Efficacy and Safety of Zanubrutinib Plus Tislelizumab for Treatment of Patients With Richter Transformation

Study Overview
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Brief Summary
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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

Detailed Description
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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.

Official Title
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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

Conditions
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Richter Transformation

Intervention / Treatment
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* Biological: Tislelizumab
* Drug: Zanubrutinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of CLL according to iwCLL criteria (Hallek et al, 2018) Confirmed histopathological diagnosis of RT Creatinine clearance ≥30ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured with 24hr urine collection 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 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) Life expectancy ≥ 6 months Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements Exclusion Criteria: Patients who did not respond to previous line of RT therapy (i.e. primary progressive patients) Patients with more than one prior line of RT therapy 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 Patients with confirmed progressive multifocal leukoencephalopathy (PML) Uncontrolled autoimmune condition Malignancies other than CLL currently requiring systemic therapies Active infection currently requiring systemic treatment 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 Requirement of therapy with strong CYP3A4 inhibitors/inducers Requirement of therapy with phenprocoumon or other vitamin K antagonists. 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 or any of the excipients 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 contraceptive 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tislelizumab + Zanubrutinib<br>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<br>* Cycle (q21d): Day 1: Tislelizumab i.v. 200 mg<br>* Other names: BGB-A317;Drug: Zanubrutinib<br>* Cycle (q21d): Zanubrutinib p.o. 160 mg twice a day<br>* Other names: BGB-3111;|

What is the study measuring?
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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 |