Status and phase
Conditions
Treatments
Study type
Funder types
Identifiers
About
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
Full 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.
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
Confirmed diagnosis of CLL according to iwCLL criteria (Hallek et al, 2018)
Confirmed histopathological diagnosis of RT (diffuse large B-cell lymphoma or Hodgkin's lymphoma [Hodgkin's lymphoma only when not eligible for more in-tensive treatment])
Previously untreated RT or patients with objective response or non-tolerance to first-line RT treatment
Adequate bone marrow function as defined by:
Creatinine clearance ≥30ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured with 24hr urine collection or an equivalent method.
Adequate liver function as indicated by a total bilirubin≤ 2 x, 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 ≤ 3 x and AST/ALT ≤ 5 x the institutional ULN value are required.
Negative serological testing for hepatitis B (HBsAg negative and anti-HBc nega-tive; 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 af-ter 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 ≥ 3 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 GVHD after prior allogeneic stem cell transplantation within any time
Patients with confirmed PML
Uncontrolled autoimmune condition
Malignancies other than CLL currently requiring systemic therapies (unless the malignant disease is in a stable remission at the discretion of the treating phy-sician)
Uncontrolled infection currently requiring systemic treatment
Any comorbidity or organ system impairment rated with a CIRS (cumulative ill-ness rating scale) 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.
Known active infection with HIV, or serologic status reflecting active hepatitis B or C infection as follows:
Major surgery within 4 weeks of the first dose of study drug.
Any uncontrolled or clinically significant cardiovascular disease including the following:
History of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood trans-fusion or other medical intervention
History of stroke or intracranial hemorrhage within 6 months before first dose of study drug
Severe or debilitating pulmonary disease
Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction
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, sonrotoclax 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:
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
Primary purpose
Allocation
Interventional model
Masking
83 participants in 2 patient groups
Loading...
Central trial contact
Othman Al-Sawaf, MD; Barbara Eichhorst, Prof.
Data sourced from clinicaltrials.gov
Clinical trials
Research sites
Resources
Legal