Efficacy and Safety of Zanubrutinib Plus Tislelizumab for Treatment of Patients With Richter Transformation (CLL-RT1)

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

The aim of the CLL-RT1 trial is 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

Study Overview

• Status: Active, not recruiting
• Conditions: Richter Transformation
• Intervention / Treatment: Biological: Tislelizumab; Drug: Zanubrutinib

Detailed Description

Richter Transformation (RT) remains one of the biggest challenges in the treatment and management of CLL. While considerable progress has been made in the treatment of CLL, the prognosis of CLL patients with malignant disease transformation still is very poor and reported median OS is between 6 to 8 months. Conventional approaches with chemo- and chemoimmunotherapy have largely failed to improve response rates in RT patients. However, as the established treatment approach for de-novo Diffuse Large B Cell Lymphoma (DLBCL) is chemoimmunotherapy with a combination of Rituximab, Cyclophosphamid, Hydroxydaunorubicin, Vincristin and Prednisolon (R-CHOP), this has become the most commonly used regimen for lack of alternative strategies, despite poor efficacy. Patients being fit enough for allogeneic transplantation are undergoing this procedure after induction with R-CHOP. However, the majority of patients are not suitable for transplantation and relapse quickly. Hence, there is urgent need to improve therapy of RT by testing new compounds and combinations for treatment of this disease. Based on the available preclinical and preliminary clinical data on checkpoint inhibition plus Bruton's tyrosine (BTK) inhibition, the current trial will systematically assess the safety and toxicity of tislelizumab, a programmed cell death protein 1 (PD-1) inhibitor, plus zanubrutinib, a BTK inhibitor in patients with RT.

• Study Type: Interventional
• Enrollment (Estimated): 57
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Barbara Eichhorst, Prof.; Phone Number: +4922147888220; Email: barbara.eichhorst@uk-koeln.de
• Study Contact Backup: Name: Othman Al-Sawaf, MD; Phone Number: +4922147888220; Email: othman.al-sawaf@uk-koeln.de

Study Locations

• Austria
  • Vienna, Austria, 1090
    • Allgemeines Krankenhaus Der Stadt Wien
• Denmark
  • Copenhagen, Denmark, 2100
    • Rigshospitalet
• Germany
  • Cologne, Germany, 50937
    • Uniklinik Koln
  • Dresden, Germany, 01307
    • Universitätsklinikum Carl Gustav Carus
  • Essen, Germany, 45147
    • Universitätsklinikum Essen
  • Kiel, Germany, 24105
    • Universitätsklinikum Schleswig-Holstein Campus Kiel
  • Landshut, Germany, 84036
    • H.O.T Praxis Landshut
  • Magdeburg, Germany, 39120
    • Universitätsklinikum Magdeburg
  • Munich, Germany, 80804
    • München Klinik Schwabing
  • Paderborn, Germany, 33098
    • Brüderkrankenhaus St. Josef Paderborn
  • Rostock, Germany, 18057
    • Universitatsmedizin Rostock
  • Ulm, Germany, 89081
    • Universitätsklinik Ulm

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Confirmed diagnosis of CLL according to iwCLL criteria (Hallek et al, 2018)
2. Confirmed histopathological diagnosis of RT
3. Creatinine clearance ≥30ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured with 24hr urine collection
4. Adequate liver function as indicated by a total bilirubin ≤ 2x, 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 ≤ 4 x and AST/ALT ≤ 5 x the institutional ULN value are required
5. 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
6. Age at least 18 years
7. 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)
8. Life expectancy ≥ 6 months
9. 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 graft-versus-host disease (GVHD) after prior allogeneic stem cell transplantation within any time
4. Patients with confirmed progressive multifocal leukoencephalopathy (PML)
5. Uncontrolled autoimmune condition
6. Malignancies other than CLL currently requiring systemic therapies
7. Active infection currently requiring systemic treatment
8. Any comorbidity or organ system impairment rated with a Cumulative Illness Rating Scale (CIRS) 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. 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
12. Known hypersensitivity to tislelizumab, zanubrutinib or any of the excipients
13. Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment)

14. 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 contraceptive method (Pearl Index <1) and one additional effective (barrier) method during study treatment and for 12 months after the end of study treatment.
15. Vaccination with a live vaccine <28 days prior to randomization
16. Legal incapacity
17. Prisoners or subjects who are institutionalized by regulatory or court order
18. Persons who are in dependence to the sponsor or an investigator

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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	Biological: Tislelizumab; Cycle (q21d): Day 1: Tislelizumab i.v. 200 mg; Other Names: BGB-A317; Drug: Zanubrutinib; Cycle (q21d): Zanubrutinib p.o. 160 mg twice a day; Other Names: BGB-3111

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate (ORR) after induction therapy according to the refined Lugano Classification (Cheson et al, 2016)	Proportion of patients having achieved complete response (CR) or partial response (PR)	18 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ORR after induction therapy according to the IWCLL criteria (Hallek et al, 2018)	Proportion of patients having achieved complete response (CR) or partial response (PR)	18 weeks
ORR after consolidation therapy	Proportion of patients having achieved complete response (CR) or partial response (PR)	36 weeks
Progression-free Survival (PFS)	Time from the date of registration to the date of first occurrence of disease progression or relapse (determined according to the IWCLL guidelines and Lugano classification) or death from any cause, whichever occurs first	Up to 15 months
Overall Survival (OS)	Time from the date of registration to the date of death due to any cause	Up to 15 months
Time to Next Treatment (TTNT)	Time from date of registration to the date of first subsequent CLL/RT treatment	Up to 15 months
Duration of response	Time from the date of first documented response to the first occurrence of progression, relapse or death by any cause, whichever occurs first. Duration of response will be evaluated both according to the refined Lugano Classification as well as according to the IWCLL criteria. In the first case it will be calculated for patients with CR or PR, in the second case for patients with (clin.) CR, (clin.) CRi, PR, or PR-L.	Up to 15 months
Type, frequency, severity of adverse events (AEs)		Up to 15 months

Collaborators and Investigators

• Sponsor: German CLL Study Group
• Investigators: Principal Investigator: Barbara Eichhorst, Prof., Department I of Internal Medicine, University Hospital Cologne

Publications and helpful links

Helpful Links

• Click here for more information about this study: CLL-RT1 (German CLL Study Group)

Study record dates

Study Major Dates

• Study Start (Actual): February 19, 2020
• Primary Completion (Estimated): December 1, 2023
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: February 14, 2020
• First Submitted That Met QC Criteria: February 14, 2020
• First Posted (Actual): February 17, 2020

Study Record Updates

• Last Update Posted (Actual): July 6, 2023
• Last Update Submitted That Met QC Criteria: July 4, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Zanubrutinib; Tislelizumab
• Other Study ID Numbers: CLL-RT1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No