Clinical Trials Register

Summary
EudraCT Number:	2021-000553-40
Sponsor's Protocol Code Number:	CNIS793E12201
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-08-16
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - PEI

A.2

EudraCT number

2021-000553-40

A.3

Full title of the trial

daNIS-3: An open-label, multi-center, phase II platform study evaluating the efficacy and safety of NIS793 and other new investigational drug combinations with standard of care (SOC) anti-cancer therapy for the second line treatment of metastatic colorectal cancer (mCRC)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Study of NIS793 and other novel investigational combinations with SOC anti-cancer therapy for the second line treatment of mCRC

A.4.1

Sponsor's protocol code number

CNIS793E12201

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Novartis Pharma AG
B.1.3.4	Country	Switzerland
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Novartis Pharma AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Pharma GmbH
B.5.2	Functional name of contact point	Medizinischer Infoservice (MCC)
B.5.3	Address:
B.5.3.1	Street Address	Roonstrasse 25
B.5.3.2	Town/ city	Nürnberg
B.5.3.3	Post code	90429
B.5.3.4	Country	Germany
B.5.4	Telephone number	+49 911 273-12100
B.5.5	Fax number	+49 911 27312160
B.5.6	E-mail	infoservice.novartis@novartis.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.2	Product code	NIS793
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	not yet available
D.3.9.2	Current sponsor code	NIS793
D.3.9.3	Other descriptive name	NIS793
D.3.9.4	EV Substance Code	SUB184323
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.2	Name of the Marketing Authorisation holder	BeiGene
D.2.1.2	Country which granted the Marketing Authorisation	China
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	tislelizumab
D.3.2	Product code	VDT482
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Tislelizumab
D.3.9.2	Current sponsor code	VDT482
D.3.9.4	EV Substance Code	SUB193656
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

metastatic colorectal cancer (mCRC)

E.1.1.1

Medical condition in easily understood language

colorectal cancer

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	PT
E.1.2	Classification code	10061451
E.1.2	Term	Colorectal cancer
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	PT
E.1.2	Classification code	10052358
E.1.2	Term	Colorectal cancer metastatic
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Safety run-in: To confirm the recommended phase 2 dose (RP2D) of each investigational arm (NIS793 or NIS793 plus tislelizumab or any investigational drug(s) in combination with SOC) (SOC: either modified FOLFOX6 + bevacizumab or FOLFIRI+ bevacizumab chemotherapy regimen)
Expansion part: To evaluate preliminary efficacy of each investigational arm (NIS793 or NIS793+tislelizumab or any investigational drug(s) in combination with SOC anti-cancer therapy) versus control arm(SOC anti-cancer therapy) in terms of progression-free survival (PFS) by Investigator's assessment per RECIST 1.1

E.2.2

Secondary objectives of the trial

Safety run-in:
1. To characterize the safety and tolerability of each investigational arm (NIS793 or NIS793+tislelizumab or any investigational drug(s) in combination with SOC)
2. Preliminary anti-tumor activity of each investigational arm
3. To characterize the pharmacokinetics (PK) of each investigational arm (NIS793 or NIS793+tislelizumab or any investigational drug(s) in combination with SOC)
4. To characterize the immunogenicity of components of each investigational arm
Expansion part:
1. To evaluate and compare efficacy of each investigational arm and control arm in terms of ORR, DCR, DOR, TTR by Investigator's assessment per RECIST 1.1
2. To evaluate and compare the overall survival (OS) of each investigational arm and control arm
3. Safety and tolerability
4. To characterize the PK of each investigational arm, control arm
5. To characterize the immunogenicity of components of each investigational arm, control arm

