Clinical trial NCT04952753: Study of NIS793 and Other Novel Investigational Combinations With SOC Anti-cancer Therapy for the 2L Treatment of mCRC
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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Metastatic Colorectal Cancer
Keywords: NIS793
metastatic colorectal cancer
colorectal cancer
transforming growth factor βeta (TGF-β)
anti PD-1 monoclonal antibody
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2021-07-07
Enrollment: 204
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Safety run-in: Percentage of participants with dose limiting toxicities (DLTs) during the first cycle (4 weeks) of treatment.
timeFrame: Up to 4 weeks
measure: Expansion: Progression-free survival (PFS) by investigator assessment per RECIST 1.1
timeFrame: From randomization up to disease progression or death, assessed up to approximately 12 months
Secondary outcomes:
measure: Safety run-in: Percentage of participants with Adverse Events (AEs)
timeFrame: Up to approximately 12 months
measure: Safety run-in: Percentage of participants with dose interruptions and dose reductions of investigational drug
timeFrame: Upto approximately 12 months
measure: Safety run-in: Dose intensity of investigational drug
timeFrame: Up to approximately 12 months
measure: Safety run-in: PFS by investigator assessment per RECIST 1.1
timeFrame: From enrollment up to disease progression or death, assessed up to approximately 12 months
measure: Safety run-in: Overall response rate (ORR) by investigator assessment per RECIST 1.1
timeFrame: Up to approximately 12 months
measure: Safety run-in: Disease control rate (DCR) by investigator assessment per RECIST 1.1
timeFrame: Up to approximately 12 months
measure: Safety run-in: Duration of response (DOR) by investigator assessment per RECIST 1.1
timeFrame: From first documented response up to disease progression or death, assessed up to approximately 12 months
measure: Safety run-in part: Overall Survival (OS)
timeFrame: From enrollment up to death, assessed up to approximately 12 months
measure: Safety run-in: Time to response (TTR) by investigator assessment per RECIST 1.1
timeFrame: From enrollment up to first documented response, assessed up to approximately 12 months
measure: Expansion: Percentage of participants with Adverse Events (AEs)
timeFrame: Up to approximately 12 months
measure: Expansion part: Percentage of participants with dose interruptions and dose reductions of investigational drug
timeFrame: Up to approximately 12 months
measure: Expansion: Dose intensity of investigational drug
timeFrame: Up to approximately 12 months
measure: Expansion: Overall response rate (ORR) by investigator assessment per RECIST 1.1
timeFrame: Up to approximately 12 months
measure: Expansion: Disease control rate (DCR) by investigator assessment per RECIST 1.1
timeFrame: Up to approximately 12 months
measure: Expansion: Duration of response (DOR) by investigator assessment per RECIST 1.1
timeFrame: From first documented response up to disease progression or death, assessed up to approximately 12 months
measure: Expansion part: Overall Survival (OS)
timeFrame: From randomization up to death, assessed up to approximately 12 months
measure: Expansion: Time to response (TTR) by investigator assessment per RECIST 1.1
timeFrame: From enrollment up to first documented response, assessed up to approximately 12 months
measure: Maximum concentration (Cmax) of NIS793
timeFrame: From the date of first study drug intake up to approximately 12 months
measure: Maximum concentration (Cmax) of tislelizumab
timeFrame: From the date of first study drug intake up to approximately 12 months
measure: Trough Concentration (Ctrough) of NIS793
timeFrame: From the date of first study drug intake up to approximately 12 months
measure: Trough Concentration (Ctrough) tislelizumab
timeFrame: From the date of first study drug intake up to approximately 12 months
measure: Antidrug antibodies (ADA) at baseline
timeFrame: Baseline
measure: ADA incidence on treatment
timeFrame: From the date of first study drug intake up to approximately 12 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: The Angeles Clinic and Research Institute
state: California
city: Ann Arbor
country: United States
facility: University of Michigan Medical
state: Michigan
city: Saint Louis
country: United States
facility: WA Uni School Of Med
state: Missouri
city: East Brunswick
country: United States
facility: Astera Cancer Center
state: New Jersey
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Houston
country: United States
facility: Uni Of TX MD Anderson Cancer Cntr
state: Texas
city: San Antonio
country: United States
facility: Mays Cancer Center
state: Texas
city: Adelaide
country: Australia
facility: Novartis Investigative Site
state: South Australia
city: Bendigo
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Perth
country: Australia
facility: Novartis Investigative Site
state: Western Australia
city: Bruxelles
country: Belgium
facility: Novartis Investigative Site
city: Bruxelles
country: Belgium
facility: Novartis Investigative Site
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Brampton
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Cambridge
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Brno
country: Czechia
facility: Novartis Investigative Site
state: Czech Republic
city: Hradec Kralove
country: Czechia
facility: Novartis Investigative Site
state: CZE
city: Praha 4
country: Czechia
facility: Novartis Investigative Site
city: Avignon
country: France
facility: Novartis Investigative Site
city: Creteil
country: France
facility: Novartis Investigative Site
city: Nantes Cedex 1
country: France
facility: Novartis Investigative Site
city: Frankfurt am Main
country: Germany
facility: Novartis Investigative Site
state: Hessen
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Bochum
country: Germany
facility: Novartis Investigative Site
city: Dresden
country: Germany
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Ulm
country: Germany
facility: Novartis Investigative Site
city: Pokfulam
country: Hong Kong
facility: Novartis Investigative Site
city: Shatin
country: Hong Kong
facility: Novartis Investigative Site
city: Haifa
country: Israel
facility: Novartis Investigative Site
city: Petach Tikva
country: Israel
facility: Novartis Investigative Site
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Rozzano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Nagoya
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Kashiwa
country: Japan
facility: Novartis Investigative Site
state: Chiba
city: Kawasaki
country: Japan
facility: Novartis Investigative Site
state: Kanagawa
city: Osaka-city
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Toyama
country: Japan
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Sabadell
country: Spain
facility: Novartis Investigative Site
state: Barcelona
city: Santander
country: Spain
facility: Novartis Investigative Site
state: Cantabria
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: St Gallen
country: Switzerland
facility: Novartis Investigative Site
city: Tainan
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Aberdeen
country: United Kingdom
facility: Novartis Investigative Site
state: Grampian Region
city: Cambridge
country: United Kingdom
facility: Novartis Investigative Site
city: Oxford
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: