Safety Run-in (SRI) part:To confirm the recommended phase 2 dose (RP2D) of NIS793 or any other investigational drug(s), in combination with SOC anti-cancer therapy. In protocol amendment 1, an arm with tislelizumab has been added. In this arm, the…
ID
Source
Brief title
Condition
- Malignant and unspecified neoplasms gastrointestinal NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary estimand is defined only for the expansion part.
The primary scientific question of interest is:
• What is the relative effect of each investigational treatment arm relative to
the SOC anti-cancer therapy arm in prolonging PFS in the second line mCRC
setting, regardless of study treatment discontinuations or start of a new
subsequent antineoplastic therapy or prohibited medication which is not part of
assigned study treatment strategy?
Secondary outcome
none
Background summary
Colorectal cancer (CRC) is the 3rd most commonly diagnosed cancer in the world
and the second highest cause of cancer death. Of newly diagnosed CRC patients,
75% have localized disease that is treated by surgical resection while 25%
present with unresectable metastatic disease. Furthermore, approximately 30% of
patients with localized CRC develop metastatic disease recurrence after the
surgical removal of the tumor. A worrying rise in patients presenting with
colorectal cancer, younger than 50 years has been observed, especially rectal
and left sided colon cancer. Patients with mCRC, after first line treatment,
still have an important unmet medical need to improve current survival outcomes
where median PFS is approximately 6 months and median overall survival (OS) is
approximately 12 months with current available treatments.
The TME plays a critical role at the different stages of the disease. The TME
confers to a CRC cell survival, immune evasion and a favorable environment to
grow and metastasize . TGF-β pathway plays a critical role in immune
regulations, stromal cell activation and fibrosis. It has been recognized that
alteration and aberrant regulation of TGF-β pathway plays a crucial role in the
initiation, proliferation, inflammation and invasiveness of CRC. Moreover,
various studies have shown that TGF-β is responsible for reducing drug
sensitivity and recurrence in patients with cancer supporting the therapeutic
potency of TGF-β inhibitors in combination with other treatments in this
setting.
Tislelizumab (also known as BGB-A317 and VDT482) is a humanized immunoglobulin
G4 (IgG4) monoclonal antibody (mAb) against human programmed cell death-1
(PD-1). Tislelizumab is being developed for treatment of human malignancies in
multiple organs and tissues and is being investigated either as monotherapy or
in combination with other therapies.
Study objective
Safety Run-in (SRI) part:
To confirm the recommended phase 2 dose (RP2D) of NIS793 or any other
investigational drug(s), in combination with SOC anti-cancer therapy. In
protocol amendment 1, an arm with tislelizumab has been added. In this arm, the
patient can be treated with SoC, NIS793 and Tislelizumab. The RP2D of
tislelizumab in combination with NIS793 is being investigated in the SRI.
Expansion part:
To evaluate preliminary efficacy of NIS793 or any other investigational
drug(-s) (in arm 2 NIS793 + tislelizumab) in combination with SOC anti-cancer
therapy versus SOC anti-cancer therapy in terms of progression-free survival
(PFS)
Study design
This is an open-label, multi-center, phase II platform study.
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 anticancer therapy for the second line treatment of mCRC.
The study will include control arm that will enroll participants treated with
SOC anticancer therapy (bevacizumab with mFOLFOX6 or FOLFIRI) for the second
line treatment of mCRC. Each investigational arm will include a combination of
an investigational drug and the SOC anti-cancer therapy.
Investigational arm #1 will include combination of NIS793 with SOC anti-cancer
therapy.
Investigational arm #2 will include combination of NIS793 + NIS793 with SOC
anti-cancer therapyn (protocol amendment 1)
Combinations of other investigational drug(-s) with SOC anti-cancer therapy may
be added later by protocol amendment as new investigational arms (i.e,
investigational arm #2, investigational arm #3 etc).
Each investigational arm will start with a Safety run-in (SRI) followed by an
Expansion part. The purpose of SRI is to confirm the dose of investigational
drug with SOC anticancer therapy.
* Each SRI will enroll up to approximately 20 participants to have at least 12
evaluable participants (6 treated by NIS793 [or any other new investigational
drug] + mFOLFOX6 + bevacizumab and 6 by NIS793 [or any other new
investigational drug] + FOLFIRI +bevacizumab)
* Each expansion will enroll approximately 75 participants in each treatment arm
The decision to open the expansion part of the study will be based on dose
confirmation of investigational drug(-s) with available safety, relevant PK and
other relevant clinical and laboratory data from the safety run-in part.
Intervention
Safety run-in:
combination of NIS793 and SOC (FOLFIRI or mFOLFOX) + bevacizumab
combination of NIS793, and tislelizumab, SOC (FOLFIRI or mFOLFOX) + bevacizumab
Expansion part:
Investigational arm 1: NIS793 and SOC (FOLFIRI or mFOLFOX) + bevacizumab
investigational arm 2: NIS793,and tislelizumab, SOC (FOLFIRI or mFOLFOX) +
bevacizumab
control arm: alone SOC FOLFIRI or mFOLFOX) + bevacizumab
Treatment cycle is defined as 28 days. Treatment will be given at day 1 and day
15.
Study burden and risks
The extra burden for the patient is mainly the duration of the visits, the
extra blood samples (especially PK and biomarker test, if applicable pregnancy
tests, eye examinations and the completion of the questionnaires. The visits
take longer because of extra blood draws, observation period after NIS793 and
tislelizumab administration.
There are a number of additional visits such as screening, end trial and if
applicable the follow-up and PK sampling visits (day 2 of the first cycles).
The frequency of visits follows the dosing schedule of the standard of care
bevacizumab + FOLFIRI/mFOLFOX.
As with any administration of drugs, side effects may occur. However, the
patient is observed before being allowed to go home and vital signs are checked
regularly.
If patient gives consent, additional biopsies are taken
Haaksbergweg 16
Amsterdam 1101 BX
NL
Haaksbergweg 16
Amsterdam 1101 BX
NL
Listed location countries
Age
Inclusion criteria
1. Signed informed consent must be obtained prior to participation in the study.
2. Age 18 years or older 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.
Exclusion criteria
1. Previously administered of anti-cancer immunotherapy or TGF-β targeted
therapies.
2. Microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR)
and/or BRAFV600 mutation positive colorectal cancer.
3. Known complete or partial dipyrimidine dehydrogenase (DPD) enzyme deficiency
4. For participants treated with irinotecan: Known history or clinical evidence
of reduced UGT1A1 activity.
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 and prior to study entry, and 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 (e.g.
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 the prohibited medications as
outlined in the protocol or in the SOC anti-cancer therapy local prescribing
information, and these cannot be discontinued >= 7 days or 5 half-lives,
whichever is longer, before the 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 the opinion of the 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 the disease under investigation with
exception of malignancy that was treated curatively and has not recurred within
2 years prior to the 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 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 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 or equivalent) or
any immunosuppressive therapy
26. History of allogeneic bone marrow or solid organ transplant
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2021-000553-40-NL |
| ClinicalTrials.gov | NCT04952753 |
| CCMO | NL79023.056.22 |