Evaluaton of ibrutinib therapy for the treatment of autoimmune Hemolytic Anemia in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma or CLL-like monoclonal B-cell lymphocytosis.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione Gimema Franco Mandelli Onlus

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

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

Trial duration

24 Nov 2023 → ongoing

Decision date (initial)

2024-07-23

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

JANSSEN-CILAG spa · Fondazione Gimema Franco Mandelli Onlus

External identifiers

EU CT number

2023-509793-38-00

EudraCT number

2023-000050-17

ClinicalTrials.gov

NCT05694312

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

The primary objective of the trial is to assess the efficacy of ibrutinib therapy for the treatment of AIHA in patients with CLL/SLL or CLL-like MBL, in terms of ORR.

Secondary objectives 11

1. the efficacy of ibrutinib therapy for AIHA treatment, in terms of ORR (intermediate/end of treatment timepoints)
2. duration of response to AIHA induced by ibrutinib
3. AIHA-related ibrutinib-induced relapse-free survival
4. blood transfusion frequency during ibrutinib treatment in patients with AIHA
5. the need for further AIHA-directed treatments during ibrutinib therapy in patients with AIHA
6. the safety/tolerability profile of ibrutinib treatment in patients with AIHA
7. Establishing response to ibrutinib treatment for CLL according to IWCLL guidelines
8. Estimate duration of response to ibrutinib treatment for CLL
9. Evaluate CLL-specific survival outcomes
10. Describe quality of life of patients with AIHA during treatment
11. Assess quantitative changes in peripheral blood T-cell subtypes, immunof characteristics. and cytokine profile during treatment with ibrutinib (end of cycle 6 and cycle 12 vs baseline) in patients with AIHA

Conditions and MedDRA coding

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma or CLL-like monoclonal B-cell lymphocytosis

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Diagnosis of CLL/small lymphocytic lymphoma (SLL) or CLL-like monoclonal B-cell lymphocytosis (MBL) according to IWCLL guidelines
2. Patients >18 years old
3. Active AIHA (warm AIHA, wAIHA, or cold hemagglutinin disease, CAD) that i) is relapsed after previous treatment with corticosteroids (with or without rituximab), or ii) is steroid-resistant (failure to obtain hematologic response within 3 weeks on at least 1 mg/kg predniso(lo)ne (2)), or iii) is steroid-dependent (need to continue on predniso (lo)ne at a dose of >10 mg/day to maintain a response (2)). AIHA is defined as: anemia (hemoglobin =10 g/dL; or hemoglobin >10 g/dL dependent on transfusions to maintain this level of hemoglobin) and laboratory evidence of hemolysis (presence of 3 of 4 markers: increased reticulocyte count, increased indirect bilirubin, increased lactate dehydrogenase, decreased haptoglobin) and positive DAT (either IgG DAT, C3 DAT or both).
4. Eligibility of patients with DAT-negative active AIHA should be confirmed by the Principal Investigator and co-Principal Investigator for the trial
5. Signed written informed consent according to ICH/EU/GCP and national local laws
6. Eastern Cooperative Oncology Group (ECOG) =2
7. Adequate renal and hepatic function, per laboratory reference range at screening as follows: o Aspartate aminotransferase (AST) =< 3.0 x ULN (within 30 days prior to day 1 of protocol therapy) o Alanine aminotransferase (ALT) =< 3.0 x ULN (within 30 days prior to day 1 of protocol therapy) o Creatinine clearance of >= 30 mL/min per 24-hour urine test or the Cockcroft-Gault formula (within 30 days prior to day 1 of protocol therapy)
8. Ability to swallow oral study medication
9. Women of childbearing potential (WOCBP): negative urine or serum pregnancy test within the screening window prior to receiving the first dose of study medication and monthly pregnancy test until the end of systemic exposure
10. Willingness of men and WOCBP, and their partners, to observe the contraceptive measures until the end of systemic exposure
11. Willingness of men not to father a child or donate sperm while receiving ibrutinib, and for 3 months following completion of treatment

Exclusion criteria 8

1. Contraindication to ibrutinib therapy as per treating physician’s discretion.
2. Contraindication to ibrutinib therapy as per ibrutinib data sheet (severe hepatic impairment, known allergy to the drug or to one of the excipients, concomitant treatment with warfarin or other vitamin K antagonists)
3. Active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) or known positive human immunodeficiency virus (HIV) o Participants who are hepatitis B core antibody (anti-HBc) positive and who are surface antigen negative will need to have a negative polymerase chain reaction (PCR). Those who are hepatitis B surface antigen (HbsAg) positive or hepatitis B PCR positive will be excluded. o Subjects who are hepatitis C antibody positive will need to have a negative PCR result. Those who are hepatitis C PCR positive will be excluded o Subjects who have an undetectable or unquantifiable HIV viral load with CD4 > 300 and are on highly active antiretroviral therapy (HAART) medication are allowed. Testing to be done only in patients suspected of having infections or exposures - Previous exposure to ibrutinib as CLL-directed therapy
4. Previous exposure to ibrutinib as CLL-directed therapy
5. Treatment with another investigational drug or device, or approved therapy for investigational use – with the exception of corticosteroids - 28 days prior to Cycle 1 Day 1, or if the half-life of the previous investigational product is known, within 5 times the half-life prior to Cycle 1 Day 1, whichever is longer
6. Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal absorption of the oral-administered study treatments
7. Vaccination with a live vaccine within 28 days prior to Cycle 1 Day 1
8. Female patients who are currently in pregnancy or are willing to be pregnant or are lactating.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint of this study is to assess AIHA ORR after 6 cycles of therapy (28-day cycles).

Secondary endpoints 15

1. AIHA ORR after 3 and 12 cycles of therapy (28-day cycles).
2. AIHA response duration (measured from the achievement of CR or PR to the loss of response).
3. AIHA-specific relapse-free survival (RFS).
4. Frequency of packed red blood cell (PRBC) transfusion while receiving ibrutinib.
5. Rate of patients needing further AIHA-directed treatment during ibrutinib therapy.
6. Incidence and type of treatment-related toxicity.
7. CLL ORR, PR and CR rate after 3, 6 and 12 cycles of therapy (28-day cycles). CLL response is defined according to IWCLL guidelines (1).
8. Duration of CLL response.
9. CLL-specific EFS.
10. CLL-specific PFS.
11. Overall OS. OS will be evaluated both in the entire cohort and in the CLL/SLL cohort (excluding patients with CLL-like MBL).
12. Quality of Life at baseline and after 3, 6 and 12 cycles of therapy (28-day cycles)
13. Number and percentage of T-cell subsets in peripheral blood at baseline and after 6 and 12cycles of therapy (28-day cycles).
14. Percentage of T cells expressing activation markers and checkpoint molecules at baseline and after 6 and 12 cycles of therapy (28-day cycles).
15. Serum concentration of T-cell related cytokines at baseline and after 6 and 12 cycles of therapy (28-day cycles).

Investigational products

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

Test 1

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

GIMEMA Centro Dati

Public contact point

Organisation

Fondazione Gimema Franco Mandelli Onlus

Contact name

GIMEMA Centro Dati

Third parties 1

Locations

1 EU/EEA country · 24 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 13 files

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

Application history

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