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Signed informed consent must be obtained prior to participation in the study.
2. Age 18 years (or older, if required by local regulations) at the time of informed consent.
3. 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.
4. Presence of at least one measurable lesion assessed by CT and/or MRI according to RECIST 1.1.
5. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1.
6. Adequate organ function as defined by the following laboratory values (assessed by central laboratory for eligibility except where indicated):
• Absolute neutrophil count ≥ 1.5 × 109/L
• Platelets count ≥ 100 × 109/L
• Hemoglobin ≥ 9 g/dL
• Calculated creatinine clearance ≥ 60 mL/min (e.g. by using Cockcroft-Gault equation)
• Albumin ≥ 3 g/dL
• PT/INR and PTT ≤ 1.5 x ULN. Participants requiring therapeutic anticoagulants are eligible if coagulation parameters are within therapeutic range.
• Total bilirubin ≤ 1.5 X ULN
• Aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase /serum glutamic pyruvic transaminase (ALT/SGPT) ≤ 3.0 x ULN (≤5 x ULN in presence of liver metastasis). In participants with elevated ALT or AST, the values must be stable for at least 2 weeks and with no evidence of biliary obstruction by imaging.
7. Women of child-bearing potential must have negative pregnancy tests during the screening period and before starting study treatment.
8. Able to adhere to study visit schedule and other protocol requirements.
9. Participant must have recovered from treatment related toxicities of prior anticancer therapies to grade ≤1 (CTCAE v5.0) at the time of screening, except alopecia.

E.4

Principal exclusion criteria

1.Previously administered of anticancer immunotherapy or TGF-βtargeted therapies.
2.Microsatellite instability-high(MSI-H)/mismatch repair-deficient (dMMR)&/or BRAFV600 mutation positive colorectal cancer(tests performed by local laboratory & per local guidelines)
3.Known complete or partial dipyrimidine dehydrogenase (DPD) nzyme deficiency(testing for DPD enzyme deficiency is not mandatory unless required by local regulations &can be conducted at local laboratory)
4.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 &can be conducted at local laboratory).
5.Presence of symptomatic CNS metastases,or CNS metastases that requires directed therapy (such as focal radiotherapy or surgery)or increasing doses of corticosteroids 2 weeks prior to study entry. Participants with treated symptomatic brain metastases should be neurologically stable for 4 weeks post-treatment &prior to study entry,&at a dose of ≤ 10 mg per day prednisone or equivalent for at least 2 weeks before administration of any study treatment.
6.Known history of severe allergy or hypersensitivity to any of the study drugs or its excipients or to drugs of similar chemical classes(monoclonal antibodies)or contraindication to any of the study drugs as outlined in the ‘Contraindications’ or‘Warnings and Precautions’ sections of the SOC local prescribing information 7.Participant is currently receiving other anti-cancer therapy (medication or radiotherapy)or received other investigational product within 30 days or 5 half-lives prior to initiation of study treatment whichever is longer.
8.Participant is currently receiving any of prohibited medications as outlined in protocol or in SOC anti-cancer therapy local prescribing information &these cannot be discontinued ≥ 7 days or 5 half-lives whichever is longer, before first dose of that drug.
9.Participant has not recovered from a major surgery performed prior to start of study treatment or has had a major surgery within 4 weeks days prior to start of study treatment. 10.Radiation therapy ≤ 4 weeks or brain-radiotherapy ≤ 4 weeks prior to start of study treatment
11.Impaired cardiac function or clinically significant cardio-vascular disease, such as:
•Congestive heart failure requiring treatment (NYHA grade ≥2)or clinically significant arrhythmia (including uncontrolled atrial flutter/fibrillation)
•Acute myocardial infarction, unstable angina pectoris, coronary stenting, or bypass surgery <6 months prior to study entry •LVEF < 50% •Elevated cardiac enzymes troponin I > 2 x ULN •Cardiac valvulopathy≥ grade 2 •Uncontrolled hypertension defined by a systolic blood pressure ≥160 mg and/or diastolic blood pressure ≥100 mg Hg • Medical history or current diagnosis of myocarditis
12.History of positive test for human immunodeficiency virus (HIV) infection 13.Active or chronic hepatitis B virus (HBV) or hepatitis C virus infections.14.Active untreated or uncontrolled systemic fungal, bacterial or viral infection (including COVID-19), which in opinion of investigator places the study participant at an unacceptable risk.
15.Use of hematopoietic growth factors or transfusion support ≤ 2 weeks prior to start of study treatment.
16.Participant has 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. 17.Serious non-healing wounds.
18.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.19.Concurrent malignancy other than disease under investigation with exception of malignancy that was treated curatively&has not recurred within 2 years prior to date of screening. Fully resected basal or squamous cell skin cancers and any carcinoma in situ are eligible.
20.Any significant medical condition, laboratory abnormality or psychiatric or social condition that would constitute unacceptable safety risks to the participants, contraindicate participant participation in the clinical study, limit participant’s ability to comply with study requirements or compromise participants compliance with protocol& all requirements of study as stated in ICF.
21.Women of child-bearing potential,unless they are willing to use highly effective methods of contraception during treatment with study drugs and for for at least 120 days after stopping treatment with tislelizumab.
22.Pregnant or breast-feeding women.
23.Use of live/attenuated vaccines within 4 weeks of initiation of study treatment 24.Active, known or suspected autoimmune disease or history thereof
25.Systemic chronic steroid therapy (>10 mg/day prednisone/
equivalent) or any immunosuppressive therapy
26.History of allogeneic bone marrow or solid organ transplant

