response rate (ORR) by investigator assessment per RECIST 1.1	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	Up to approximately 12 months
Safety run-in: Disease control rate (DCR) by investigator assessment per RECIST 1.1	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	Up to approximately 12 months
Safety run-in: Duration of response (DOR) by investigator assessment per RECIST 1.1	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	From first documented response up to disease progression or death, assessed up to approximately 12 months
Safety run-in part: Overall Survival (OS)	OS is defined as the time from the date of enrollment to date of death due to any cause.	From enrollment up to death, assessed up to approximately 12 months
Safety run-in: Time to response (TTR) by investigator assessment per RECIST 1.1	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.	From enrollment up to first documented response, assessed up to approximately 12 months
Expansion: Percentage of participants with Adverse Events (AEs)	Percentage of participants with AEs and SAEs including changes in laboratory parameters, vital signs, body weight and cardiac assessments	Up to approximately 12 months
Expansion part: Percentage of participants with dose interruptions and dose reductions of investigational drug	Tolerability measured by the percentage of subjects who have dose adjustments (interruptions) of investigational drug (e.g. NIS793, NIS793+tislelizumab)	Up to approximately 12 months
Expansion: Dose intensity of investigational drug	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	Up to approximately 12 months
Expansion: Overall response rate (ORR) by investigator assessment per RECIST 1.1	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	Up to approximately 12 months
Expansion: Disease control rate (DCR) by investigator assessment per RECIST 1.1	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	Up to approximately 12 months
Expansion part: Overall Survival (OS)	OS is defined as the time from the date of enrollment to date of death due to any cause.	From randomization up to death, assessed up to approximately 12 months
Expansion: Time to response (TTR) by investigator assessment per RECIST 1.1	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.	From enrollment up to first documented response, assessed up to approximately 12 months
Maximum concentration (Cmax) of NIS793	Blood samples will be collected at indicated time-points for analysis of Cmax of NIS793	From the date of first study drug intake up to approximately 12 months
Maximum concentration (Cmax) of tislelizumab	Blood samples will be collected at indicated time-points for analysis of Cmax of tislelizumab	From the date of first study drug intake up to approximately 12 months
Maximum concentration (Cmax) of bevacizumab	Blood samples will be collected at indicated time-points for analysis of Cmax of bevacizumab	From the date of first study drug intake up to approximately 12 months
Maximum concentration (Cmax) of irinotecan and its metabolite (SN38)	Blood samples will be collected at indicated time-points for analysis of Cmax of irinotecan and SN-38	From the date of first study drug intake up to approximately 12 months
Trough Concentration (Ctrough) of NIS793	Blood samples will be collected at indicated time-points for analysis of Ctrough of NIS793	From the date of first study drug intake up to approximately 12 months
Trough Concentration (Ctrough) tislelizumab	Blood samples will be collected at indicated time-points for analysis of Ctrough of tislelizumab	From the date of first study drug intake up to approximately 12 months
Trough Concentration (Ctrough) of bevacizumab	Blood samples will be collected at indicated time-points for analysis of Ctrough of bevacizumab	From the date of first study intake up to approximately 12 months.
Trough Concentration (Ctrough) of irinotecan and its metabolite (SN38)	Blood samples will be collected at indicated time-points for analysis of Ctrough of irinotecan and SN-38	From the date of first study drug intake up to approximately 12 months.
Antidrug antibodies (ADA) at baseline	Prevalence of ADA (anti-NIS793, anti-bevacizumab, anti-tislelizumab) at baseline is defined as the proportion of participants who have an ADA positive result at baseline	Baseline
ADA incidence on treatment	Incidence of ADA (anti-NIS793, anti-bevacizumab, 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)	From the date of first study drug intake up to approximately 12 months

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): November 15, 2021
• Primary Completion (Estimated): September 2, 2024
• Study Completion (Estimated): September 11, 2024

Study Registration Dates

• First Submitted: June 28, 2021
• First Submitted That Met QC Criteria: June 28, 2021
• First Posted (Actual): July 7, 2021

Study Record Updates

• Last Update Posted (Actual): March 7, 2024
• Last Update Submitted That Met QC Criteria: March 6, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: colorectal cancer; metastatic colorectal cancer; NIS793; transforming growth factor βeta (TGF-β); anti PD-1 monoclonal antibody
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protective Agents; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Micronutrients; Vitamins; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Oxaliplatin; Bevacizumab; Leucovorin; Irinotecan; Levoleucovorin; Tislelizumab
• Other Study ID Numbers: CNIS793E12201; 2021-000553-40 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No