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

  • STATUS
    Recruiting
  • End date
    Jun 15, 2023
  • participants needed
    48
  • sponsor
    German CLL Study Group
Updated on 28 February 2022

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

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.

Details
Condition Richter Transformation
Treatment Zanubrutinib, tislelizumab
Clinical Study IdentifierNCT04271956
SponsorGerman CLL Study Group
Last Modified on28 February 2022

Eligibility

Yes No Not Sure

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 investigators 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
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