A PROSPECTIVE, OPEN-LABEL, MULTICENTRE PHASE-II-TRIAL TO EVALUATE THE EFFICACY AND SAFETY OF ZANUBRUTINIB (BGB-3111), A BTK INHIBI-TOR, PLUS TISLELIZUMAB (BGB-A317), A PD-1 INHIBITOR, WITH AND WITH-OUT SONROTOCLAX (BGB-11417), A BCL2 INHIBITOR, FOR TREATMENT OF PATIENTS WITH RICHTER TRANSFORMATION - CLL-RT1-Trial

Phase 2

Recruiting

• Conditions: Patients with previously untreated Richter Transformation or patients who responded to up to one prior line of RT therapy

• Registration Number: 2023-504653-12-00
• Lead Sponsor: University Of Cologne

Brief Summary

The primary objective of the study is to evaluate the efficacy of a

combinational therapy with tislelizumab and zanubrutinib in CLL patients

with Richter transformation to DLBCL (cohort 1).

Detailed Description

Not available

Study Timeline

• Study First Posted: 2023-10-24
• Last Update Posted: 2025-01-31

Recruitment & Eligibility

• Status: Ongoing, recruiting
• Sex: Not specified
• Target Recruitment: 85

Inclusion Criteria

Confirmed diagnosis of CLL according to iwCLL criteria (Hallek et al, 2018)

Life expectancy ≥ 3 months

Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements

Confirmed histopathological diagnosis of RT (diffuse large B-cell lymphoma or Hodgkin's lymphoma [Hodgkin's lym-phoma only when not eligible for more intensive treatment])

Previously untreated RT or patients with objective response or non-tolerance to first-line RT treatment

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

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

Adequate liver function as indicated by a total bilirubin≤ 2 x, AST/ALT ≤ 2.5 x the institu-tional 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. (For patients who start study treatment with elevated liver enzymes due to CLL/RT or Gilbert’s syndrome, toxicity and AE reporting will follow CTCAE grading once these values further increase. E.g. if a patient starts with a bilirubin value of 2.0 mg/dl, which rises to 3.0 mg/dl after one cycle, this should be reported as grade 2 bilirubinemia (see CTCAE v5))

Negative serological testing for hepatitis B (HBsAg negative and anti-HBc negative; 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 after last dose of zanubrutinib), negative testing for hepatitis-C RNA and negative HIV test within 6 weeks prior to registration

Age at least 18 years

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)

Exclusion Criteria

Patients who did not respond to previous line of RT therapy (i.e. primary progressive patients) ( In cases with urgent need for treatment, a prephase treatment with steroids, vincristine (up to 2 mg IV) or cyclo-phosphamide (up to 200 mg2 daily for max 3 days) can be administered at the discretion of the treating physician prior to enrolment or start of study medication. )

Requirement of therapy with phenprocoumon or other vitamin K antagonists.

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 antibody (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 under-go monitoring every 4 weeks for HBV reactivation. - Presence of hepatitis C virus (HCV) antibody. Patients with presence of HCV anti-body are eligible if HCV RNA is undetectable

Major surgery within 4 weeks of the first dose of study drug.

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 tachycardia, ven-tricular fibrillation, torsades de pointes)

History of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention

History of stroke or intracranial hemorrhage within 6 months before first dose of study drug

Severe or debilitating pulmonary disease

Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric sur-gery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction

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

Known hypersensitivity to tislelizumab, zanubrutinib, sonrotoclax or any of the excipients

Patients with more than one prior line of RT therapy

Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment)

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 effective contra-ceptive method (Pearl Index <1) and one additional effective (barrier) method during study treatment and for 12 months after the end of study treatment.

Vaccination with a live vaccine <28 days prior to randomization

Legal incapacity

Prisoners or subjects who are institutionalized by regulatory or court order

Persons who are in dependence to the sponsor or an investigator

Allogenic stem cell transplantation within the last 100 days or signs of active GVHD after prior allogeneic stem cell transplantation within any time

Patients with confirmed PML

Uncontrolled autoimmune condition

Malignancies other than CLL currently requiring systemic therapies (unless the malignant disease is in a stable remission at the discretion of the treating physician)

Uncontrolled infection currently requiring systemic treatment

Any comorbidity or organ system impairment rated with a CIRS (cumulative illness 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 inves-tigator´s opinion could comprise the patients safety or interfere with the absorption or me-tabolism of the study drugs

Requirement of therapy with strong CYP3A4 inhibitors/ inducers

Study & Design

• Study Type: Not specified
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Overall response rate (ORR) after induction therapy (i.e. 6 cycles) according to the refined Lugano Classification (Cheson et al, 2016). - Complete response (CR) - Partial response (PR)		Overall response rate (ORR) after induction therapy (i.e. 6 cycles) according to the refined Lugano Classification (Cheson et al, 2016). - Complete response (CR) - Partial response (PR)

Trial Locations

Locations (11)

Medical University Of Vienna; 🇦🇹 Vienna, Austria

Dr. Vehling-Kaiser MVZ GmbH; 🇩🇪 Landshut, Germany

Rostock University Medical Center; 🇩🇪 Rostock, Germany

Charite Universitaetsmedizin Berlin KöR; 🇩🇪 Berlin, Germany

University Medical Centre Schleswig-Holstein; 🇩🇪 Kiel, Germany

Medizinisches Versorgungszentrum des Bruederkrankenhauses St. Josef Paderborn gGmbH; 🇩🇪 Paderborn, Germany

Universitaetsklinikum Ulm AöR; 🇩🇪 Ulm, Germany

Technische Universitat Dresden; 🇩🇪 Dresden, Germany

University Hospital Cologne AöR; 🇩🇪 Cologne, Germany

Universitaetsklinikum Essen AöR; 🇩🇪 Essen, Germany

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Medical University Of Vienna

🇦🇹Vienna, Austria

Philipp Staber

Site contact

+4314040044100

philipp.staber@meduniwien.ac.at