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