Combining zanubrutinib and tislelizumab for treating Richter Transformation
A Prospective, Open-label, Multicenter Phase-II Trial to Evaluate the Efficacy and Safety of Zanubrutinib (BGB-3111), a BTK Inhibitor, Plus Tislelizumab (BGB-A317), a PD1 Inhibitor, for Treatment of Patients with Richter Transformation with or Without Sonrotoclax（BGB-11417), a Bcl-2 Inhibitor (CLL-RT1-trial of the GCLLSG).
This study is testing a new combination of two drugs, zanubrutinib and tislelizumab, to see if they can help people with Richter Transformation, a serious complication of chronic lymphocytic leukemia, when other treatments haven't worked.
Quick facts
| Phase | Phase 2 |
|---|---|
| Study type | Interventional |
| Enrollment | 83 (estimated) |
| Ages | 18 Years and up |
| Sex | All |
| Sponsor | German CLL Study Group Academic / other |
| Drugs / interventions | tislelizumab, zanubrutinib, Rituximab |
| Locations | 11 sites (Vienna and 10 other locations) |
| Trial ID | NCT04271956 on ClinicalTrials.gov |
What this trial studies
This trial evaluates the efficacy and safety of zanubrutinib, a BTK inhibitor, in combination with tislelizumab, a PD-1 inhibitor, for patients suffering from Richter Transformation, a severe complication of chronic lymphocytic leukemia (CLL). The study aims to address the poor prognosis associated with this condition, where conventional treatments have largely failed. By systematically assessing the safety and toxicity of this combination, the trial seeks to provide a new therapeutic strategy for patients who are not suitable for traditional treatments or transplantation. Additionally, the trial may explore the potential role of sonrotoclax in this treatment regimen.
Who should consider this trial
Good fit: Ideal candidates include patients with a confirmed diagnosis of CLL and histopathological diagnosis of Richter Transformation who have not received prior treatment or have not tolerated first-line therapy.
Not a fit: Patients with other forms of lymphoma or those who are not eligible for intensive treatment may not benefit from this study.
Why it matters
Potential benefit: If successful, this treatment could significantly improve outcomes for patients with Richter Transformation, potentially extending survival and enhancing quality of life.
How similar studies have performed: While there have been studies exploring similar combinations, this specific approach is novel and aims to address a significant unmet need in the treatment of Richter Transformation.
Eligibility criteria
Show full inclusion / exclusion criteria
Inclusion Criteria:
1. Confirmed diagnosis of CLL according to iwCLL criteria (Hallek et al, 2018)
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:
1. Patients who did not respond to previous line of RT therapy (i.e. primary progressive patients)
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
Where this trial is running
Vienna and 10 other locations
- Allgemeines Krankenhaus der Stadt Wien — Vienna, Austria (Recruiting)
- Rigshospitalet — Copenhagen, Denmark (Recruiting)
- Charité Berlin — Berlin, State of Berlin, Germany (Not_yet_recruiting)
- Uniklinik Köln — Cologne, Germany (Recruiting)
- Universitätsklinikum Carl Gustav Carus — Dresden, Germany (Recruiting)
- Universitätsklinikum Essen — Essen, Germany (Recruiting)
- Universitätsklinikum Schleswig-Holstein Campus Kiel — Kiel, Germany (Recruiting)
- H.O.T Praxis Landshut — Landshut, Germany (Recruiting)
- Brüderkrankenhaus St. Josef Paderborn — Paderborn, Germany (Recruiting)
- Universitätsmedizin Rostock — Rostock, Germany (Recruiting)
- Universitätsklinik Ulm — Ulm, Germany (Recruiting)
Study contacts
- Principal investigator: Barbara Eichhorst, Prof. — Department I of Internal Medicine, University Hospital Cologne
- Study coordinator: Barbara Eichhorst, Prof.
- Email: barbara.eichhorst@uk-koeln.de
- Phone: +4922147888220
How to participate
- Review the eligibility criteria above with your treating physician.
- Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
- Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.