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

Metastatic Colorectal Cancer Clinical Trial

— daNIS-3  

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)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04952753
• Other study ID #: CNIS793E12201
• Secondary ID: 2021-000553-40
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: November 15, 2021
• Est. completion date: September 12, 2024

Study information

• Verified date: June 2024
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 204
• Est. completion date: September 12, 2024
• Est. primary completion date: September 12, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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-ß 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

Related Conditions & MeSH terms

• Colorectal Neoplasms
• Metastatic Colorectal Cancer

Intervention

Drug:
• NIS793
Investigational drug NIS793 will be administered intravenously (IV) at the dose and schedule determined in the safety run-in part.
• Bevacizumab
Bevacizumab will be administered IV
• Modified FOLFOX6
5-fluorouracil [continuous infusion], leucovorin [administered IV] (or levoleucovorin [administered IV]), and oxaliplatin [administered IV]
• FOLFIRI
5-fluorouracil [continuous infusion], leucovorin [administered IV] (or levoleucovorin [administered IV]), and irinotecan [administered IV]
• Tislelizumab
Investigational drug tislelizumab will be administered intravenously (IV).

Locations

Country	Name	City	State
Australia	Novartis Investigative Site	Adelaide	South Australia
Australia	Novartis Investigative Site	Bendigo	Victoria
Australia	Novartis Investigative Site	Perth	Western Australia
Belgium	Novartis Investigative Site	Bruxelles
Belgium	Novartis Investigative Site	Bruxelles
Belgium	Novartis Investigative Site	Leuven
Canada	Novartis Investigative Site	Brampton	Ontario
Canada	Novartis Investigative Site	Cambridge	Ontario
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Montreal	Quebec
Czechia	Novartis Investigative Site	Brno	Czech Republic
Czechia	Novartis Investigative Site	Hradec Kralove	CZE
Czechia	Novartis Investigative Site	Praha 4
France	Novartis Investigative Site	Avignon
France	Novartis Investigative Site	Creteil
France	Novartis Investigative Site	Nantes Cedex 1
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Bochum
Germany	Novartis Investigative Site	Dresden
Germany	Novartis Investigative Site	Essen
Germany	Novartis Investigative Site	Frankfurt
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Ulm
Hong Kong	Novartis Investigative Site	Pokfulam
Hong Kong	Novartis Investigative Site	Shatin New Territories
Israel	Novartis Investigative Site	Haifa
Israel	Novartis Investigative Site	Petach Tikva
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Rozzano	MI
Japan	Novartis Investigative Site	Kashiwa	Chiba
Japan	Novartis Investigative Site	Kawasaki-city	Kanagawa
Japan	Novartis Investigative Site	Nagoya	Aichi
Japan	Novartis Investigative Site	Osaka-city	Osaka
Japan	Novartis Investigative Site	Toyama-city	Toyama
Korea, Republic of	Novartis Investigative Site	Seoul
Singapore	Novartis Investigative Site	Singapore
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Sabadell	Barcelona
Spain	Novartis Investigative Site	Santander	Cantabria
Switzerland	Novartis Investigative Site	St. Gallen
Taiwan	Novartis Investigative Site	Tainan
Taiwan	Novartis Investigative Site	Taipei
United Kingdom	Novartis Investigative Site	Aberdeen	Scotland
United Kingdom	Novartis Investigative Site	Cambridge
United Kingdom	Novartis Investigative Site	Oxford
United States	University of Michigan Medical .	Ann Arbor	Michigan
United States	Astera Cancer Center	East Brunswick	New Jersey
United States	Uni of TX MD Anderson Cancer Cntr	Houston	Texas
United States	The Angeles Clinic and Research Institute .	Los Angeles	California
United States	Sarah Cannon Research Institute DeptofSarahCannonRes Inst 2	Nashville	Tennessee
United States	WA Uni School Of Med .	Saint Louis	Missouri
United States	Mays Cancer Center	San Antonio	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  Czechia,  France,  Germany,  Hong Kong,  Israel,  Italy,  Japan,  Korea, Republic of,  Singapore,  Spain,  Switzerland,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Expansion: 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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Antidrug antibodies (ADA) at 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	Baseline
Secondary	ADA incidence on treatment	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)	From the date of first study drug intake up to approximately 12 months