First-line combination of Bcl-2 inhibitor and monoclonal antibody followed by administration of Bcl-2 inhibitor alone or combination of Bcl-2 inhibitor with BTK inhibitor according to disease status of the young patient with high risk Chronic Lymphatic Leukemia

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione Gimema Franco Mandelli Onlus

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

21 Jul 2023 → ongoing

Decision date (initial)

2024-07-16

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Roche S.p.A. · Fondazione GIMEMA Franco Mandelli onlus · BeiGene

External identifiers

EU CT number

2023-510431-11-00

EudraCT number

2022-002579-12

ClinicalTrials.gov

NCT05478512

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Therapy

To evaluate in young CLL patients with an adverse biologic profile the following co-primary objectives:
1. The benefit of front-line therapy with venetoclax and obinutuzumab (VenObi) in terms of rate of patients with uMRD by ASO-PCR in the PB and BM measured at the end
of combination therapy (EOCT month 9).
2. The benefit of adding Zanubrutinib to Venetoclax (VenZan) in terms of rate of patients with uMRD by ASO-PCR in the PB and BM in patients with residual disease at the EOCT with VenObi (month 21).

Secondary objectives 9

1. The benefit of front-line therapy with venetoclax and obinutuzumab (VenObi) in terms of rate of patients with uMRD by flow-cytometry at the end of combination therapy (EOCT month 9).
2. The benefit of treatment with VenObi+Ven in terms of rate of patients with uMRD, L-MRD and H-MRD by: a) ASO-PCR b) Flow-cytometry.
3. The benefit of treatment with VenObi+VenZan in terms of rate of patients with uMRD, L-MRD and H-MRD by: a) ASO-PCR b) Flow-cytometry
4. Rate of patients with uMRD according to the baseline clinical and the biologic characteristics of CLL
5. Progression Free Survival (PFS)
6. Overall Survival (OS)
7. Survival outcomes (OS and PFS) according to the: a) levels of MRD b) response c) treatment after VenObi d) the clinical and the biologic characteristics of CLL
8. The benefits on the hematological improvement of treatment with VenObi+Ven or VenObi+VenZan.
9. The toxicity profile of treatment.

Conditions and MedDRA coding

Chronic Lymphocytic Leukemia

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Patients older than18 years and 65 years or less.
2. Diagnosis of CLL meeting the iwCLL 2018 criteria.
3. Total CIRS <6, creatinine clearance >30 ml/min [Cockcroft-Gault]) and ECOG performance status of 0-1.
4. No prior treatment.
5. Patients with unmutated IGHV, and, or TP53 mutation assessed by an ERIC certified laboratory, and, or deletion 17p assessed by FISH analysis (Appendix N).
6. Active disease meeting at least 1 of the iwCLL 2018 criteria for treatment requirement.
7. Adequate hematologic parameters unless due to disease under study: • Absolute neutrophil count (ANC) =1.0 x 109/L unless neutropenia is clearly due to disease under study (per investigator discretion) • Platelet count = 75,000/mm3 - OR - Platelet count = 20,000/mm3 if thrombocytopenia is clearly due to disease under study (per investigator discretion) • Hemoglobin =9.0 g/dL unless anemia is clearly due to marrow involvement of CLL (per investigator discretion)
8. Adequate renal and hepatic function, per laboratory reference range at Screening as follows: • AST/SGOT, ALT/SGPT =2.0 x ULN • Total bilirubin =1.5 x ULN unless considered secondary to Gilbert’s syndrome, in which case =3 x ULN
9. QT-interval corrected according to Fridericia’s formula (QTcF) =450 milliseconds (ms).
10. For females of childbearing potential, a negative serum pregnancy test within 7 days of study treatment.
11. For female patients of childbearing potential, agreement to use highly effective form(s) of contraception (i.e., one that results in a low failure rate [<1% per year] when used consistently and correctly) or remain abstinent (refrain from heterosexual intercourse) during the treatment period and to continue its use for 90 days after the last dose of zanubrutinib AND 30 days after the last dose of venetoclax AND for 18 months after the last dose of obinutuzumab (whichever date is later). For men with a female partner of childbearing potential or a pregnant female partner: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom during the treatment period and to continue its use for 90 days after the last dose of zanubrutinib, or venetoclax AND for 18 months after the last dose of obinutuzumab (whichever date is later).
12. A signed informed consent document indicating that they understand the purpose of and the procedures required for the study, including biomarkers, and are willing to participate in the study.
13. Ability and willingness to comply with the requirements of the study protocol.

