Efficacy and Safety of Zanubrutinib Plus Tislelizumab Treatment with or Without Sonrotoclax for Patients with Richter Transformation

NCT04271956 | Recruiting Phase 2 DMC

• 2 other identifiers: CLL-RT12023-504653-12-00
• Study Type: interventional
• Target: 83
• Locations: 3 countries
• Sites: 11

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

Conditions

Richter Transformation

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (7)

• ORR after induction therapy according to the IWCLL criteria (Hallek et al, 2018)

  18 weeks

• ORR after consolidation therapy

  36 weeks

• Progression-free Survival (PFS)

  Up to 15 months

• Overall Survival (OS)

  Up to 15 months

• Time to Next Treatment (TTNT)

  Up to 15 months

Study Arms (2)

Tislelizumab + Zanubrutinib

EXPERIMENTAL

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; Drug: Zanubrutinib

Tislelizumab + Zanubrutinib + Sonrotoclax

EXPERIMENTAL

Induction: 6 cycles (q21d) of Tislelizumab + Zanubrutinib + Sonrotoclax Consolidation: 6 cycles (q21d) of Tislelizumab + Zanubrutinib + Sonrotoclax Maintenance: Patients with response to therapy continue to take Tislelizumab + Zanubrutinib (Q3W) + Sonrotoclax until disease progression, non-tolerance or when receiving allogeneic stem cell transplantation (SCT) for consolidation

Biological: Tislelizumab; Drug: Zanubrutinib; Drug: Sonrotoclax

Interventions

Tislelizumab BIOLOGICAL

Cycle (q21d): Day 1: Tislelizumab i.v. 200 mg

Also known as: BGB-A317

Tislelizumab + Zanubrutinib; Tislelizumab + Zanubrutinib + Sonrotoclax

Zanubrutinib DRUG

Cycle (q21d): Zanubrutinib p.o. 160 mg twice a day

Also known as: BGB-3111

Tislelizumab + Zanubrutinib; Tislelizumab + Zanubrutinib + Sonrotoclax

Sonrotoclax DRUG

Cycle 1: Sonrotoclax Start Ramp-up to 320 mg QD po Days 1-2 Sonrotoclax 2 mg (2 tabl. at 1mg) Days 3-4 Sonrotoclax 5 mg (1 tabl. at 5mg) Days 5-6 Sonrotoclax 10 mg (2 tabl. at 5mg) Days 7-8 Sonrotoclax 20 mg (1 tabl. at 20mg) Days 9-10 Sonrotoclax 40 mg (2 tabl. at 20mg) Days 11-12 Sonrotoclax 80 mg (1 tabl. at 80mg) Days 13-14 Sonrotoclax 160 mg (2 tabl. at 80mg) Days 15-16 Sonrotoclax 320 mg (4 tabl. at 80mg) Cycle 2-6: Day 1-21 Sonrotoclax 320 mg QD po

Also known as: BGB-11417

Tislelizumab + Zanubrutinib + Sonrotoclax

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• Absolute neutrophil count (ANC) ≥ 1000/mm3, except for patients with bone marrow involvement in which ANC must be ≥ 500/mm3
• Platelet ≥ 75,000/mm3, except for patients with bone marrow involvement in which the platelet count must be ≥ 30,000/mm3
• 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

You may not qualify if:

• 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:
• Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core anti-body (HBcAb). Patients with presence of HBcAb, but absence of HBsAg, are eligible if hepatitis B virus (HBV) DNA is undetectable (\< 20 IU), and if they are willing to undergo monitoring every 4 weeks for HBV reactivation.
• Presence of hepatitis C virus (HCV) antibody. Patients with presence of HCV antibody are eligible if HCV RNA is undetectable.
• Major surgery within 4 weeks of the first dose of study drug.
• Any uncontrolled or clinically significant cardiovascular disease including the following:

Sponsors & Collaborators

• German CLL Study Group: lead

Study Sites (11)

Allgemeines Krankenhaus der Stadt Wien

Vienna, 1090, Austria

RECRUITING

Rigshospitalet

Copenhagen, 2100, Denmark

RECRUITING

Charité Berlin

Berlin, State of Berlin, 12203, Germany

NOT YET RECRUITING

Uniklinik Köln

Cologne, 50937, Germany

RECRUITING

Universitätsklinikum Carl Gustav Carus

Dresden, 01307, Germany

RECRUITING

Universitätsklinikum Essen

Essen, 45147, Germany

RECRUITING

Universitätsklinikum Schleswig-Holstein Campus Kiel

Kiel, 24105, Germany

RECRUITING

H.O.T Praxis Landshut

Landshut, 84036, Germany

RECRUITING

Brüderkrankenhaus St. Josef Paderborn

Paderborn, 33098, Germany

RECRUITING

Universitätsmedizin Rostock

Rostock, 18057, Germany

RECRUITING

Universitätsklinik Ulm

Ulm, 89081, Germany

RECRUITING

Related Publications (1)

• Al-Sawaf O, Ligtvoet R, Robrecht S, Stumpf J, Fink AM, Tausch E, Schneider C, Boettcher S, Mikusko M, Ritgen M, Schetelig J, von Tresckow J, Vehling-Kaiser U, Gaska T, Wendtner CM, Chapuy B, Fischer K, Kreuzer KA, Stilgenbauer S, Staber P, Niemann C, Hallek M, Eichhorst B. Tislelizumab plus zanubrutinib for Richter transformation: the phase 2 RT1 trial. Nat Med. 2024 Jan;30(1):240-248. doi: 10.1038/s41591-023-02722-9. Epub 2023 Dec 9.

  PMID: 38071379 DERIVED

Related Links

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

MeSH Terms

Interventions

tislelizumab; zanubrutinib

Study Officials

• Barbara Eichhorst, Prof.

  Department I of Internal Medicine, University Hospital Cologne

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Barbara Eichhorst, Prof.

CONTACT

+4922147888220; barbara.eichhorst@uk-koeln.de

Othman Al-Sawaf, MD

CONTACT

+4922147888220; othman.al-sawaf@uk-koeln.de

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Recruitment in cohort 1 (double combination therapy) has already been completed. Recruitment in new cohort 2 (triple combination therapy) will start in Q3 2024.

Study Record Dates

• First Submitted: February 14, 2020
• First Posted: February 17, 2020
• Study Start: February 19, 2020
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): August 1, 2026
• Last Updated: December 30, 2024

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will not share

Locations

AU (1); DK (1); DE (9)