E.5 End points

E.5.1

Primary end point(s)

Safety run-in: Incidence of DLTs during the first treatment cycle (4 weeks) of treatment
Expansion part: Progression-free survival (PFS) by Investigator’s assessment per RECIST 1.1

E.5.1.1

Timepoint(s) of evaluation of this end point

safety run-in: 4 weeks of treatment
expansion part: until progression of the disease

E.5.2

Secondary end point(s)

Safety run-in:
1. Safety: Incidence and severity of AEs including changes in laboratory parameters, vital signs and ECG parameters
2. Tolerability: Dose interruptions, reductions and dose intensity
3. PFS, overall response rate (ORR), disease control rate (DCR), duration of response (DOR) and time to response (TTR)by Investigator's assessment per RECIST 1.1 and Overall survival (OS)
4. Drug concentrations in serum or plasma of each investigational treatment and components of SOC therapy (bevacizumab, irinotecan, SN-38) over time and derived PK parameters (e.g. Ctrough, Cmax)
5. Incidence of antidrug antibodies (ADA), prevalence at baseline and ADA incidence during the treatment for investigational treatment(s) and bevacizumab.
expansion part:
1. ORR, DCR, DOR, TTR by investigator's assessment by RECIST 1.1
2. OS
3. Incidence and severity of AEs, changes in laboratory parameters, vital signs and ECG parameters; dose interruptions, reductions and dose intensity
4. Drug concentrations in serum or plasma of each investigational treatment and components of SOC therapy (bevacizumab, irinotecan, SN-38) over time and derived PK parameters (e.g. Ctrough, Cmax)
5. Incidence of antidrug antibodies (ADA), prevalence at baseline and ADA incidence during the treatment for investigational treatment(s) and bevacizumab.

E.5.2.1

Timepoint(s) of evaluation of this end point

safety run-in:
1,2 - 4 weeks of treatment
3 - end of treatment
4,5 - at protocol defined timepoints
expansion part:
1, 2, 3 - at the end of treatment
4,5 - at protocol defined timepoints

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

platform study

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

SoC chemotherapy

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Singapore

Switzerland

Taiwan

Australia

Belgium

Canada

Czechia

France

Germany

Hungary

Israel

Italy

Japan

Korea, Republic of

Netherlands

Spain

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

When all participants
• have completed 2 years of potential survival follow-up or 80% OS events for each treatment arm have occurred
• until death or lost to follow-up, or withdrawal of consent
• another clinical study with NIS793 or any other new investigational drug becomes available in this participant population and all participants ongoing are eligible to be transferred to that clinical study, in the event of an early study termination decision, the date of that decision.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

164

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

102

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

266

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

n/a

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-11-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-09-30

P. End of Trial
P.	End of Trial Status	Ongoing

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