| 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 |
|
| 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 | 27.0 |
| 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 | No |
| 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 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 or NIS793 plus 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
treatment (NIS793 or NIS793+tislelizumab in combination with SOC)
4. To characterize the immunogenicity of each investigational treatment
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 treatment (NIS793 or NIS793+tislelizumab in combination with SOC)
5. To characterize the immunogenicity of components of each
investigational arm, control arm |
|
| E.2.3 | Trial contains a sub-study | No |
| 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 anti-cancer immunotherapy or TGF-β targeted therapies
2.Microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) &/or BRAFV600 mutation positive colorectal cancer (tests performed by local laboratory and per local guidelines)
3.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)
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 and can be conducted at a 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 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 the prohibited medications as outlined in the protocol or in the SOC anti-cancer therapy local prescribing information & these cannot be discontinued ≥ 7 days or 5 half-lives whichever is longer before the first dose of 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 &/or diastolic blood pressure ≥100 mg Hg
•Medical history or current diagnosis of myocarditis
12.History of positive test for human immunodeficiency virus (HIV)
13.Active or chronic hepatitis B virus (HBV) or hepatitis C virus
14.Active untreated or uncontrolled systemic fungal, bacterial or viral infection (incl. COVID-19) which in the opinion of the investigator places the study participant at 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 or history of significant bleeding
17.Serious non-healing wounds
18.Stroke or transient ischemic attack or other ischemic event or thromboembolic event (deep venous thrombosis, pulmonary embolism) within 3 months before start of study treatment
19.Concurrent malignancy other than the disease under investigation with exception of malignancy that was treated curatively & has not recurred within 2 years prior to the date of screening. Fully resected basal or squamous cell skin cancers & any carcinoma 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 the participant's ability to comply with study requirements, or compromise participant's compliance with the protocol
and all requirements of the study as stated in the Informed Consent Form.
21.Women of child-bearing potential, unless they are willing to use highly effective methods of contraception during treatment with study drugs and for at least 120 days after stopping treatment with tisle
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 or
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 | No |
| E.6.2 | Prophylaxis | No |
| 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 | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| 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 | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 37 |
| 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 | No |
| 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 |
| Canada |
| Israel |
| Japan |
| Korea, Republic of |
| United Kingdom |
| United States |
| Belgium |
| Czechia |
| France |
| Germany |
| Hungary |
| Italy |
| Netherlands |
| Spain |
|
| 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
|
Following the recommendation to stop administration of NIS793 and
tislelizumab, participants continuing to derive clinical benefit from the
SOC therapy in the opinion of the Investigator may continue such
treatment outside of the study. The study will be considered complete
when each participant discontinued the study, transitioned off to
alternative treatments, died, withdrew consent, or is lost to follow-up,
whichever occurs earliest or, in the event of an early study termination.
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 3 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 10 |
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