A Prospective, Open-Label, Multicentre Phase-Ii-Trial to Evaluate the Efficacy and Safety of Zanubrutinib (BGB-3111), a Btk Inhibi-Tor, Plus Tislelizumab (BGB-A317), a PD-1 Inhibitor, with and With-Out Sonrotoclax (BGB-11417), a BCL2 Inhibitor, for Treatment of Patients with Richter Transformation - CLL-RT1-Trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

University Of Cologne

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

10 Feb 2020 → ongoing

Decision date (initial)

2023-11-22

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Beigene Ltd., Cayman Islands

External identifiers

EU CT number

2023-504653-12-00

EudraCT number

2018-002492-17

ClinicalTrials.gov

NCT04271956

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

The primary objectives of the study are:
• To evaluate the efficacy of a combinational therapy with tislelizumab and zanubrutinib in CLL patients with Richter transformation to DLBCL (cohort 1).
• To evaluate the efficacy of a combinational therapy with tislelizumab and zanubrutinib with sonrotoclax in CLL patients with Richter transformation to DLBCL (cohort 2).

Secondary objectives 1

1. The secondary objective is to evaluate the safety of a combinational therapy with tislelizumab and zanubrutinib with or without sonrotoclax in CLL patients with Richter transformation to DLBCL (cohort 1 and cohort 2).

Conditions and MedDRA coding

Patients with previously untreated Richter Transformation or patients who responded to up to one prior line of RT therapy

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Confirmed diagnosis of CLL (incl. SLL) according to iwCLL criteria (Hallek et al, 2018)
2. Confirmed histopathological diagnosis of RT (diffuse large B-cell lymphoma or Hodgkin's lymphoma [Hodgkin's lym-phoma only when not eligible for more intensive treatment])
3. Previously untreated RT or patients with objective response or non-tolerance to first-line RT treatment
4. 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
5. 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
6. Adequate liver function as indicated by a total bilirubin≤ 2 x, AST/ALT ≤ 2.5 x the institu-tional 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. (For patients who start study treatment with elevated liver enzymes due to CLL/RT or Gilbert’s syndrome, toxicity and AE reporting will follow CTCAE grading once these values further increase. E.g. if a patient starts with a bilirubin value of 2.0 mg/dl, which rises to 3.0 mg/dl after one cycle, this should be reported as grade 2 bilirubinemia (see CTCAE v5))
7. 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
8. Age at least 18 years
9. 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)
10. Life expectancy ≥ 3 months
11. Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements

Exclusion criteria 25

1. Patients who did not respond to previous line of RT therapy (i.e. primary progressive patients) ( In cases with urgent need for treatment, a prephase treatment with steroids, vincristine (up to 2 mg IV) or cyclo-phosphamide (up to 200 mg2 daily for max 3 days) can be administered at the discretion of the treating physician prior to enrolment or start of study medication. )
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 GVHD after prior allogeneic stem cell transplantation within any time
4. Patients with confirmed PML
5. Uncontrolled autoimmune condition
6. Malignancies other than CLL currently requiring systemic therapies (unless the malignant disease is in a stable remission at the discretion of the treating physician)
7. Uncontrolled infection currently requiring systemic treatment
8. Any comorbidity or organ system impairment rated with a CIRS (cumulative illness 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 inves-tigator´s opinion could comprise the patients safety or interfere with the absorption or me-tabolism 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. 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 antibody (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 under-go monitoring every 4 weeks for HBV reactivation. - Presence of hepatitis C virus (HCV) antibody. Patients with presence of HCV anti-body are eligible if HCV RNA is undetectable
12. Major surgery within 4 weeks of the first dose of study drug.
13. Any uncontrolled or clinically significant cardiovascular disease including the following: - Myocardial infarction within 6 months before screening - Unstable angina within 3 months before screening - New York Heart Association class III or IV congestive heart failure - History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ven-tricular fibrillation, torsades de pointes)
14. History of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention
15. History of stroke or intracranial hemorrhage within 6 months before first dose of study drug
16. Severe or debilitating pulmonary disease
17. Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric sur-gery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction
18. 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
19. Known hypersensitivity to tislelizumab, zanubrutinib, sonrotoclax or any of the excipients
20. Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment)
21. 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 contra-ceptive method (Pearl Index <1) and one additional effective (barrier) method during study treatment and 120 days after the last dose of tislelizumab, >7 days after sonrotoclax and 30 days after zanubrutinib respectively
22. Vaccination with a live vaccine <28 days prior to randomization
23. Legal incapacity
24. Prisoners or subjects who are institutionalized by regulatory or court order
25. Persons who are in dependence to the sponsor or an investigator

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Overall response rate (ORR) after induction therapy (i.e. 6 cycles) according to the refined Lugano Classification (Cheson et al, 2016). - Complete response (CR) - Partial response (PR)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

University Of Cologne

Sponsor organisation

University Of Cologne

Address

Albertus-Magnus-Platz 1

City

Cologne

Postcode

50923

Country

Germany

Scientific contact point

Organisation

University Of Cologne

Contact name

Barbara Eichhorst

Public contact point

Organisation

University Of Cologne

Contact name

Barbara Eichhorst

Third parties 8

Locations

3 EU/EEA countries · 11 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 49 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications