tislelizUMaB in canceR patients with molEcuLar residuaL disease (UMBRELLA)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut Gustave Roussy

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06], Diseases [C] - Respiratory Tract Diseases [C08], Diseases [C] - Neoplasms [C04]

Trial duration

26 Sep 2024 → ongoing

Decision date (initial)

2024-03-29

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

C2i Genomics · Beigene · IHU de Gustave Roussy

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy

Assess the efficacy of tislelizumab compared to placebo as measured by DFS in patients with MRD (MRD) positive status [MRD (+)] at minimum 2 months and maximum 5 months after completion of standard curative-intent therapy (Arm A vs Arm B).

Secondary objectives 11

1. Estimation of DFS in subjects without MRD [(MRD negative status, MRD (-)] minimum 2 months and maximum 5 months after completion of standard curative-intent therapy
2. Estimation of overall survival (OS) at 12 months, 24 months and 48 months.
3. Estimation of the percentage of MRD (+) subjects at minimum 2 months and maximum 5 months after completion of standard curative-intent therapy
4. Estimation of elapsed time between detection of MRD and detection of relapse at imaging.
5. Estimation of MRD assessment failure.
6. For MRD (+) subjects minimum 2 months and maximum 5 months after completion of standard curative-intent therapy, estimation of the time to become MRD (-)
7. Evaluation of the safety and tolerability of tislelizumab (applicable for Arms A and B) according to the NCI-CTCAE version 5.
8. Evaluation of Health-Related Quality of Life (HRQoL) (EORTC QLQ-C30 and EuroQol EQ-5D-5).
9. Cost effectiveness analysis.
10. Estimation of complete MR rates at 6 and 12 months in MRD (+) subjects starting treatment with tislelizumab or placebo at minimum 2 months and maximum 5 months after curative-intent therapy
11. For subjects who are MRD (+) at minimum 2 months and maximum 5 months after completion of standard curative-intent therapy and with relapse on tislelizumab/placebo (group from Arm A and B); estimation of objective response rate and of progression-free survival (PFS2) on the next line of therapy

Conditions and MedDRA coding

patients with a positive status for molecular residual disease (MRD) [MRD (+)] 2 to 5 months after the end of standard end of standard curative treatment

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. Age ≥ 18 years,
2. Completion of surgical and peri-operative treatments as per international guidelines
3. Subject must have completed standard curative-intent therapy for minimum 2 months and maximum 5 months and must not have standard treatment at least 2 months before blood sampling for ctDNA analyses
4. Patients must not have blood transfusion at least 3 months before blood sampling for ctDNA analyses
5. Histology: TNM stage II-III NSCLC, Stage II-III colorectal cancer, stage I-III pancreatic cancer, grade 3 soft-tissue sarcoma,
6. Subjects must have sufficient amount of archived primary tumor material for ctDNA and translational research analyses that will be conducted as defined in the protocol,
7. Subjects must have a valid (positive or negative) ctDNA test result prior to randomization,
8. Subjects must not have had prior immunotherapy (anti-PD-1 or anti-PD-L1),
9. No evidence of disease on imaging as per RECIST criteria 1.1,
10. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1,
11. Subjects must have adequate organ function as indicated by the following laboratory values (obtained within 7 days prior to randomization): a) Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, haemoglobin ≥90 g/L. Note: Patients must not have required a blood transfusion or growth factor support ≤ 14 days before sample collection. b) International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x upper limit of normal (ULN). c) Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN. d) Serum total bilirubin ≤ 1.5 x ULN (total bilirubin must be < 3 x ULN for patients with Gilbert's syndrome). e) Aspartate and alanine aminotransferase (AST and ALT) ≤ 3 x ULN f)Creatinine clearance ≥60 mL/min for participants with creatinine levels above institutional normal (≥ULN). Creatinine clearance should be calculated per the Cockcroft-Gault formula (or local institutional standard method)
12. Subjects with a social security in compliance with the French law relating to biomedical research (Article L.1121-11 of French Public Health Code),
13. Subjects should understand, sign, and date the written informed consent form prior to any protocol-specific procedures performed. Patient should be able and willing to comply with study visits and procedures as per protocol,
14. Females of childbearing potential must be willing to use a highly effective method of birth control for the duration of the trial, and ≥ 120 days after the last dose of the trial drug and have a negative serum pregnancy test ≤ 7 days of the first dose of the trial drug. A barrier contraceptive method (e.g., condom) is also required. A woman is considered of childbearing potential following menarche and until becoming post-menopausal (≥ 12 months of non-therapy-induced amenorrhea) unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral oophorectomy and bilateral salpingectomy with surgery at least 1 month before the first dose of study drug or confirmed by follicle stimulating hormone (FSH) test >40 mIU/mL and estradiol <40 pg/mL (<140 pmol/L).
15. Nonsterile males must be willing to use a highly effective method of birth control for the duration of the study and for ≥ 120 days after the last dose of the trial drug. A barrier contraceptive method (e.g., condom) is also required.(...)The following methods are considered as unacceptable methods (non-exhaustive list): periodic abstinence (calendar, symptothermal, post-ovulation methods) and withdrawal (coitus interruptus).

Exclusion criteria 23

1. Participation in another clinical trial with an investigational product during the last 2 to 5 months and while on study treatment
2. Administration of a live, attenuated vaccine within 4 weeks prior to enrolment or anticipation that such a live, attenuated vaccine will be required during the study or within 5 months after the last dose of the study drugs (except anti-COVID-19 vaccines)
3. Active or history of autoimmune disease or immune deficiency, with the exception of history of treated autoimmune-related hypothyroidism and Type 1 diabetes mellitus on insulin regimen
4. History of idiopathic pulmonary fibrosis (including pneumonitis or interstitial lung disease), drug-induced pneumonitis, organizing pneumonia (i.e. bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis (history of radiation pneumonitis in the radiation field (fibrosis) is permitted).
5. Patients who underwent major surgery within 28 days prior to inclusion or until the surgical wound is fully healed
6. History of HIV infection
7. Patients with active hepatitis infection (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA
8. Active tuberculosis
9. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
10. Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
11. Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment
12. Any condition which in the Investigator’s opinion makes it undesirable for the subject to participate in a clinical trial or which would jeopardize compliance with the protocol,
13. Significant cardiovascular disease, such as: • History of myocardial infarction, acute coronary syndromes or coronary angioplasty/stenting/bypass grafting within the past 6 months, o Congestive Heart Failure (CHF) NYHA class III or IV or history of CHF NYHA class III or IV, unless an echocardiogram or multi-gated acquisition scan performed within 3 months day 1 reveals a left ventricular ejection fraction ≥ 55%
14. Uncontrolled hypertension defined by systolic pressure > 150 and/or diastolic pressure > 110 mmHg, with or without anti-hypertensive medication. Patients with initial blood pressure elevations are eligible if initiation or adjustment of anti-hypertensive medication lowers blood pressure to meet entry criteria
15. History of stroke or transient ischemic attack within 6 months prior to randomization
16. Pregnant or breastfeeding women
17. Subjects under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving its consent.
18. Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin−2) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to enrolment
19. Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate and thalidomide) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions: o Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids as premedication for hypersensitivity reaction (e.g., CT scan premedication)) are eligible for the study after Principal investigator approval has been obtained o Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study o Patients who received intranasal, inhaled, topical or local steroid injections (e.g., intra articular injection)
20. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE > Grade 1.
21. Known intolerance the study drugs or any of their excipients
22. Patients with prior allogeneic stem cell or solid organ transplantation
23. Patients with confirmed EGFR exon 19 deletions or exon 21 L858R substitutions are excluded from the study, due to the potential benefit from adjuvant osimertinib treatment, which represents a standard of care for these genetic profiles in non-small cell lung cancer (NSCLC). Similarly, patients with confirmed ALK rearrangements are also excluded, as adjuvant alectinib is recommended as a standard treatment for this molecular subtype

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. DFS for MRD (+) patients defined as the time from randomization to relapse or death, whichever occurs first. DFS rate will also be assessed at 12 months, 24 months, 48 months and 60 months.

Secondary endpoints 11

1. DFS for MRD (-) patients defined as the time from randomization to relapse or death, whichever occurs first.
2. OS defined as the time from randomization to death from any cause at 12, 24, 48 and 60 months.
3. Percentage of MRD (+) subjects minimum 2 months and maximum 5 months after completion of standard curative-intent therapy
4. Time from detection of MRD to relapse at imaging as documented per RECIST v1.1.
5. Percentage of subjects with MRD assessment failure.
6. Time from baseline to detection of MRD (-) status in subjects who were MRD (+) at baseline
7. Incidence and severity of treatment-emergent adverse events (TEAEs) including all non-serious and serious AEs. Percentage of subjects with: i) TEAEs leading to dose interruptions ii) TEAEs leading to discontinuation
8. Scores from EORTC QLQ-C30 and EuroQol EQ-5D-5L questionnaires at baseline and at months 6, 12, 18 and 24.
9. Incremental costs and QALY and ICER (€/QALY).
10. Percentage of MRD (+) subjects with complete MR rates at 6 and 12 months in subjects starting systemic therapy with tislelizumab or placebo after curative-intent therapy, defined as patients with undetectable ctDNA at the time of analysis
11. Objective response rate and progression-free survival (PFS2) on the next line of therapy. (applicable for Arm A and B)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut Gustave Roussy

Sponsor organisation

Institut Gustave Roussy

Address

114 Rue Edouard Vaillant

City

Villejuif

Postcode

94800

Country

France

Scientific contact point

Organisation

Institut Gustave Roussy

Contact name

Regulatory Affairs Officer

Public contact point

Organisation

Institut Gustave Roussy

Contact name

Regulatory Affairs Officer

Locations

1 EU/EEA country · 13 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 7 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications