Efficacy and Safety of Zanubrutinib Plus Tislelizumab Treatment with or Without Sonrotoclax for Patients with Richter Transformation
NCT ID: NCT04271956
Last Updated: 2024-12-30
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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RECRUITING
PHASE2
83 participants
INTERVENTIONAL
2020-02-19
2026-08-31
Brief Summary
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Detailed Description
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Conditions
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Study Design
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NON_RANDOMIZED
SINGLE_GROUP
TREATMENT
NONE
Study Groups
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Tislelizumab + Zanubrutinib
Induction: 6 cycles (q21d) of Tislelizumab + Zanubrutinib
Consolidation: 6 cycles (q21d) of Tislelizumab + Zanubrutinib
Maintenance: Patients with response to therapy continue to take Tislelizumab + Zanubrutinib (Q3W) until disease progression, non-tolerance or when receiving allogeneic stem cell transplantation (SCT) for consolidation
Tislelizumab
Cycle (q21d): Day 1: Tislelizumab i.v. 200 mg
Zanubrutinib
Cycle (q21d): Zanubrutinib p.o. 160 mg twice a day
Tislelizumab + Zanubrutinib + Sonrotoclax
Induction: 6 cycles (q21d) of Tislelizumab + Zanubrutinib + Sonrotoclax
Consolidation: 6 cycles (q21d) of Tislelizumab + Zanubrutinib + Sonrotoclax
Maintenance: Patients with response to therapy continue to take Tislelizumab + Zanubrutinib (Q3W) + Sonrotoclax until disease progression, non-tolerance or when receiving allogeneic stem cell transplantation (SCT) for consolidation
Tislelizumab
Cycle (q21d): Day 1: Tislelizumab i.v. 200 mg
Zanubrutinib
Cycle (q21d): Zanubrutinib p.o. 160 mg twice a day
Sonrotoclax
Cycle 1: Sonrotoclax Start Ramp-up to 320 mg QD po Days 1-2 Sonrotoclax 2 mg (2 tabl. at 1mg) Days 3-4 Sonrotoclax 5 mg (1 tabl. at 5mg) Days 5-6 Sonrotoclax 10 mg (2 tabl. at 5mg) Days 7-8 Sonrotoclax 20 mg (1 tabl. at 20mg) Days 9-10 Sonrotoclax 40 mg (2 tabl. at 20mg) Days 11-12 Sonrotoclax 80 mg (1 tabl. at 80mg) Days 13-14 Sonrotoclax 160 mg (2 tabl. at 80mg) Days 15-16 Sonrotoclax 320 mg (4 tabl. at 80mg)
Cycle 2-6: Day 1-21 Sonrotoclax 320 mg QD po
Interventions
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Tislelizumab
Cycle (q21d): Day 1: Tislelizumab i.v. 200 mg
Zanubrutinib
Cycle (q21d): Zanubrutinib p.o. 160 mg twice a day
Sonrotoclax
Cycle 1: Sonrotoclax Start Ramp-up to 320 mg QD po Days 1-2 Sonrotoclax 2 mg (2 tabl. at 1mg) Days 3-4 Sonrotoclax 5 mg (1 tabl. at 5mg) Days 5-6 Sonrotoclax 10 mg (2 tabl. at 5mg) Days 7-8 Sonrotoclax 20 mg (1 tabl. at 20mg) Days 9-10 Sonrotoclax 40 mg (2 tabl. at 20mg) Days 11-12 Sonrotoclax 80 mg (1 tabl. at 80mg) Days 13-14 Sonrotoclax 160 mg (2 tabl. at 80mg) Days 15-16 Sonrotoclax 320 mg (4 tabl. at 80mg)
Cycle 2-6: Day 1-21 Sonrotoclax 320 mg QD po
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
2. Confirmed histopathological diagnosis of RT (diffuse large B-cell lymphoma or Hodgkin's lymphoma \[Hodgkin's lymphoma only when not eligible for more in-tensive treatment\])
3. Previously untreated RT or patients with objective response or non-tolerance to first-line RT treatment
4. Adequate bone marrow function as defined by:
* Absolute neutrophil count (ANC) ≥ 1000/mm3, except for patients with bone marrow involvement in which ANC must be ≥ 500/mm3
* Platelet ≥ 75,000/mm3, except for patients with bone marrow involvement in which the platelet count must be ≥ 30,000/mm3
5. Creatinine clearance ≥30ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured with 24hr urine collection or an equivalent method.
6. Adequate liver function as indicated by a total bilirubin≤ 2 x, AST/ALT ≤ 2.5 x the institutional ULN value, unless directly attributable to the patient's CLL/RT or to Gilbert's Syndrome, in which case a max. total bilirubin ≤ 3 x and AST/ALT ≤ 5 x the institutional ULN value are required.
7. Negative serological testing for hepatitis B (HBsAg negative and anti-HBc nega-tive; patients positive for anti-HBc may be included if PCR for HBV DNA is negative and HBV-DNA PCR is performed every two months until 2 months af-ter last dose of zanubrutinib), negative testing for hepatitis-C RNA and negative HIV test within 6 weeks prior to registration
8. Age at least 18 years
9. ECOG performance status 0-2, ECOG 3 is only permitted if related to CLL or RT (e.g. due to anaemia or severe constitutional symptoms)
10. Life expectancy ≥ 3 months
11. Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements
Exclusion Criteria
2. Patients with more than one prior line of RT therapy
3. Allogenic stem cell transplantation within the last 100 days or signs of active GVHD after prior allogeneic stem cell transplantation within any time
4. Patients with confirmed PML
5. Uncontrolled autoimmune condition
6. Malignancies other than CLL currently requiring systemic therapies (unless the malignant disease is in a stable remission at the discretion of the treating phy-sician)
7. Uncontrolled infection currently requiring systemic treatment
8. Any comorbidity or organ system impairment rated with a CIRS (cumulative ill-ness rating scale) score of 4, excluding the eyes/ears/nose/throat/larynx organ system , or any other life-threatening illness, medical condition or organ system dysfunction that - in the investigator´s opinion could comprise the patients safety or interfere with the absorption or metabolism of the study drugs
9. Requirement of therapy with strong CYP3A4 inhibitors/ inducers
10. Requirement of therapy with phenprocoumon or other vitamin K antagonists.
11. Known active infection with HIV, or serologic status reflecting active hepatitis B or C infection as follows:
* Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core anti-body (HBcAb). Patients with presence of HBcAb, but absence of HBsAg, are eligible if hepatitis B virus (HBV) DNA is undetectable (\< 20 IU), and if they are willing to undergo monitoring every 4 weeks for HBV reactivation.
* Presence of hepatitis C virus (HCV) antibody. Patients with presence of HCV antibody are eligible if HCV RNA is undetectable.
12. Major surgery within 4 weeks of the first dose of study drug.
13. Any uncontrolled or clinically significant cardiovascular disease including the following:
* Myocardial infarction within 6 months before screening
* Unstable angina within 3 months before screening
* New York Heart Association class III or IV congestive heart failure
* History of clinically significant arrhythmias (eg, sustained ventricular tachy-cardia, ventricular fibrillation, torsades de pointes)
14. History of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood trans-fusion or other medical intervention
15. History of stroke or intracranial hemorrhage within 6 months before first dose of study drug
16. Severe or debilitating pulmonary disease
17. Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction
18. Use of investigational agents, e.g. monoclonal antibodies or other experimental drugs within clinical trials, which might interfere with the study drug within 28 days (or 5 times half-life \[t1/2\] of the compound, whichever is longer) prior to registration
19. Known hypersensitivity to tislelizumab, zanubrutinib, sonrotoclax or any of the excipients
20. Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment)
21. Fertile men or women of childbearing potential unless:
* surgically sterile or ≥ 2 years after the onset of menopause, or
* willing to use two methods of reliable contraception including one highly ef-fective contraceptive method (Pearl Index \<1) and one additional effective (barrier) method during study treatment and for 6 months after the end of study treatment.
22. Vaccination with a live vaccine \<28 days prior to randomization
23. Legal incapacity
24. Prisoners or subjects who are institutionalized by regulatory or court order
25. Persons who are in dependence to the sponsor or an investigator
18 Years
ALL
No
Sponsors
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German CLL Study Group
OTHER
Responsible Party
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Principal Investigators
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Barbara Eichhorst, Prof.
Role: PRINCIPAL_INVESTIGATOR
Department I of Internal Medicine, University Hospital Cologne
Locations
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Allgemeines Krankenhaus der Stadt Wien
Vienna, , Austria
Rigshospitalet
Copenhagen, , Denmark
Charité Berlin
Berlin, State of Berlin, Germany
Uniklinik Köln
Cologne, , Germany
Universitätsklinikum Carl Gustav Carus
Dresden, , Germany
Universitätsklinikum Essen
Essen, , Germany
Universitätsklinikum Schleswig-Holstein Campus Kiel
Kiel, , Germany
H.O.T Praxis Landshut
Landshut, , Germany
Brüderkrankenhaus St. Josef Paderborn
Paderborn, , Germany
Universitätsmedizin Rostock
Rostock, , Germany
Universitätsklinik Ulm
Ulm, , Germany
Countries
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Central Contacts
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References
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Al-Sawaf O, Ligtvoet R, Robrecht S, Stumpf J, Fink AM, Tausch E, Schneider C, Boettcher S, Mikusko M, Ritgen M, Schetelig J, von Tresckow J, Vehling-Kaiser U, Gaska T, Wendtner CM, Chapuy B, Fischer K, Kreuzer KA, Stilgenbauer S, Staber P, Niemann C, Hallek M, Eichhorst B. Tislelizumab plus zanubrutinib for Richter transformation: the phase 2 RT1 trial. Nat Med. 2024 Jan;30(1):240-248. doi: 10.1038/s41591-023-02722-9. Epub 2023 Dec 9.
Related Links
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Click here for more information about this study: CLL-RT1 (German CLL Study Group)
Other Identifiers
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2023-504653-12-00
Identifier Type: CTIS
Identifier Source: secondary_id
CLL-RT1
Identifier Type: -
Identifier Source: org_study_id