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

• ClinicalTrials.gov Identifier: NCT04271956
• Recruitment Status: Active, not recruiting
• First Posted: February 17, 2020
• Last Update Posted: February 23, 2023
• Sponsor: German CLL Study Group
• Information provided by (Responsible Party): German CLL Study Group

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Richter Transformation	Biological: Tislelizumab; Drug: Zanubrutinib	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 57 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: February 19, 2020
• Estimated Primary Completion Date: May 2023
• Estimated Study Completion Date: December 2023

Arms and Interventions

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 Name: BGB-A317; Drug: Zanubrutinib; Cycle (q21d): Zanubrutinib p.o. 160 mg twice a day; Other Name: BGB-3111

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. ORR after induction therapy according to the IWCLL criteria (Hallek et al, 2018) [ Time Frame: 18 weeks ]
   Proportion of patients having achieved complete response (CR) or partial response (PR)
2. ORR after consolidation therapy [ Time Frame: 36 weeks ]
   Proportion of patients having achieved complete response (CR) or partial response (PR)
3. Progression-free Survival (PFS) [ Time Frame: Up to 15 months ]
   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
4. Overall Survival (OS) [ Time Frame: Up to 15 months ]
   Time from the date of registration to the date of death due to any cause
5. Time to Next Treatment (TTNT) [ Time Frame: Up to 15 months ]
   Time from date of registration to the date of first subsequent CLL/RT treatment
6. Duration of response [ Time Frame: Up to 15 months ]

   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.

7. Type, frequency, severity of adverse events (AEs) [ Time Frame: Up to 15 months ]

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

Austria

Allgemeines Krankenhaus der Stadt Wien

Vienna, Austria, 1090

Denmark

Rigshospitalet

Copenhagen, Denmark, 2100

Germany

Uniklinik Köln

Cologne, Germany, 50937

Universitätsklinikum Carl Gustav Carus

Dresden, Germany, 01307

Universitätsklinikum Essen

Essen, Germany, 45147

Universitätsklinikum Schleswig-Holstein Campus Kiel

Kiel, Germany, 24105

H.O.T Praxis Landshut

Landshut, Germany, 84036

Universitätsklinikum Magdeburg

Magdeburg, Germany, 39120

München Klinik Schwabing

Munich, Germany, 80804

Brüderkrankenhaus St. Josef Paderborn

Paderborn, Germany, 33098

Universitätsmedizin Rostock

Rostock, Germany, 18057

Universitätsklinik Ulm

Ulm, Germany, 89081

Sponsors and Collaborators

German CLL Study Group

Investigators

• Principal Investigator: Barbara Eichhorst, Prof.; Department I of Internal Medicine, University Hospital Cologne

More Information

Additional Information:

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

• Responsible Party: German CLL Study Group
• ClinicalTrials.gov Identifier: NCT04271956
• Other Study ID Numbers: CLL-RT1
• First Posted: February 17, 2020
• Last Update Posted: February 23, 2023
• Last Verified: February 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Zanubrutinib; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action