Exclusion criteria 8

1. Any significant concurrent, uncontrolled medical condition or organ system dysfunction and laboratory abnormality or psychiatric disease, which, in the investigator's opinion, could compromise the subject's safety or put the study outcomes at undue risk or prevent the subject from signing the informed consent form.
2. Known active histological transformation from CLL to an aggressive lymphoma (i.e., Richter’s transformation or pro-lymphocytic leukemia).
3. Known central nervous system involvement.
4. Active malignancy or systemic therapy for another malignancy within 3 years Except: • Malignancies surgically treated with curative intent and with no known active disease present for = 3 years before randomization • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease • Adequately treated cervical carcinoma in situ without evidence of disease • Surgically/adequately treated low grade, early stage localized prostate cancer without evidence of disease
5. Co-morbidities: • Uncontrolled autoimmune hemolytic anemia or thrombocytopenia • Any uncontrolled illness that, in the opinion of the investigator, would preclude administration of study therapy. • History of stroke or intracranial hemorrhage within 180 days before first dose of study drug. • History of severe bleeding disorder or history of spontaneous bleeding requiring blood transfusion or other medical intervention due to thrombocytopenia or inherited or acquired bleeding disorders due to deficiency or functional abnormality of any coagulation proteins. • History of significant cardiovascular disease, defined as: a. Congestive heart failure greater than New York Heart Association (NYHA) class II according to the NYHA functional classification. b. Unstable angina or myocardial infarction with 6 months of enrollment. c. Serious cardiac arrhythmia or clinically significant ECG abnormality: corrected QT wave (QTcF) > 480 msec based on the Fridericia's formula or other ECG abnormalities including second-degree atrioventricular block type II, third-degree atrioventricular block. Participants who have a pacemaker will be allowed on study despite ECG abnormalities or the inability to calculate the QTc. • Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 4 weeks prior to Cycle 1, Day 1. • History of tuberculosis within the last five years or recent exposure to tuberculosis equal to or less than 6 months. • History of progressive multifocal leukoencephalopathy (PML). • History of HIV infection or active hepatitis B (chronic or acute) or hepatitis C infection: I. Patients with occult or prior HBV infection (defined as positive total hepatitis B core antibody [HBcAb] and negative HBsAg) may be included if HBV DNA is undetectable. These patients must be willing to take appropriate anti-viral prophylaxis as indicated and undergo monthly DNA testing. II. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA. • Inadequate renal function: CrCl < 30 mL/min. • Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis. • History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products. • Known intolerance or hypersensitivity to any of the components of the therapeutic regimen. • Receipt of live-virus vaccines within 28 days prior to the initiation of study treatment or need for live-virus vaccines at any time during study treatment. • Prior major surgical procedure within 4 weeks of study, or anticipation of need for a major surgical procedure during the course of the study. • Known condition or other clinical situation that would affect oral absorption. • Psychiatric illness/social situations that would interfere with study compliance. • Inability to swallow a large number of tablets.
6. Concomitant medications and drug interactions: • Patients who are on treatment with the following agents within 7 days prior to treatment: Strong CYP3A inhibitors such as fluconazole, ketoconazole, and clarithromycin Strong CYP3A inducers such as rifampin, carbamazepine and strong inhibitors or inducers of CYP2C8, CYP2C9 and CYP2C19. The same applied for moderate inhibitors or inducers of CYP3A Requires warfarin, marcumar, or phenprocoumon (due to potential drug-drug interactions that may potentially increase the exposure of warfarin or phenprocoumon) • Prior anti-CD20 monoclonal antibody therapy for non-malignant indication
7. Females who are currently pregnant or breastfeeding.
8. Participation in a separate investigational therapeutic study unless authorized by PI

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. To evaluate in young CLL patients with an adverse biologic profile: 1. The benefit of front-line therapy with Venetoclax and Obinutuzumab (VenObi) in terms of rate of patients with uMRD by ASO-PCR in the PB and BM measured at the end of combination therapy (EOCT month 9).
2. To evaluate in young CLL patients with an adverse biologic profile: The benefit of adding Zanubrutinib to Venetoclax (VenZan) in terms of rate of patients with uMRD by ASO-PCR in the PB and BM in patients with residual disease at the EOCT with VenObi (month 21).

Secondary endpoints 9

1. The benefit of front-line therapy with Venetoclax and Obinutuzumab (VenObi) in terms of rate of patients with uMRD by flow-cytometry in the PB and BM measured at the end of combination therapy (EOCT month 9).
2. The benefit of treatment with VenObi+Ven in terms of rate of patients with uMRD, L-MRD and H-MRD in the PB and BM at month 15, 21, 27, 33, 36 by: a. ASO-PCR b. Flow-cytometry
3. The benefit of treatment with VenObi+VenZan in terms of rate of patients with uMRD, L-MRD and H-MRD in the PB and BM at month 15, 21, 27, 33, 36 by: a. ASO-PCR b. Flow-cytometry 4. Rate of patients with uMRD according to the clinical and the biologic characteristics of CLL
4. Rate of patients with uMRD according to the clinical and the biologic characteristics of CLL
5. Progression Free Survival (PFS) at 36 months
6. Overall Survival (OS) at 36 months
7. Survival outcomes (OS and PFS) estimates at 36 months according to the: a. levels of MRD (uMRD, L-MRD, H-MRD); b. response (CR, PR, stable disease); c. treatment (Ven-Obi+Ven or VenObi+VenZan); d. the clinical and the biologic characteristics of CLL (CD38, CD49d, IGHV, FISH profile, mutations of TP53, NOTCH1, BIRC3, SF3B1)
8. The benefit of treatment with VenObi+Ven or VenObi+VenZan on the improvement of Hb value, granulocyte, and platelet counts and immunoglobulin levels.
9. The toxicity profile of treatment in terms of AE/SAE.

Investigational products

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

Test 5

Auxiliary 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione Gimema Franco Mandelli Onlus

Sponsor organisation

Fondazione Gimema Franco Mandelli Onlus

Address

Via Casilina 5

City

Rome

Postcode

00182

Country

Italy

Scientific contact point

Organisation

Fondazione Gimema Franco Mandelli Onlus

Contact name

Centro Dati GIMEMA

Public contact point

Organisation

Fondazione Gimema Franco Mandelli Onlus

Contact name

Centro Dati GIMEMA

Third parties 1

Locations

1 EU/EEA country · 41 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 10 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