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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04952753
Recruitment Status : Recruiting
First Posted : July 7, 2021
Last Update Posted : December 30, 2022
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Description
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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.


Condition or disease Intervention/treatment Phase
Metastatic Colorectal Cancer Drug: NIS793 Drug: Bevacizumab Drug: Modified FOLFOX6 Drug: FOLFIRI Drug: Tislelizumab Phase 2

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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 266 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : November 15, 2021
Estimated Primary Completion Date : September 2, 2024
Estimated Study Completion Date : September 11, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Medicines

Arms and Interventions
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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 Name: 5FU+Leucovorin+Oxaliplatin

Drug: FOLFIRI
5-fluorouracil [continuous infusion], leucovorin [administered IV] (or levoleucovorin [administered IV]), and irinotecan [administered IV]
Other Name: 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 Name: 5FU+Leucovorin+Oxaliplatin

Drug: FOLFIRI
5-fluorouracil [continuous infusion], leucovorin [administered IV] (or levoleucovorin [administered IV]), and irinotecan [administered IV]
Other Name: 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 Name: 5FU+Leucovorin+Oxaliplatin

Drug: FOLFIRI
5-fluorouracil [continuous infusion], leucovorin [administered IV] (or levoleucovorin [administered IV]), and irinotecan [administered IV]
Other Name: 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 Name: 5FU+Leucovorin+Oxaliplatin

Drug: FOLFIRI
5-fluorouracil [continuous infusion], leucovorin [administered IV] (or levoleucovorin [administered IV]), and irinotecan [administered IV]
Other Name: 5FU+Leucovorin+Irinotecan

Drug: Tislelizumab
Investigational drug tislelizumab will be administered intravenously (IV).
Other Name: 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 Name: 5FU+Leucovorin+Oxaliplatin

Drug: FOLFIRI
5-fluorouracil [continuous infusion], leucovorin [administered IV] (or levoleucovorin [administered IV]), and irinotecan [administered IV]
Other Name: 5FU+Leucovorin+Irinotecan

Drug: Tislelizumab
Investigational drug tislelizumab will be administered intravenously (IV).
Other Name: VDT482


Outcome Measures
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Primary Outcome Measures :
  1. Safety run-in: Percentage of participants with dose limiting toxicities (DLTs) during the first cycle (4 weeks) of treatment. [ Time Frame: 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.

  2. Expansion: Progression-free survival (PFS) by investigator assessment per RECIST 1.1 [ Time Frame: 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 :
  1. Safety run-in: Percentage of participants with Adverse Events (AEs) [ Time Frame: Up to approximately 12 months ]
    Percentage of participants with AEs and SAEs including changes in laboratory parameters, vital signs, body weight and cardiac assessments

  2. Safety run-in: Percentage of participants with dose interruptions and dose reductions of investigational drug [ Time Frame: 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)

  3. Safety run-in: Dose intensity of investigational drug [ Time Frame: 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

  4. Safety run-in: PFS by investigator assessment per RECIST 1.1 [ Time Frame: 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.

  5. Safety run-in: Overall response rate (ORR) by investigator assessment per RECIST 1.1 [ Time Frame: 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

  6. Safety run-in: Disease control rate (DCR) by investigator assessment per RECIST 1.1 [ Time Frame: 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

  7. Safety run-in: Duration of response (DOR) by investigator assessment per RECIST 1.1 [ Time Frame: 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

  8. Safety run-in part: Overall Survival (OS) [ Time Frame: 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.

  9. Safety run-in: Time to response (TTR) by investigator assessment per RECIST 1.1 [ Time Frame: 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.

  10. Expansion: Percentage of participants with Adverse Events (AEs) [ Time Frame: Up to approximately 12 months ]
    Percentage of participants with AEs and SAEs including changes in laboratory parameters, vital signs, body weight and cardiac assessments

  11. Expansion part: Percentage of participants with dose interruptions and dose reductions of investigational drug [ Time Frame: 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)

  12. Expansion: Dose intensity of investigational drug [ Time Frame: 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

  13. Expansion: Overall response rate (ORR) by investigator assessment per RECIST 1.1 [ Time Frame: 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

  14. Expansion: Disease control rate (DCR) by investigator assessment per RECIST 1.1 [ Time Frame: 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

  15. Expansion part: Overall Survival (OS) [ Time Frame: 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.

  16. Expansion: Time to response (TTR) by investigator assessment per RECIST 1.1 [ Time Frame: 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.

  17. Maximum concentration (Cmax) of NIS793 [ Time Frame: 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

  18. Maximum concentration (Cmax) of tislelizumab [ Time Frame: 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

  19. Maximum concentration (Cmax) of bevacizumab [ Time Frame: 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 bevacizumab

  20. Maximum concentration (Cmax) of irinotecan and its metabolite (SN38) [ Time Frame: 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 irinotecan and SN-38

  21. Trough Concentration (Ctrough) of NIS793 [ Time Frame: 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

  22. Trough Concentration (Ctrough) tislelizumab [ Time Frame: 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

  23. Trough Concentration (Ctrough) of bevacizumab [ Time Frame: From the date of first study intake up to approximately 12 months. ]
    Blood samples will be collected at indicated time-points for analysis of Ctrough of bevacizumab

  24. Trough Concentration (Ctrough) of irinotecan and its metabolite (SN38) [ Time Frame: 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 irinotecan and SN-38

  25. Antidrug antibodies (ADA) at baseline [ Time Frame: 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

  26. ADA incidence on treatment [ Time Frame: From the date of first study drug intake up to approximately 12 months ]
    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)


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04952753


Contacts
Layout table for location contacts
Contact: Novartis Pharmaceuticals 1-888-669-6682 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111

Locations
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Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
More Information
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT04952753    
Other Study ID Numbers: CNIS793E12201
2021-000553-40 ( EudraCT Number )
First Posted: July 7, 2021    Key Record Dates
Last Update Posted: December 30, 2022
Last Verified: December 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
NIS793
metastatic colorectal cancer
colorectal cancer
transforming growth factor βeta (TGF-β)
anti PD-1 monoclonal antibody
Additional relevant MeSH terms:
Layout table for MeSH terms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Leucovorin
Bevacizumab
Oxaliplatin
Irinotecan
 Levoleucovorin
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antidotes
Protective Agents
Vitamin B Complex